سلوكية 1

Chapter 1Chapter 1BehavioralBehavioral

NeurochemistryNeurochemistryDr. Mohamed Abu-AlsebahDr. Mohamed Abu-Alsebah

General-, Forensic- & Neuro-General-, Forensic- & Neuro-PsychiatristPsychiatrist

Community Mental Health Community Mental Health SpecialistSpecialist

Director of Mh Services, MoHDirector of Mh Services, MoH

I. Introduction: Complexities in the I. Introduction: Complexities in the Neurochemistry of Behavioral DisordersNeurochemistry of Behavioral Disorders

Certain chemical substances may influence Certain chemical substances may influence mood, thought, and action. mood, thought, and action.

With the discovery of neuroleptics, With the discovery of neuroleptics, antidepressants, lithium, L-dopa, LSD, and antidepressants, lithium, L-dopa, LSD, and other drugs that have a profound effect on other drugs that have a profound effect on normal and abnormal behavior, the field of normal and abnormal behavior, the field of psychopharmacology has grown psychopharmacology has grown considerably and, with it, interest in the considerably and, with it, interest in the basic biochemistry of behavior. basic biochemistry of behavior.

A. Neurotransmitter disturbancesA. Neurotransmitter disturbancesMany behavioral disorders – particularly Many behavioral disorders – particularly

psychiatric and movement disorders – are psychiatric and movement disorders – are associated with disturbances of specific associated with disturbances of specific neurotransmitters.neurotransmitters.

1. 1. Although schizophrenia, tardive dyskinesia, and Although schizophrenia, tardive dyskinesia, and Parkinson’s disease are associated with Parkinson’s disease are associated with dopaminergic dopaminergic abnormalities, and depression abnormalities, and depression with dysfunction in norepinephrine pathways, with dysfunction in norepinephrine pathways, many neurochemical abnormalities are proposed many neurochemical abnormalities are proposed for each of these conditions.for each of these conditions.

2.2. Response to drugs is a complex issue i.e., very Response to drugs is a complex issue i.e., very few psychopharmacologic drugs affect a single few psychopharmacologic drugs affect a single transmitter system.transmitter system.

B. Underlying pathologyB. Underlying pathology

All behavioral abnormalities represent: All behavioral abnormalities represent:

1.1. The primary pathologic process The primary pathologic process

2.2. Brain’s attempt to correct or compensate for it. Brain’s attempt to correct or compensate for it.

Conditions involving only a limited number of Conditions involving only a limited number of neurochemical systems usually demonstrate neurochemical systems usually demonstrate changes in other neurochemical systems.changes in other neurochemical systems.

C. Other factorsC. Other factors that influence a patient’s that influence a patient’s neurochemical status include age, gender, diet, neurochemical status include age, gender, diet, and pharmacotherapy – all of which affect and pharmacotherapy – all of which affect behavior.behavior.

II. Neuronal Transmission of InformationII. Neuronal Transmission of InformationRoman y CajalRoman y Cajal: “: “neuron doctrineneuron doctrine” The ” The

neuron is the basic unit of the nervous system. neuron is the basic unit of the nervous system.

Information basic to behavior is transferred,Information basic to behavior is transferred, in in the form of specific chemicals and energy, boththe form of specific chemicals and energy, both within neurons and between neurons.within neurons and between neurons.

A. Neuronal membranesA. Neuronal membranesNeuronal membranes play an important role in Neuronal membranes play an important role in

both intra-neuronal and inter-neuronal processes. both intra-neuronal and inter-neuronal processes.

They contain the means by which information is They contain the means by which information is transferred from one neuron to the next. transferred from one neuron to the next.

Information transfer across neurons occurs via Information transfer across neurons occurs via electrical or chemical changes.electrical or chemical changes.

1. Ion channels1. Ion channelsThe The electrical meanselectrical means of neuronal transfer of neuronal transfer involves involves

the action potential:the action potential: When a neuron is When a neuron is stimulated, a dramatic change in the electrical stimulated, a dramatic change in the electrical potential across the axonal membrane is potential across the axonal membrane is propagated down the length of the axon.propagated down the length of the axon.

a.a. The action potential depends on the The action potential depends on the opening opening and closing of ion channelsand closing of ion channels that allow the that allow the passage of ions such as Na, K, Cl, and Ca.passage of ions such as Na, K, Cl, and Ca.

b.b. The The passage of these ions passage of these ions across the neuronal across the neuronal membrane membrane causes depolarizationcauses depolarization (in which the (in which the electrical potential differences across the electrical potential differences across the membrane rises from approximately -70 mV to -membrane rises from approximately -70 mV to -15 mV), 15 mV), followed by repolarizationfollowed by repolarization (the (the baseline high potential differences is restored).baseline high potential differences is restored).

2. Receptors2. Receptors

The The chemical meanschemical means of information transfer of information transfer across neurons across neurons involves neurochemical involves neurochemical receptorsreceptors located in the membrane itself. located in the membrane itself.

a.a. Neurochemical receptors are proteins that Neurochemical receptors are proteins that bind to specific chemical substances, which bind to specific chemical substances, which results in the eventual triggering of specific results in the eventual triggering of specific processes within the neuron.processes within the neuron.

b. b. These receptors are important for the action These receptors are important for the action of of neurotransmitters, neuromodulators, neurotransmitters, neuromodulators, and and neurohormonesneurohormones..

B. Intra-neuronal transportB. Intra-neuronal transport

Information – in the form of specific Information – in the form of specific chemical substances – can pass through the chemical substances – can pass through the body of a neuron from one portion to body of a neuron from one portion to another, often along axons or dendrites, another, often along axons or dendrites, and can influence some specific aspect of and can influence some specific aspect of neuronal function (e.g., nuclear processes, neuronal function (e.g., nuclear processes, energy metabolism). energy metabolism).

Cyclic nucleotides, calcium, Cyclic nucleotides, calcium, and and phosphatidyl-inositol phosphatidyl-inositol are are important important intra-neuronal “messengers”.intra-neuronal “messengers”.

1. Cyclic nucleotides1. Cyclic nucleotides are substances such as are substances such as cAMPcAMP and and cGMPcGMP. .

They are called They are called second messengerssecond messengers because because they help translate the information received from they help translate the information received from extracellular messengers (e.g., neurotransmitters, extracellular messengers (e.g., neurotransmitters, hormones) into an intracellular response. hormones) into an intracellular response.

Not all neurotransmitters exert their effects Not all neurotransmitters exert their effects through the cyclic nucleotide system.through the cyclic nucleotide system.

a. a. Certain Certain neurotransmittersneurotransmitters – by binding to – by binding to receptors –receptors – activate adenylate cyclase, activate adenylate cyclase, the the enzyme that catalyses the formation of cAMP enzyme that catalyses the formation of cAMP from ATP. from ATP.

The increase in cAMP concentration may The increase in cAMP concentration may then activate cAMP-dependent protein then activate cAMP-dependent protein phosphorylation, causing a change in ion phosphorylation, causing a change in ion permeability in the neuronal membrane.permeability in the neuronal membrane.

b. b. Some Some receptors receptors (possibly including α(possibly including α22--adrenergic receptors, dopamine Dadrenergic receptors, dopamine D22 receptors, somatostatin receptors, certain receptors, somatostatin receptors, certain muscarinic cholinergic receptors and muscarinic cholinergic receptors and opiate receptors) opiate receptors) inhibit, inhibit, rather than rather than activate, activate, adenylate cyclase.adenylate cyclase.

c.c. The regulation of adenylate cyclase occurs The regulation of adenylate cyclase occurs through guanine-nucleotide binding proteins, through guanine-nucleotide binding proteins, G proteins.G proteins.

Gs proteins stimulate and Gi proteins inhibit Gs proteins stimulate and Gi proteins inhibit adenylate cyclase; the exact function of Go adenylate cyclase; the exact function of Go proteins is less clear.proteins is less clear.

2. Calcium2. Calcium and several associated binding and several associated binding proteins – most notably proteins – most notably calmodulincalmodulin – form – form another second messenger system.another second messenger system.

a. a. Depolarization is associated with significant Depolarization is associated with significant quantities of calcium entering the neuron.quantities of calcium entering the neuron.

b.b. The calcium binds with calmodulin, to associate The calcium binds with calmodulin, to associate with and modulate a number of calcium-with and modulate a number of calcium-dependent enzymes, such as a calcium-dependent enzymes, such as a calcium-calmodulin-dependent protein kinase, certain calmodulin-dependent protein kinase, certain types of adenylate cyclase, phosphodiesterase, types of adenylate cyclase, phosphodiesterase, and ATPase.and ATPase.

3.3. Phosphatidyl-inositolPhosphatidyl-inositol is a membrane is a membrane phospholipid that is hydrolyzed by a specific phospholipid that is hydrolyzed by a specific phospholipase C following receptor occupation to phospholipase C following receptor occupation to yield diacylglycerol (DAG) and inositol yield diacylglycerol (DAG) and inositol triphosphate, which in turn activate protein kinase triphosphate, which in turn activate protein kinase C and increase intracellular calcium, respectively.C and increase intracellular calcium, respectively.

C. Inter-neuronal transportC. Inter-neuronal transport1. 1. Synapse = connectionSynapse = connection, the , the synapsessynapses are the are the

primary facilitators of the inter-neuronal transfer primary facilitators of the inter-neuronal transfer of information. of information.

Three synapses Three synapses : chemical, electrical, and conjoint.: chemical, electrical, and conjoint.a. Chemical synapses:a. Chemical synapses: the most important type. the most important type. Each consists of a specific region where the Each consists of a specific region where the

membranes of two neurons are in close membranes of two neurons are in close approximation. approximation.

A chemical messenger released from the pre-A chemical messenger released from the pre-synaptic membrane synaptic membrane travels across the synaptic travels across the synaptic cleftcleft and acts on a specific receptor on the and acts on a specific receptor on the postsynaptic membrane. postsynaptic membrane.

In some cases the messenger act on In some cases the messenger act on receptors, known as receptors, known as auto-receptorsauto-receptors,, on the presynaptic membrane.on the presynaptic membrane.

b. Electrical synapses,b. Electrical synapses, transmit transmit information directlyinformation directly through the through the transfer of an electrical charge and do transfer of an electrical charge and do not employ chemical messengers.not employ chemical messengers.

c. Conjoint synapsesc. Conjoint synapses operate through operate through both chemical and electrical means.both chemical and electrical means.

2. 2. NeuroregulatorsNeuroregulators are chemicals that carry are chemicals that carry information between neurons. information between neurons.

They include They include neurotransmitters, neurotransmitters, neuromodulators, neuromodulators, andand neurohormones. neurohormones.

a.a. NeurotransmittersNeurotransmitters are neuroregulators are neuroregulators that that exert their effects on specific pre- or exert their effects on specific pre- or postsynaptic receptors.postsynaptic receptors.

The transfer of information by The transfer of information by neurotransmitters takes 1 to 2 m.sec, in neurotransmitters takes 1 to 2 m.sec, in contrast to that mediated by other contrast to that mediated by other neuroregulators, which takes much longer.neuroregulators, which takes much longer.

b. b. Neuromodulators,Neuromodulators, released from presynaptic released from presynaptic membranes and exert their effects on receptors. membranes and exert their effects on receptors.

Neuromodulators are released from membranes Neuromodulators are released from membranes other than synaptic ones, and they may act on other than synaptic ones, and they may act on receptors located on large numbers of neurons. receptors located on large numbers of neurons.

Their effects last longer than those of Their effects last longer than those of neurotransmitters on certain synapsesneurotransmitters on certain synapses..

c. c. NeurohormonesNeurohormones also act on receptors located also act on receptors located on neurons and are released into the systemic on neurons and are released into the systemic circulation and, thus, travel throughout the body, circulation and, thus, travel throughout the body, unlike the other neuroregulators.unlike the other neuroregulators.

3. Types of neurotransmitters3. Types of neurotransmittersa. a. They are divided into They are divided into two typestwo types, depending on , depending on

their effects on the postsynaptic neuron.their effects on the postsynaptic neuron.(1) Excitatory neurotransmitters(1) Excitatory neurotransmitters increase the increase the

firing of the postsynaptic neuron.firing of the postsynaptic neuron.(2) Inhibitory neurotransmitters(2) Inhibitory neurotransmitters decrease the decrease the

firing of the postsynaptic neuron.firing of the postsynaptic neuron.b.b. Some neurotransmitters are Some neurotransmitters are solely excitatory solely excitatory

(e.g., glutamate, aspartate) or (e.g., glutamate, aspartate) or solely inhibitorysolely inhibitory (e.g., GABA, glycine), others may function (e.g., GABA, glycine), others may function either wayeither way (e.g., dopamine, acetylcholine). (e.g., dopamine, acetylcholine).

c. c. Some transmitters are excitatory or inhibitory at Some transmitters are excitatory or inhibitory at different synapses on the same neuron.different synapses on the same neuron.

4. Neurotransmitter criteria4. Neurotransmitter criteriaa. Criteriaa. Criteria to be considered a to be considered a

neurotransmitter.neurotransmitter.(1)(1) It must be present in nerve terminals. It must be present in nerve terminals. (2)(2) Stimulation of the nerve must cause the Stimulation of the nerve must cause the

release of the transmitter in sufficient release of the transmitter in sufficient amounts to exert its actions on the amounts to exert its actions on the postsynaptic neuron.postsynaptic neuron.

(3)(3) The effects of the transmitter on the The effects of the transmitter on the postsynaptic membrane must be similar to postsynaptic membrane must be similar to those of transmitter stimulation of the those of transmitter stimulation of the presynaptic nerve, presynaptic nerve, such as activating the such as activating the same ion channels.same ion channels.

(4)(4) Pharmacologic agents should Pharmacologic agents should alter the dose-response curve of the alter the dose-response curve of the applied neurotransmitter in the applied neurotransmitter in the same magnitude and direction that same magnitude and direction that they alter the naturally occurring they alter the naturally occurring synaptic potential.synaptic potential.

(5)(5) A mechanism for inactivation or A mechanism for inactivation or metabolism of the transmitter must metabolism of the transmitter must exist in the vicinity of the synapse.exist in the vicinity of the synapse.

b. Classificationb. Classification

(1) (1) Neurotransmitters that Neurotransmitters that meet all meet all of the criteria are of the criteria are consideredconsidered definitedefinite neurotransmitters neurotransmitters and include and include ACh, dopamine, norepinephrine, epinephrine, ACh, dopamine, norepinephrine, epinephrine, GABA, serotonin, and glycine.GABA, serotonin, and glycine.

(2)(2) Those that Those that meet some, but not allmeet some, but not all, of the criteria , of the criteria are considered are considered supposedsupposed neurotransmitters neurotransmitters and and include glutamate, aspartate, and substance P.include glutamate, aspartate, and substance P.

(3)(3) Those that Those that meet only one or two meet only one or two criteria are criteria are considered considered neurotransmitter neurotransmitter candidatescandidates and and include adenosine, cAMP, prostaglandins, and most include adenosine, cAMP, prostaglandins, and most peptides.peptides.

5. Steps in neurochemical transmission5. Steps in neurochemical transmissiona. Synthesis a. Synthesis May occur either near the presynaptic membrane May occur either near the presynaptic membrane

where it is to be released or elsewhere in the where it is to be released or elsewhere in the neuron. neuron.

Peptide neurotransmitters are synthesized in the Peptide neurotransmitters are synthesized in the soma of the neuron and transported along the soma of the neuron and transported along the axon to the nerve terminals.axon to the nerve terminals.

b. Transportb. TransportIt is moved from the site of its synthesis to the site It is moved from the site of its synthesis to the site

of its storage or release.of its storage or release.c. Storagec. Storage Often occurs in vesicles specific to that purpose.Often occurs in vesicles specific to that purpose.

d. Released. Release(1)(1) For some neuroregulators, a vesicle For some neuroregulators, a vesicle

containing the regulator liberates its contents. containing the regulator liberates its contents. The regulator may simply diffuses out of both The regulator may simply diffuses out of both the vesicle and the neuron or the vesicle the vesicle and the neuron or the vesicle combines with the neuron plasma membrane, combines with the neuron plasma membrane, externalizing its contents through the process externalizing its contents through the process of of exocytosisexocytosis..

(2)(2) The process of release is The process of release is dependent on the dependent on the influx of calciuminflux of calcium that occurs with that occurs with depolarization of the pre-synaptic membrane.depolarization of the pre-synaptic membrane.

(3)(3) Autoreceptors on the presynaptic neuron can Autoreceptors on the presynaptic neuron can modulate the release of that transmitter.modulate the release of that transmitter.

e. Terminatione. TerminationThe action of a neuroregulator may be terminated The action of a neuroregulator may be terminated

by by diffusion out diffusion out of the receptor area, of the receptor area, metabolismmetabolism of the regulator, or of the regulator, or reuptakereuptake of the of the regulator, usually into the presynaptic neuron. regulator, usually into the presynaptic neuron.

ReuptakeReuptake is the most important process for is the most important process for monoamines,monoamines, whereas whereas metabolismmetabolism is important is important for ACh and the peptides.for ACh and the peptides.

6. Mechanism of neuro-regulator effects6. Mechanism of neuro-regulator effectsa. Bindinga. Binding Binding to the recognition site of specific Binding to the recognition site of specific

receptors is the receptors is the first step first step in the action of in the action of neurotransmitters.neurotransmitters.

b. Transductionb. Transduction

It is the process by which regulator It is the process by which regulator bindingbinding with the with the receptor receptor results in a biologic response of the neuronresults in a biologic response of the neuron..

(1)(1) Transduction occurs through so-called Transduction occurs through so-called effector effector proteins,proteins, which are closely linked to the receptor which are closely linked to the receptor protein. protein.

The basic types of The basic types of effector proteinseffector proteins include nucleotide include nucleotide cyclases that catalyze the formation of cyclic cyclases that catalyze the formation of cyclic nucleotides and ion channels that control passage of nucleotides and ion channels that control passage of certain ions through the membrane.certain ions through the membrane.

(2)(2) Modulator proteinsModulator proteins may be interposed between may be interposed between the receptor and effector proteins and may the receptor and effector proteins and may themselves have binding sites for neuromodulators themselves have binding sites for neuromodulators and neurohormones. and neurohormones.

Modulator proteins, such as G proteins, Modulator proteins, such as G proteins, may provide the means through which may provide the means through which neuromodulators and neurohormones neuromodulators and neurohormones affect synaptic function.affect synaptic function.

(a)(a) Some neuromodulators, usually Some neuromodulators, usually peptides, coexist with neurotransmitters peptides, coexist with neurotransmitters in the same neuron and may regulate the in the same neuron and may regulate the time course and the magnitude of the time course and the magnitude of the postsynaptic activity of the postsynaptic activity of the neurotransmitter.neurotransmitter.

(b)(b) It was thought at one time that It was thought at one time that one neuronone neuron could possess only could possess only one neuroregulatorone neuroregulator, which , which had the same function (excitation or inhibition) had the same function (excitation or inhibition) at every synapse of that neuron. This was at every synapse of that neuron. This was referred to as referred to as Dale’s principleDale’s principle, , but it is now but it is now known to be incorrect.known to be incorrect.

c. Amplificationc. AmplificationFollowing transduction, the full response of the Following transduction, the full response of the

neuron to the neurotransmitter occurs through neuron to the neurotransmitter occurs through amplification of the initial response, which amplification of the initial response, which may occur through the activation of enzymes, may occur through the activation of enzymes, proteins phosphorylation, hormone release, or proteins phosphorylation, hormone release, or other mechanisms.other mechanisms.

7. Neurochemical methods7. Neurochemical methodsThere are two basic ways to study the interaction There are two basic ways to study the interaction

between neurotransmitters, hormones, or drugs between neurotransmitters, hormones, or drugs and receptors: and receptors:

Measurement of the Measurement of the biologic responsebiologic response of an of an isolated organ preparation and measurement of isolated organ preparation and measurement of ligand bindingligand binding to tissue slices or homogenates. to tissue slices or homogenates.

The ligand can be one of many agonists or The ligand can be one of many agonists or antagonists that bind to a certain receptor.antagonists that bind to a certain receptor.

a. Identifying supposed receptorsa. Identifying supposed receptors(1)(1) Ideally, putative receptors are identified by Ideally, putative receptors are identified by

receptor saturability, specificity, and receptor saturability, specificity, and reversibility.reversibility.

(a)(a) Specific binding of a ligand is Specific binding of a ligand is characterized by high affinity and low characterized by high affinity and low capacity.capacity.

(b)(b) Nonspecific binding is characterized by Nonspecific binding is characterized by low affinity and high capacity.low affinity and high capacity.

(c)(c) Binding of ligand to receptor should be Binding of ligand to receptor should be reversible.reversible.

(2)(2) Much can be learned about receptors using Much can be learned about receptors using radioactive ligands, or radioactive ligands, or radioligands.radioligands.

The number and affinity of receptors can be The number and affinity of receptors can be determined from a binding assay, in which determined from a binding assay, in which receptors are mixed with radioligands.receptors are mixed with radioligands.

(3) Receptors can be isolated and (3) Receptors can be isolated and purified,purified, then a functional system then a functional system reconstituted using the purified receptor reconstituted using the purified receptor and transduction machinery.and transduction machinery.

b. Identifying specific neurotransmitters b. Identifying specific neurotransmitters or receptors in the CNSor receptors in the CNS

(1) Immunocytochemistry(1) Immunocytochemistry..(2) In situ hybridization(2) In situ hybridization uses uses

radiolabeled DNA to localize mRNAs radiolabeled DNA to localize mRNAs specific for particular proteins.specific for particular proteins.

(3) Autoradiography(3) Autoradiography employs: employs: Information obtained is similar to that Information obtained is similar to that obtained using immunocytochemistry.obtained using immunocytochemistry.

(4) High performance liquid (4) High performance liquid chromatography (HPLC)chromatography (HPLC). .

(5)(5) Neural tracts may be identified by Neural tracts may be identified by intracellular dye injections, selective intracellular dye injections, selective lesioning, retrograde labeling with lesioning, retrograde labeling with horseradish peroxidase, or anterograde horseradish peroxidase, or anterograde labeling with certain lectins.labeling with certain lectins.

III. BIOLOGIC AMINESIII. BIOLOGIC AMINESA. DopamineA. Dopamine1. Synthesis1. SynthesisTyrosine hydroxylation Tyrosine hydroxylation is the rate-limiting step is the rate-limiting step

in the synthesis of all major catecholamines in the synthesis of all major catecholamines (i.e., dopamine, norepinephrine, and (i.e., dopamine, norepinephrine, and epinephrine).epinephrine).

2. Metabolism2. Metabolisma. a. Two Two enzymesenzymes are important for the are important for the

inactivation of catecholamines.inactivation of catecholamines.(1) Monoamine oxidase (MAO)(1) Monoamine oxidase (MAO) is located on the is located on the

outer membrane of the mitochondria outer membrane of the mitochondria oxidative deamination of intracellular, extra oxidative deamination of intracellular, extra vesicular catecholamines. vesicular catecholamines.

Two forms of MAO exist. Dopamine is deaminated Two forms of MAO exist. Dopamine is deaminated by both forms.by both forms.

(a) MAO-A(a) MAO-A deaminates norepinephrine and deaminates norepinephrine and serotonin.serotonin.

(b) MAO-B(b) MAO-B deaminates β-phenylethylamine and deaminates β-phenylethylamine and benzylamine.benzylamine.

(2) Catechol-(2) Catechol-OO-methyltransferase (COMT) -methyltransferase (COMT) is is found on the outer plasma membranes of most found on the outer plasma membranes of most cells. COMT cells. COMT methylatesmethylates most extracellular most extracellular catecholamines.catecholamines.

b. A major metabolite of dopamine b. A major metabolite of dopamine in urine and in urine and plasma is plasma is homovanillic acid (HVA),homovanillic acid (HVA), which is which is formed through the action of both formed through the action of both MAO and MAO and COMT, in either order.COMT, in either order.

3. Receptors3. ReceptorsThe action of dopamine is either inhibitory or The action of dopamine is either inhibitory or

excitatory. excitatory. Inhibition is the more common Inhibition is the more common effecteffect. .

There are five types of dopamine receptors:There are five types of dopamine receptors:a. D1 receptorsa. D1 receptors are are generally postsynaptic generally postsynaptic and and

activate adenylate cyclase.activate adenylate cyclase.b. D2 receptorsb. D2 receptors are both are both postsynaptic and postsynaptic and

presynapticpresynapticThe therapeutic efficacy of antipsychotic drugs are The therapeutic efficacy of antipsychotic drugs are

correlated strongly with their affinities for the D2 correlated strongly with their affinities for the D2 receptor, implicating this subtype as an important receptor, implicating this subtype as an important site for the action of antipsychotic drugs. site for the action of antipsychotic drugs.

c. c. The three additional dopamine receptors are: The three additional dopamine receptors are: D3, D3, D4,D4, and and D5D5 dopamine receptors. dopamine receptors.

Based on their regional brain distributions and Based on their regional brain distributions and primary effector mechanisms, the D3 and D4 primary effector mechanisms, the D3 and D4 receptors are D2-like, and D5 are D1-like. receptors are D2-like, and D5 are D1-like.

4. Important brain tracts4. Important brain tractsa. Major dopaminergic tracts (pathways)a. Major dopaminergic tracts (pathways)(1) Nigrostriatal tract(1) Nigrostriatal tractRuns from the pars compacta of the substantia nigra Runs from the pars compacta of the substantia nigra

to the striatum. to the striatum. This pathway is This pathway is important in the initiation of important in the initiation of

movementmovement as its destruction causes a reduction or as its destruction causes a reduction or loss of movement.loss of movement.

(2) Mesolimbic and mesocortical tracts(2) Mesolimbic and mesocortical tractsThe dopaminergic neurons that form these The dopaminergic neurons that form these

tracts are found in the ventral tegmental tracts are found in the ventral tegmental area of Tsai, which lies superior and medial area of Tsai, which lies superior and medial to the substantia nigra. to the substantia nigra.

The neurons project to the limbic system – The neurons project to the limbic system – including the amygdala, nucleus including the amygdala, nucleus accumbens, septum, and cingulate gyrus – accumbens, septum, and cingulate gyrus – and to the cerebral cortex, predominantly to and to the cerebral cortex, predominantly to the frontal lobes. the frontal lobes.

These tracts are These tracts are important in affect, important in affect, cognition, and motivation.cognition, and motivation.

(3) Tuberoinfundibular (tuberohypophyseal) tract(3) Tuberoinfundibular (tuberohypophyseal) tractThe dopaminergic neurons of this tract are located in The dopaminergic neurons of this tract are located in

the arcuate and periventricular nuclei of the the arcuate and periventricular nuclei of the hypothalamushypothalamus and project to the median eminence and project to the median eminence of the hypothalamus and to the intermediate lobe of of the hypothalamus and to the intermediate lobe of the the pituitary gland.pituitary gland.

Dopamine is thought to be Dopamine is thought to be important in the important in the regulation of prolactin release.regulation of prolactin release.

(4) Medullary periventricular tract(4) Medullary periventricular tractDopaminergic cell bodies are located in the Dopaminergic cell bodies are located in the motor motor

nucleus of the vagus nervenucleus of the vagus nerve projecting to the projecting to the periventricular and periaqueductal gray areas, periventricular and periaqueductal gray areas, the reticular formation, and the spinal cord gray the reticular formation, and the spinal cord gray areasareas. .

(5) Incertohypothalamic tract(5) Incertohypothalamic tract

A small group of neurons in the zona incerta A small group of neurons in the zona incerta project from the dorsal posterior hypothalamus project from the dorsal posterior hypothalamus to the dorsal anterior hypothalamus and to the to the dorsal anterior hypothalamus and to the septum. septum.

b. Other sitesb. Other sites

Dopaminergic neurons are also located in the Dopaminergic neurons are also located in the interplexiform cells of the inner nuclear layer of interplexiform cells of the inner nuclear layer of the the retinaretina and in the periglomerular cells of the and in the periglomerular cells of the olfactory bulb.olfactory bulb.

These neurons lack axons and make connections These neurons lack axons and make connections via dendrodendritic synapses.via dendrodendritic synapses.

5. Effects on behavior5. Effects on behaviorFrom a behavioral perspective, the most From a behavioral perspective, the most

important dopaminergic tracts are the important dopaminergic tracts are the nigrostriatal, mesolimbic, and nigrostriatal, mesolimbic, and mesocortical tracts.mesocortical tracts.

a. Parkinsonism and other movement a. Parkinsonism and other movement disordersdisorders

Normal control of voluntary movements Normal control of voluntary movements relies on a balance between relies on a balance between dopaminergic and cholinergic dopaminergic and cholinergic components of the basal ganglia.components of the basal ganglia.

(1) (1) The The nigrostriatal tract degenerates in nigrostriatal tract degenerates in Parkinson’s diseaseParkinson’s disease, , resulting in the resulting in the clinical picture of akinesia, tremor, rigidity, clinical picture of akinesia, tremor, rigidity, and loss of postural reflexes.and loss of postural reflexes.

(2) Neuroleptic drugs(2) Neuroleptic drugs (because they block (because they block postsynaptic dopamine receptors)postsynaptic dopamine receptors) and and reserpine reserpine (because it depletes dopamine) (because it depletes dopamine) also also cause Parkinsonism.cause Parkinsonism.

(3) (3) CertainCertain hyperkinetic disorders hyperkinetic disorders (e.g., (e.g., Huntington’s disease, tardive dyskinesia) Huntington’s disease, tardive dyskinesia) are related to a relativeare related to a relative excessexcess of of dopamine transmission.dopamine transmission.

Tardive dyskinesia occurs after long-term Tardive dyskinesia occurs after long-term treatment with neuroleptic drugs and treatment with neuroleptic drugs and usually appears as choreoathetoid usually appears as choreoathetoid movements of the mouth and hands.movements of the mouth and hands.

(a)(a) Tardive dyskinesia: long-term treatment Tardive dyskinesia: long-term treatment with neuroleptic drugs causes super-with neuroleptic drugs causes super-sensitivity of postsynaptic D2 receptors.sensitivity of postsynaptic D2 receptors.

(b)(b) This hypothesis has been questioned and This hypothesis has been questioned and may not explain the development of tardive may not explain the development of tardive dyskinesia only in some patients.dyskinesia only in some patients.

b. Schizophreniab. Schizophrenia

Dopamine is also important for the Dopamine is also important for the organization organization of thought and feeling.of thought and feeling.

(1)(1) Schizophrenia – a disorder marked by Schizophrenia – a disorder marked by hallucinations, delusions, thought disorder, and hallucinations, delusions, thought disorder, and inappropriate or blunted affect – is related to inappropriate or blunted affect – is related to abnormalities in dopamine transmission in the abnormalities in dopamine transmission in the mesolimbic and mesocortical areas of the brain. mesolimbic and mesocortical areas of the brain.

TThis is known as the his is known as the dopamine hypothesis of dopamine hypothesis of schizophrenia.schizophrenia. Dopaminergic abnormalities Dopaminergic abnormalities alone do not account for the entire clinical alone do not account for the entire clinical picture.picture.

(2)(2) The psychotic symptoms of schizophrenia result The psychotic symptoms of schizophrenia result from from a hyperdopaminergic statea hyperdopaminergic state, based on some of , based on some of the evidence listed below.the evidence listed below.

(a)(a) The ability of neuroleptic drugs to block D2 The ability of neuroleptic drugs to block D2 receptors correlates significantly with their receptors correlates significantly with their antipsychotic potency.antipsychotic potency.

(b)(b) Drugs that enhance dopaminergic transmission Drugs that enhance dopaminergic transmission (e.g., amphetamine, L-dopa) tend to worsen (e.g., amphetamine, L-dopa) tend to worsen schizophrenic symptoms and can produce schizophrenic symptoms and can produce hallucinations and delusions in normal individuals.hallucinations and delusions in normal individuals.

(c)(c) Increased concentrations of dopamine and Increased concentrations of dopamine and dopamine receptor activity in patients with dopamine receptor activity in patients with schizophrenia.schizophrenia.

B. NorepinephrineB. Norepinephrine

1. Synthesis1. Synthesis

2. Metabolism2. Metabolism

a. a. TwoTwo metabolites metabolites of norepinephrine are of norepinephrine are commonly measured in plasma or urine: commonly measured in plasma or urine: 3-3-methoxy-4-hydroxyphenylglycol (MHPG)methoxy-4-hydroxyphenylglycol (MHPG) and and 3-methoxy-4-hydroxymandelic acid3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid, or VMA). 30-40% of (vanillylmandelic acid, or VMA). 30-40% of urinary MHPG is formed in the brain. Both urinary MHPG is formed in the brain. Both MHPG and VMA are formed through the MHPG and VMA are formed through the oxidative deamination of norepinephrine oxidative deamination of norepinephrine involving the enzyme MAO-A.involving the enzyme MAO-A.

b. b. Norepinephrine is Norepinephrine is released into the released into the synaptic cleftsynaptic cleft from storage vesicles by the from storage vesicles by the process of exocytosis. After release, there process of exocytosis. After release, there is an active reuptake process that removes is an active reuptake process that removes norepinephrine from the synaptic cleft.norepinephrine from the synaptic cleft.


a. α1-Receptorsa. α1-Receptors are postsynaptic and act by are postsynaptic and act by raising intracellular calcium. raising intracellular calcium.

Prazosin exerts a relatively selective Prazosin exerts a relatively selective α1-α1-receptorreceptor blockade. blockade.

b. α2-Receptorsb. α2-Receptors are mainly postsynaptic, are mainly postsynaptic, negatively linked to adenylate cyclase, negatively linked to adenylate cyclase, and decrease the synthesis of and decrease the synthesis of norepinephrine in the presynaptic neuron norepinephrine in the presynaptic neuron when stimulated. At low doses, clonidine when stimulated. At low doses, clonidine is an α2-agonist and piperoxan and is an α2-agonist and piperoxan and yohimbine are selective α2-antagonists.yohimbine are selective α2-antagonists.

c. β1-Receptorsc. β1-Receptors are mainly postsynaptic are mainly postsynaptic and are positively linked to adenylate and are positively linked to adenylate cyclase.cyclase.

d. β2-Receptorsd. β2-Receptors are mainly postsynaptic and are mainly postsynaptic and also positively linked to adenylate cyclase.also positively linked to adenylate cyclase.

e.e. In the periphery, β1-receptors are found In the periphery, β1-receptors are found predominantly in the heart, whereas β2-predominantly in the heart, whereas β2-receptors are found mainly in the lungs, blood receptors are found mainly in the lungs, blood vessels, and vascular beds in skeletal muscle.vessels, and vascular beds in skeletal muscle.

f. Nonselective β-agonists and β-antagonistsf. Nonselective β-agonists and β-antagonists

(1)(1) Nonselective β-agonists include epinephrine Nonselective β-agonists include epinephrine and norepinephrine; these are equipotent on and norepinephrine; these are equipotent on β1-receptors, but epinephrine is much more β1-receptors, but epinephrine is much more potent than norepinephrine on β2-receptors.potent than norepinephrine on β2-receptors.

(2)(2) Nonselective β-antagonists: propranolol, Nonselective β-antagonists: propranolol, alprenolol, nadolol, and timolol.alprenolol, nadolol, and timolol.

4. Important brain tracts4. Important brain tracts

Two major groups of noradrenergic neuron Two major groups of noradrenergic neuron tracts exist in the brain.tracts exist in the brain.

a.a. The first group arises from the The first group arises from the locus locus ceruleus (“blue spot”),ceruleus (“blue spot”), which is a cluster which is a cluster of pigmented neurons located within the of pigmented neurons located within the pontine central gray area pontine central gray area along the lateral along the lateral aspect of the fourth ventricle. aspect of the fourth ventricle.

This nucleus sends projections to the This nucleus sends projections to the cerebellum and spinal cord and cerebellum and spinal cord and through the median forebrain bundle through the median forebrain bundle to the hippocampus, ventral striatum, to the hippocampus, ventral striatum, and entire cerebral cortex.and entire cerebral cortex.

b. b. The second group of tracts originates The second group of tracts originates in the in the lateral ventral tegmental arealateral ventral tegmental area and projects to basal forebrain areas and projects to basal forebrain areas such as the septum and amygdala.such as the septum and amygdala.

5. Effects on behavior5. Effects on behavior

a. Neuromodulatory functionsa. Neuromodulatory functions

Noradrenergic axons projects to most areas Noradrenergic axons projects to most areas of the brain, and norepinephrine is likely of the brain, and norepinephrine is likely an important neuromodulators.an important neuromodulators.

(1)(1) Norepinephrine enhances locomotor Norepinephrine enhances locomotor responses to dopamine; it plays a role in responses to dopamine; it plays a role in various physiologic functions, including various physiologic functions, including the sleep-wake cycle, pain, anxiety, and the sleep-wake cycle, pain, anxiety, and arousal.arousal.

(2)(2) Norepinephrine system mediates an Norepinephrine system mediates an organism’s orientation to the environment: organism’s orientation to the environment: When unexpected external sensory stimuli When unexpected external sensory stimuli arise, norepinephrine neuronal firing arise, norepinephrine neuronal firing increases, whereas it decreases during increases, whereas it decreases during tonic vegetative activities.tonic vegetative activities.

b. Moodb. Mood

Norepinephrine is important in the genesis Norepinephrine is important in the genesis and maintenance of mood and may be and maintenance of mood and may be related to mood and anxiety disorders.related to mood and anxiety disorders.

(1)(1) The The catecholamine theory of mood catecholamine theory of mood disorders disorders states that reduced activity of states that reduced activity of catecholaminergic systems (usually the catecholaminergic systems (usually the noradrenergic system) in certain brain area noradrenergic system) in certain brain area may be associated with depression and may be associated with depression and higher activity with mania.higher activity with mania.

(a) Reserpine,(a) Reserpine, which depletes which depletes norepinephrine, causes a state similar to norepinephrine, causes a state similar to depression.depression.

(b) MAO inhibitors(b) MAO inhibitors (e.g., iproniazid, (e.g., iproniazid, phenelzine) have antidepressant properties.phenelzine) have antidepressant properties.

(c) Amphetamines,(c) Amphetamines, which cause the release of which cause the release of norepinephrine, cause an elevation of mood.norepinephrine, cause an elevation of mood.

(d) Tricyclic antidepressants(d) Tricyclic antidepressants increase the increase the availability of norepinephrine.availability of norepinephrine.

(e) Propranolol,(e) Propranolol, a nonselective β-blocker, a nonselective β-blocker, causes symptom improvement in some patients causes symptom improvement in some patients with mania, but also to worsen depression.with mania, but also to worsen depression.

(2)(2) There is some indirect pharmacologic There is some indirect pharmacologic evidence of evidence of norepinephrine hyperactivitynorepinephrine hyperactivity in in some schizophrenic patients and in patients some schizophrenic patients and in patients with anxiety disorders.with anxiety disorders.

c. Movement disordersc. Movement disorders

Norepinephrine is involved in various Norepinephrine is involved in various movement disorders [i.e., autosomal movement disorders [i.e., autosomal dominant torsion dystonia, Parkinson’s dominant torsion dystonia, Parkinson’s disease, Tourette’s syndrome (which is disease, Tourette’s syndrome (which is marked by vocal and tics), akathisia (a marked by vocal and tics), akathisia (a disorder of motor restlessness associated disorder of motor restlessness associated with neuroleptic drugs)]. Some evidence with neuroleptic drugs)]. Some evidence suggests noradrenergic hyperactivity in at suggests noradrenergic hyperactivity in at least a subset of patients with tardive least a subset of patients with tardive dyskinesiadyskinesia

C. Serotonin [5-hydroxytryptamine (5-HT)]C. Serotonin [5-hydroxytryptamine (5-HT)]

1. Synthesis 1. Synthesis


a. Serotonin catabolisma. Serotonin catabolism involves oxidation involves oxidation of the amino group, which is catalyzed by of the amino group, which is catalyzed by MAO (primarily MAO-A), followed by MAO (primarily MAO-A), followed by rapid oxidation to 5-hydroxyindoleacetic rapid oxidation to 5-hydroxyindoleacetic acid (5-HIAA).acid (5-HIAA).

(1) Melatonin(1) Melatonin is an is an NN-acetylated derivative of -acetylated derivative of serotonin that is made in the pineal gland.serotonin that is made in the pineal gland.

(2)(2) Apart from Apart from degradationdegradation, , serotonin may be serotonin may be inactivated by inactivated by reuptakereuptake into the presynaptic into the presynaptic neuron, neuron, a process that is inhibited by tricyclic a process that is inhibited by tricyclic antidepressants. Drugs such as reserpine and antidepressants. Drugs such as reserpine and tetrabenazine deplete serotonin from the tetrabenazine deplete serotonin from the vesicles.vesicles.


a. Typesa. Types

(1) 5-HT1 receptors(1) 5-HT1 receptors preferentially bind serotonin preferentially bind serotonin and are separated into several subclasses.and are separated into several subclasses.

(a) 5-HT1A (a) 5-HT1A receptors, found in the hippocampus, receptors, found in the hippocampus, inhibit cyclic AMP production.inhibit cyclic AMP production.

(b) 5-HT1B (b) 5-HT1B receptors, found in high density receptors, found in high density in the striatum, function as in the striatum, function as autoreceptorsautoreceptors..

(c) 5-HT1C (c) 5-HT1C receptors in the choroids plexus; receptors in the choroids plexus; occupation of 5-HT1C receptors is linked to occupation of 5-HT1C receptors is linked to phosphatidylinositol turnoverphosphatidylinositol turnover

(2) 5-HT2 receptors(2) 5-HT2 receptors preferentially bind preferentially bind spiperone (a drug that is also a D2-spiperone (a drug that is also a D2-antagonist) and are thought to be more antagonist) and are thought to be more important in mediating the behavioral effects important in mediating the behavioral effects of serotonin. They are found in the of serotonin. They are found in the neocortex and hippocampus and in plateletsneocortex and hippocampus and in platelets

(3) 5-HT3 receptor(3) 5-HT3 receptor produces rapid excitatory produces rapid excitatory effects in postsynaptic neurons. The receptor effects in postsynaptic neurons. The receptor is expressed within the hippocampus, is expressed within the hippocampus, neocortex, amygdala, hypothalamus, and neocortex, amygdala, hypothalamus, and brainstem motor nuclei. Outside the brain, it brainstem motor nuclei. Outside the brain, it is found in the pituitary gland, enteric nervous is found in the pituitary gland, enteric nervous system sympathetic ganglia, and in sensory system sympathetic ganglia, and in sensory ganglia. 5-HT3 receptor antagonists such as ganglia. 5-HT3 receptor antagonists such as ondansetron (Zofran) have been used as anti-ondansetron (Zofran) have been used as anti-emetic agents and are under evaluation as emetic agents and are under evaluation as potential anti-anxiety and cognitive-potential anti-anxiety and cognitive-enhancing agents.enhancing agents.

(4) Other serotonin receptors: (4) Other serotonin receptors: recently recently identified 5-HT4; 5-HT5, including subtypes 5-identified 5-HT4; 5-HT5, including subtypes 5-HT5A and 5-HT5B; 5-HT6 and 5-HT7 HT5A and 5-HT5B; 5-HT6 and 5-HT7 receptors.receptors.

(5) Presynaptic serotonin receptors (5) Presynaptic serotonin receptors also exist. also exist. LSD acts as both a receptor blocker and a LSD acts as both a receptor blocker and a partial agonist, and it exerts more potent effects partial agonist, and it exerts more potent effects on presynaptic serotonin receptors.on presynaptic serotonin receptors.

b. Actionsb. Actions

The predominant action of serotonin on receptors The predominant action of serotonin on receptors is is inhibition,inhibition, although excitation has been although excitation has been described in some cases.described in some cases.


The most important serotonergic neurons in The most important serotonergic neurons in the brain are located in clusters in or around the brain are located in clusters in or around the middle, or raphe, of the pons and the middle, or raphe, of the pons and mesencephalon, including the mesencephalon, including the median and median and dorsal raphe nuclei.dorsal raphe nuclei.

a. a. The median raphe neurons innervate limbic The median raphe neurons innervate limbic structures including amygdala.structures including amygdala.

b. b. The dorsal raphe neurons innervate the The dorsal raphe neurons innervate the striatum, cerebral cortex, thalamus, and striatum, cerebral cortex, thalamus, and cerebellum.cerebellum.


Serotonin is important for many Serotonin is important for many central central processes,processes, including pain perception, including pain perception, aggression, appetite, thermoregulation, blood aggression, appetite, thermoregulation, blood pressure control, heart rate, and respiration. It is pressure control, heart rate, and respiration. It is important for induction of sleep and important for induction of sleep and wakefulness.wakefulness.

a. mood disordersa. mood disorders

(1)(1) It has been suggested that low activity of It has been suggested that low activity of serotonin in the brain is associated with serotonin in the brain is associated with depression, whereas high activity is associated depression, whereas high activity is associated with mania.with mania.

(2)(2) Another theory, known as the Another theory, known as the permissive serotonin hypothesis, permissive serotonin hypothesis, states that lowered serotonin activity states that lowered serotonin activity “permits” low levels of catecholamines “permits” low levels of catecholamines to cause depression and high levels to to cause depression and high levels to cause mania.cause mania.

(3)(3) Some serotonin reuptake blockers Some serotonin reuptake blockers (e.g., fluoxetine, fluvoxamine) are (e.g., fluoxetine, fluvoxamine) are powerful antidepressants.powerful antidepressants.

b. Schizophreniab. Schizophrenia

The The transmethylation hypothesistransmethylation hypothesis of of schizophrenia asserts that certain methylated schizophrenia asserts that certain methylated derivatives of serotonin, formed as a result of derivatives of serotonin, formed as a result of errors in metabolism, may cause psychosis.errors in metabolism, may cause psychosis.

(1)(1) This theory is supported by the finding that This theory is supported by the finding that LSD and serotonin derivatives (e.g., LSD and serotonin derivatives (e.g., dimethyltryptamine, harmaline, psilocybin) dimethyltryptamine, harmaline, psilocybin) cause hallucinations and behavioral cause hallucinations and behavioral abnormalities.abnormalities.

c.c. Serotonin also probably is involved in Serotonin also probably is involved in OCD.OCD.

D. Histamine D. Histamine



Histamine is methylated to methyl-histamine and Histamine is methylated to methyl-histamine and subsequently is oxidized to 1,4-subsequently is oxidized to 1,4-methylimidazoleacetic acid.methylimidazoleacetic acid.


There are three types of histamine receptors, H1, There are three types of histamine receptors, H1, H2, and H3. They exist in the brain and in the H2, and H3. They exist in the brain and in the periphery. H1 and H2 receptors activate periphery. H1 and H2 receptors activate adenylate cyclase.adenylate cyclase.

Histamine H1 and H2 receptors are Histamine H1 and H2 receptors are excitatory excitatory in in the hypothalamus, hippocampal formation, the hypothalamus, hippocampal formation, and thalamus; it is mainly and thalamus; it is mainly inhibitoryinhibitory in the in the cerebral cortex. cerebral cortex.

a. a. Histamine type 1 (H1) receptors are expressed Histamine type 1 (H1) receptors are expressed throughout the body, in smooth muscle of the throughout the body, in smooth muscle of the GIT and blood vessel walls. H1 receptors are GIT and blood vessel walls. H1 receptors are widely distributed throughout the CNS.widely distributed throughout the CNS.

b. b. H2 receptors are widely distributed H2 receptors are widely distributed throughout the body, and are found in gastric throughout the body, and are found in gastric mucosa, smooth muscle, cardiac muscle, and mucosa, smooth muscle, cardiac muscle, and cells of the immune system.cells of the immune system.

Within the CNS, H2 receptors are abundantly Within the CNS, H2 receptors are abundantly expressed in the neocortex, hippocampus, expressed in the neocortex, hippocampus, amygdala, and striatum. H2 receptor antagonists amygdala, and striatum. H2 receptor antagonists are widely used in the treatment of peptic ulcer are widely used in the treatment of peptic ulcer disease. disease.

c. c. Unlike H1 and H2 histamine receptors, H3 Unlike H1 and H2 histamine receptors, H3 receptors are located receptors are located presynapticallypresynaptically on axon on axon terminals. Those located on histaminergic terminals. Those located on histaminergic terminals act as terminals act as autoreceptors to inhibit histamine autoreceptors to inhibit histamine releaserelease..

H3 receptors are also located on nonhistaminergic H3 receptors are also located on nonhistaminergic nerve terminals, where they inhibit the release of nerve terminals, where they inhibit the release of a variety of neurotransmitters.a variety of neurotransmitters.

Particularly high levels of H3 receptor Particularly high levels of H3 receptor binding are found in the frontal cortex, binding are found in the frontal cortex, striatum, amygdaloid complex, and striatum, amygdaloid complex, and substantia nigra. substantia nigra.

Lower levels are found in peripheral tissues Lower levels are found in peripheral tissues such as the gastrointestinal tract, pancreas, such as the gastrointestinal tract, pancreas, and lung. and lung.

Antagonists of H3 receptors have been Antagonists of H3 receptors have been proposed to have proposed to have appetite suppressant, appetite suppressant, arousing, and cognitive-enhancing arousing, and cognitive-enhancing propertiesproperties..


Histamine is found in high concentrations in Histamine is found in high concentrations in the mesencephalon, hippocampus, thalamus, the mesencephalon, hippocampus, thalamus, basal ganglia, and cerebral cortex.basal ganglia, and cerebral cortex.


Histamine is important in arousal, water Histamine is important in arousal, water intake, vasopressin release, intake, vasopressin release, thermoregulation, and cardiovascular thermoregulation, and cardiovascular function. function.

Blockade of histamine receptors leads to Blockade of histamine receptors leads to weight gain, sedation, and hypotension.weight gain, sedation, and hypotension.

a. Anorexia nervosa,a. Anorexia nervosa, an illness an illness characterized by excessive weight loss, has characterized by excessive weight loss, has been reported to be treated successfully been reported to be treated successfully with cyproheptadine, a drug that blocks H2 with cyproheptadine, a drug that blocks H2 receptors (it also blocks5-HT receptors).receptors (it also blocks5-HT receptors).

b.b. The tricyclic antidepressant doxepin, in The tricyclic antidepressant doxepin, in addition to being a serotonin agonist, also addition to being a serotonin agonist, also has powerful H1- and H2-receptor-has powerful H1- and H2-receptor-blocking abilities, although it is not clear blocking abilities, although it is not clear how this relates to its antidepressant how this relates to its antidepressant potential.potential.

IV. ACETYLCHOLINEIV. ACETYLCHOLINE

A. SynthesisA. Synthesis

Choline cannot be synthesized in neurons; Choline cannot be synthesized in neurons; it is transported into the brain by high-it is transported into the brain by high-affinity and low-affinity transport affinity and low-affinity transport processes. processes.

The high-affinity process, which is The high-affinity process, which is inhibited by hemicholinium-3inhibited by hemicholinium-3, is the , is the primary factor regulating the amount of primary factor regulating the amount of ACh present in neurons.ACh present in neurons.

B. MetabolismB. Metabolism

ACh is inactivated by ACh is inactivated by cholinesterasescholinesterases, , includingincluding pseudo-cholinesterase and pseudo-cholinesterase and acetylcholinesterase; the latter is reversibly acetylcholinesterase; the latter is reversibly inhibited by physostigmine and almost inhibited by physostigmine and almost irreversibly inhibited by organophosphorus irreversibly inhibited by organophosphorus compounds such as those used in insecticides.compounds such as those used in insecticides.

C. ReceptorsC. Receptors

The two main types of ACh receptors – nicotinic The two main types of ACh receptors – nicotinic and muscarinic receptors – both occur in the and muscarinic receptors – both occur in the brain.brain.

1. Nicotinic receptors1. Nicotinic receptors are channels allowing sodium to are channels allowing sodium to enter the neuron. Therefore, they are enter the neuron. Therefore, they are excitatory.excitatory.

a. Sitesa. Sites

(1) (1) Nicotinic receptors in the peripheral nervous system Nicotinic receptors in the peripheral nervous system are located on the cell bodies of postganglionic are located on the cell bodies of postganglionic neurons of both the sympathetic and parasympathetic neurons of both the sympathetic and parasympathetic divisions of the ANS.divisions of the ANS.

(2)(2) Also are located at the junctions of motor nerves and Also are located at the junctions of motor nerves and skeletal muscle.skeletal muscle.

(3)(3) In the brain but less is known about them than about In the brain but less is known about them than about muscarinic receptors.muscarinic receptors.

b. Nicotinic receptor b. Nicotinic receptor agonistsagonists include nicotine, and include nicotine, and antagonistsantagonists include curare drugs. include curare drugs.

2. Muscarinic receptors2. Muscarinic receptors may be may be excitatory or excitatory or inhibitoryinhibitory.. Presynaptic ACh receptors are mainly Presynaptic ACh receptors are mainly muscarinic.muscarinic.

a. Sitesa. Sites

Muscarinic receptors are located Muscarinic receptors are located in the peripheral in the peripheral ganglia of both the sympathetic and parasympathetic ganglia of both the sympathetic and parasympathetic nervous systemnervous system..

They also are located on the They also are located on the end organs of the end organs of the parasympathetic nervous systemparasympathetic nervous system (i.e., smooth muscle (i.e., smooth muscle and glands).and glands).

b. Muscarinic receptor agonistsb. Muscarinic receptor agonists include muscarine (a include muscarine (a mushroom alkaloid), pilocarpine, and oxotremorine. mushroom alkaloid), pilocarpine, and oxotremorine. AntagonistsAntagonists include atropine. include atropine.

c. Typesc. Types

Muscarinic receptors are divided into two types, Muscarinic receptors are divided into two types, M1 and M2.M1 and M2.

(1) M1 receptors (1) M1 receptors are postsynaptic and are postsynaptic and excitatory and are widespread throughout the excitatory and are widespread throughout the neocortex.neocortex.

(2) M2 receptors (2) M2 receptors are concentrated in the cortical are concentrated in the cortical laminae that demonstrate the greatest choline laminae that demonstrate the greatest choline acetyltransferase activity. acetyltransferase activity.

They are presynaptic and modulate the release They are presynaptic and modulate the release of ACh, probably through inhibition of of ACh, probably through inhibition of adenylate cyclase.adenylate cyclase.

D. Important brain tractsD. Important brain tracts

There is an important cholinergic pathway from the There is an important cholinergic pathway from the basal forebrain (the nucleus basalis) to the basal forebrain (the nucleus basalis) to the hippocampus and probably to the cerebral cortex. hippocampus and probably to the cerebral cortex. The striatum is rich in ACh, where it is found The striatum is rich in ACh, where it is found mainly in short intrastriatal neurons.mainly in short intrastriatal neurons.

E. Effects on behaviorE. Effects on behavior

In animals, ACh is believed to be important in In animals, ACh is believed to be important in movement, sleep, aggression, exploratory movement, sleep, aggression, exploratory behavior, sexual behavior, and memory. For behavior, sexual behavior, and memory. For humans, the most important effects involve humans, the most important effects involve movement and memory.movement and memory.

1. ACh is important in movement1. ACh is important in movement both peripherally both peripherally and centrally.and centrally.

a. Peripherallya. Peripherally

ACh is the main transmitter for skeletal muscles; ACh is the main transmitter for skeletal muscles; many powerful neurotoxins (e.g., curare, α-many powerful neurotoxins (e.g., curare, α-bungarotoxin) paralyze by blocking ACh receptors.bungarotoxin) paralyze by blocking ACh receptors.

b. Centrallyb. Centrally

ACh and dopamine exist in reciprocal balance in the ACh and dopamine exist in reciprocal balance in the extrapyramidal motor system. A decrease in one extrapyramidal motor system. A decrease in one (e.g., a decrease in dopamine in Parkinson’s disease) (e.g., a decrease in dopamine in Parkinson’s disease) can be offset somewhat by decreasing the other can be offset somewhat by decreasing the other (e.g., by using anticholinergic drugs).(e.g., by using anticholinergic drugs).

2. ACh also is important in memory and 2. ACh also is important in memory and cognitioncognition

Dementing illnesses such as Alzheimer’s Dementing illnesses such as Alzheimer’s disease is associated with a loss of disease is associated with a loss of cholinergic transmission in the brain – both cholinergic transmission in the brain – both to the hippocampus and to the cerebral to the hippocampus and to the cerebral cortex. cortex.

A decreased number of cholinergic neurons in A decreased number of cholinergic neurons in the nucleus basalis of Meynert (located in the the nucleus basalis of Meynert (located in the basal forebrain) has been reported in patients basal forebrain) has been reported in patients with Alzheimer’s disease and certain other with Alzheimer’s disease and certain other dementing disorders. dementing disorders.

V. AMINO ACIDSV. AMINO ACIDS

A. Inhibitory neurotransmittersA. Inhibitory neurotransmitters

1. GABA1. GABA

It has proved to be purely inhibitory in all It has proved to be purely inhibitory in all studies to date. studies to date.

Unlike most other neurotransmitters, GABA Unlike most other neurotransmitters, GABA is limited almost entirely to the CNS. is limited almost entirely to the CNS.

Present in as many as 60% of synapses, Present in as many as 60% of synapses, GABA is 200 to 1000 timeGABA is 200 to 1000 times more abundant s more abundant than dopamine, ACh, norepinephrine, and than dopamine, ACh, norepinephrine, and other transmitters.other transmitters.

a. Synthesisa. Synthesis

b. Metabolismb. Metabolism

GABA is catalyzed by GABA transaminase to GABA is catalyzed by GABA transaminase to succinic semialdehyde, which is oxidized to succinic semialdehyde, which is oxidized to succinic acid, which enters the citric acid cycle.succinic acid, which enters the citric acid cycle.

c. Receptorsc. Receptors

At least two types of GABAergic receptors exist At least two types of GABAergic receptors exist in the CNS.in the CNS.

(1) GABA-A receptors(1) GABA-A receptors are are the classic the classic postsynaptic GABA receptorspostsynaptic GABA receptors. Muscimol is a . Muscimol is a selective agonist, and bicuculline (a convulsant) selective agonist, and bicuculline (a convulsant) and picrotoxin are selective antagonists.and picrotoxin are selective antagonists.

(a)(a) Some GABA-A receptors are coupled to a Some GABA-A receptors are coupled to a recognition site for benzodiazepines, which recognition site for benzodiazepines, which potentiate GABA’s inhibitory action.potentiate GABA’s inhibitory action.

(b)(b) Benzodiazepine receptors exist in two forms. Benzodiazepine receptors exist in two forms.

(2) GABA-B receptors: (2) GABA-B receptors: Baclofen, a drug used Baclofen, a drug used to treat spasticity, is a selective agonist.to treat spasticity, is a selective agonist.

d. Important brain tractsd. Important brain tracts

Many brain pathways contain GABA.Many brain pathways contain GABA.

(1)(1) GABA is the primary neurotransmitter for GABA is the primary neurotransmitter for Purkinje cells,Purkinje cells, which are the only efferent which are the only efferent neurons for the entire cerebellar cortex.neurons for the entire cerebellar cortex.

(2)(2) Inhibitory interneurons in almost all Inhibitory interneurons in almost all areas of the brain contain GABA.areas of the brain contain GABA.

(3)(3) GABAergic pathways extend from the GABAergic pathways extend from the striatum to the substantia nigra and to the striatum to the substantia nigra and to the globus pallidus, which may be important globus pallidus, which may be important in movement disorders such as in movement disorders such as Parkinson’s and Huntington’s diseases. Parkinson’s and Huntington’s diseases.

(4) (4) GABAergic pathway extends from the GABAergic pathway extends from the magnocellular neurons of the posterior magnocellular neurons of the posterior hypothalamus to the neocortex.hypothalamus to the neocortex.

2. Glycine2. Glycine structurally is the simplest amino structurally is the simplest amino acid.acid.

a. a. Like GABA, glycine is an inhibitory Like GABA, glycine is an inhibitory neurotransmitter. neurotransmitter.

Its action is much more restricted than that Its action is much more restricted than that of GABA, however, as it is found only in of GABA, however, as it is found only in the brain stem and spinal cord and, the brain stem and spinal cord and, possibly, in the retina and diencephalons.possibly, in the retina and diencephalons.

b.b. Strychnine blocks the action of glycine. Strychnine blocks the action of glycine.

3. Other possibly inhibitory amino acids3. Other possibly inhibitory amino acids include alanine, cystathionine, and serine. include alanine, cystathionine, and serine.

B. Excitatory neurotransmittersB. Excitatory neurotransmitters

The only amino acids act as excitatory The only amino acids act as excitatory neurotransmitters are neurotransmitters are glutamateglutamate and and aspartateaspartate.. These neurotransmitters, as These neurotransmitters, as well as some of their analogs (e.g., kainic well as some of their analogs (e.g., kainic acid), are acid), are neurotoxicneurotoxic under certain under certain conditions.conditions.


Both glutamate and aspartate can be Both glutamate and aspartate can be synthesized synthesized from glucosefrom glucose..


There are multiple receptor subtypes for glutamate.There are multiple receptor subtypes for glutamate.

a. Kainate receptorsa. Kainate receptors and and quisqualate receptorsquisqualate receptors operate to operate to allow the influx of sodiumallow the influx of sodium; ; N-methy-N-methy-D-aspartate (NMDA) receptors,D-aspartate (NMDA) receptors, which normally which normally are are blocked by physiologic concentrations of blocked by physiologic concentrations of magnesiummagnesium, open to allow sodium and calcium , open to allow sodium and calcium into the cell upon depolarization.into the cell upon depolarization.

b. Phencyclidine (PCP),b. Phencyclidine (PCP), a common drug of abuse, a common drug of abuse, is an antagonist at the NMDA receptor and has is an antagonist at the NMDA receptor and has effects on the σ-opioid receptor.effects on the σ-opioid receptor.


Glutamate exists in the Glutamate exists in the corticostriatal pathwaycorticostriatal pathway and in and in cerebellar granule cells,cerebellar granule cells, and that and that aspartate exists in the aspartate exists in the hippocampal hippocampal commissural pathway.commissural pathway.

Glutamate and aspartate may be the primary Glutamate and aspartate may be the primary excitatory transmitters of the brain.excitatory transmitters of the brain.


a.a. Glutamate, especially via NMDA receptors, Glutamate, especially via NMDA receptors, may be involved in may be involved in long-term potentiationlong-term potentiation of of neurons in the hippocampus, neurons in the hippocampus, a process a process important for memory storageimportant for memory storage..

b.b. It also is important for It also is important for kindling,kindling, where repeated where repeated subthreshold electrical stimulation eventually subthreshold electrical stimulation eventually results in a results in a seizureseizure..

VI. Other Non-peptide Neurotransmitter VI. Other Non-peptide Neurotransmitter CandidatesCandidates

A. Prostaglandins and thromboxanesA. Prostaglandins and thromboxanes

1. Synthesis and biochemistry1. Synthesis and biochemistry

They belong to a family of substances known as They belong to a family of substances known as eicosanoids,eicosanoids, which are products of arachidonic acid which are products of arachidonic acid metabolism.metabolism.

a.a. These hormone-like substances are among the most These hormone-like substances are among the most abundant of abundant of autacoidsautacoids (i.e., compounds synthesized (i.e., compounds synthesized at or close to their sites of actionat or close to their sites of action

b.b. Prostaglandins and thromboxanes exist in Prostaglandins and thromboxanes exist in every tissue and body fluid, their synthesis is every tissue and body fluid, their synthesis is increased in response to widely varied stimuli, increased in response to widely varied stimuli, and they have diverse and complicated biologic and they have diverse and complicated biologic actions.actions.

2. Nervous system effects2. Nervous system effects

a.a. Prostaglandins do not appear to function as Prostaglandins do not appear to function as neurotransmitters, but they may play a neurotransmitters, but they may play a neuromodulatory role. neuromodulatory role.

Prostaglandin E2 act to Prostaglandin E2 act to inhibitinhibit the stimulated the stimulated release of dopamine and norepinephrine. PGE2 release of dopamine and norepinephrine. PGE2 modulates the serotonin system.modulates the serotonin system.

b. b. Eicosanoids are released from brain tissue Eicosanoids are released from brain tissue following ischemia or trauma and may following ischemia or trauma and may contribute to the development of edema and to contribute to the development of edema and to deterioration of blood-brain barrier.deterioration of blood-brain barrier.

B. PurinesB. Purines

1. ATP1. ATP may function as a neurotransmitter in the may function as a neurotransmitter in the intrinsic, nonadrenergic, noncholinergic neurons intrinsic, nonadrenergic, noncholinergic neurons of visceral smooth muscle.of visceral smooth muscle.

2.2. Adenosine may serve as an inhibitory Adenosine may serve as an inhibitory neuromodulators of excitatory cells in the neuromodulators of excitatory cells in the cerebellum, hippocampus, medial geniculate cerebellum, hippocampus, medial geniculate body, and septum. body, and septum.

Adenosine receptors also are found in the striatum, Adenosine receptors also are found in the striatum, where adenosine may help modulate where adenosine may help modulate dopaminergic transmission.dopaminergic transmission.

VII. NEUROPEPTIDESVII. NEUROPEPTIDES

- Neuropeptides function principally as - Neuropeptides function principally as neurohormones. neurohormones.

- They are important in - They are important in psychoneuroendocrinology. psychoneuroendocrinology.

- They may serve as - They may serve as neuromodulatorsneuromodulators and, in and, in some cases, as some cases, as neurotransmittersneurotransmitters (their course of (their course of action is much slower than that of ACh, action is much slower than that of ACh, dopamine, and norepinephrine). dopamine, and norepinephrine).

- Peptides coexist with the simpler (“classic”) - Peptides coexist with the simpler (“classic”) transmitters within a single neuron, which transmitters within a single neuron, which contradicts Dale’s principle. contradicts Dale’s principle.

A. Endogenous opioidsA. Endogenous opioids

1. Overview and terminology1. Overview and terminology

a. Opiuma. Opium has been used as a pain reliever and has been used as a pain reliever and psychotomimetic drug for millennia. In the psychotomimetic drug for millennia. In the nineteenth century, it was determined that nineteenth century, it was determined that most of this action is due to the alkaloid most of this action is due to the alkaloid morphine.morphine.

b.b. In the 1970’s, a class of endogenous In the 1970’s, a class of endogenous neuropeptides that bind to receptors that neuropeptides that bind to receptors that mediate response to opioids named mediate response to opioids named enkephalinsenkephalins (meaning “in the head”). (meaning “in the head”).

Other substances called Other substances called endorphinsendorphins (a (a contraction of “endogenous” and “morphine”).contraction of “endogenous” and “morphine”).

c.c. Enkephalins and endorphins are called the Enkephalins and endorphins are called the endogenous opioidsendogenous opioids. .

2. Endogenous opioids families2. Endogenous opioids families

Numerous endogenous opioids have been Numerous endogenous opioids have been identified, which fall into one of three families: identified, which fall into one of three families: enkephalins [e.g., methionine and leucine enkephalins [e.g., methionine and leucine enkephalin (met- and leu-enkephalin)], enkephalin (met- and leu-enkephalin)], endorphins (e.g., α-, β-, and γ-endorphins), and endorphins (e.g., α-, β-, and γ-endorphins), and dynorphins (e.g., dynorphin A, dynorphin B).dynorphins (e.g., dynorphin A, dynorphin B).

3. Opioid receptors3. Opioid receptors

a. Mu (μ) receptorsa. Mu (μ) receptors mediate supraspinal mediate supraspinal analgesia, respiratory depression, and euphoria. analgesia, respiratory depression, and euphoria. Morphine and met-enkephalin are agonists at Morphine and met-enkephalin are agonists at these receptors.these receptors.

b. Kappa (κ) receptorsb. Kappa (κ) receptors mediate spinal mediate spinal analgesia and papillary miosis. Dynorphins are analgesia and papillary miosis. Dynorphins are agonists at these receptors.agonists at these receptors.

c. Delta (δ) receptorsc. Delta (δ) receptors in the CNS are associated in the CNS are associated with mood components of opioid action. Leu-with mood components of opioid action. Leu-enkephalin is an agonist at these receptors.enkephalin is an agonist at these receptors.

d. Epsilon (ε) receptorsd. Epsilon (ε) receptors may produce catatonia. may produce catatonia. β-endorphin is an agonist at these receptors.β-endorphin is an agonist at these receptors.

e. Sigma (σ) receptorse. Sigma (σ) receptors are associated with are associated with psychotomimetic effects of certain opiates. psychotomimetic effects of certain opiates.


a.a. Many behavioral states and neuropsychiatric Many behavioral states and neuropsychiatric disorders, including thermoregulation, seizure disorders, including thermoregulation, seizure induction, alcoholism, schizophrenia, general induction, alcoholism, schizophrenia, general effects on locomotion (especially hypomotility effects on locomotion (especially hypomotility and some movement disorders), and analgesia, and some movement disorders), and analgesia, are associated with alterations in endogenous are associated with alterations in endogenous opioids, particularly β-endorphin.opioids, particularly β-endorphin.

b.b. The treatment with opiate antagonists (e.g., The treatment with opiate antagonists (e.g., naloxone, naltrexone): in the case of narcotic naloxone, naltrexone): in the case of narcotic overdose & may be helpful in some cases of overdose & may be helpful in some cases of self-mutilatory behavior.self-mutilatory behavior.

B. Gut peptidesB. Gut peptides

They are found in both the brain and the They are found in both the brain and the digestive tract.digestive tract.

1. Substance P1. Substance P has been found in the spinal has been found in the spinal cord, substantia nigra, striatum, amygdala, cord, substantia nigra, striatum, amygdala, hypothalamus, and cerebral cortex.hypothalamus, and cerebral cortex.

a. a. Substance P may be the principal Substance P may be the principal neurotransmitter for the primary afferent neurotransmitter for the primary afferent sensory fibers that travel through the dorsal sensory fibers that travel through the dorsal roots to the substantia gelatinosa of the spinal roots to the substantia gelatinosa of the spinal cord and cord and carry information about pain.carry information about pain.

b. b. It also may be involved in a It also may be involved in a major major excitatory outflow tractexcitatory outflow tract from the from the striatum to the substantia nigra and striatum to the substantia nigra and globus pallidus and, thus, be important globus pallidus and, thus, be important for for movement.movement.

Substance P abnormalities have been Substance P abnormalities have been implicated in the pathophysiology of implicated in the pathophysiology of Huntington’s disease,Huntington’s disease, a hereditary a hereditary movement disorder in which its levels movement disorder in which its levels have been reported to be reduced.have been reported to be reduced.

2. Cholecystokinin (CCK)2. Cholecystokinin (CCK) is a polypeptide that is is a polypeptide that is released from the gut in response to chime, amino released from the gut in response to chime, amino acids, fats, and other substances, whereupon it acids, fats, and other substances, whereupon it stimulates gallbladder motility and secretion of stimulates gallbladder motility and secretion of pancreatic enzymes. pancreatic enzymes.

CCK is found in the hippocampus, neocortex, brain CCK is found in the hippocampus, neocortex, brain stem, basal ganglia, hypothalamus, and amygdala.stem, basal ganglia, hypothalamus, and amygdala.

a.a. Behaviorally, CCK may be associated with satiety. Behaviorally, CCK may be associated with satiety.

b.b. CCK coexist with dopamine in neurons in the CCK coexist with dopamine in neurons in the ventral tegmental area of the brain stem and in the ventral tegmental area of the brain stem and in the nucleus accumbens – brain regions that are thought nucleus accumbens – brain regions that are thought to be important in the pathophysiology of to be important in the pathophysiology of schizophrenia.schizophrenia.

3. Vasoactive intestinal polypeptide (VIP)3. Vasoactive intestinal polypeptide (VIP) is a 29-amino acid peptide originally is a 29-amino acid peptide originally discovered in the intestine and named for discovered in the intestine and named for its ability to alter blood flow in the gut.its ability to alter blood flow in the gut.

a. a. VIP is extremely common in the VIP is extremely common in the neocortex, where it has been found in a neocortex, where it has been found in a distribution indicating the VIP neurons may distribution indicating the VIP neurons may be localized to single cortical columns.be localized to single cortical columns.

b. b. VIP appears to be excitatory in action and VIP appears to be excitatory in action and to be coupled with cAMP.to be coupled with cAMP.

4. Somatostatin4. Somatostatin

a.a. It is found in the GIT, in the islets of It is found in the GIT, in the islets of Langerhans, and in several areas in the Langerhans, and in several areas in the nervous system.nervous system.

b.b. Its hormonal actions include suppression Its hormonal actions include suppression of the release of GH and TSH in the brain of the release of GH and TSH in the brain and suppression of the release of glucagon and suppression of the release of glucagon and insulin in the pancreas.and insulin in the pancreas.

c.c. It is thought to be important in the It is thought to be important in the production of slow wave sleep and REM production of slow wave sleep and REM sleep, in appetite, and in motor control.sleep, in appetite, and in motor control.

d.d. Somatostatin injection in animals is Somatostatin injection in animals is associated with decreased spontaneous associated with decreased spontaneous motor activity.motor activity.

e.e. Increased Somatostatin levels have been Increased Somatostatin levels have been reported in the corpus striatum of patients reported in the corpus striatum of patients with Huntington’s disease, whereas with Huntington’s disease, whereas decreased levels have been reported in the decreased levels have been reported in the cortex of patients with Alzheimer’s cortex of patients with Alzheimer’s disease.disease.

f. f. Somatostatin may modulate the activity of Somatostatin may modulate the activity of the nigrostriatal dopamine tract.the nigrostriatal dopamine tract.

5. Neurotensin5. Neurotensin is found in the substantia is found in the substantia gelatinosa of the spinal cord, the brain stem gelatinosa of the spinal cord, the brain stem (especially in the motor nucleus of the (especially in the motor nucleus of the trigeminal nerve and substantia nigra), trigeminal nerve and substantia nigra), hypothalamus, amygdala, nucleus accumbens, hypothalamus, amygdala, nucleus accumbens, septum, and anterior pituitary gland. septum, and anterior pituitary gland.

- Neurotensin is excitatory and may play a role in - Neurotensin is excitatory and may play a role in arousal, thermoregulation, and pain perception. arousal, thermoregulation, and pain perception.

- It is involved in the pathophysiology of - It is involved in the pathophysiology of schizophrenia, mostly because of its coexistence schizophrenia, mostly because of its coexistence with dopamine in some axon terminals.with dopamine in some axon terminals.

C. Pituitary, hypothalamic, and pineal C. Pituitary, hypothalamic, and pineal peptidespeptides

1. Overview1. Overview

a. Pituitary hormonesa. Pituitary hormones

The pituitary gland consists of two main lobes.The pituitary gland consists of two main lobes.

(1)(1) The The anterior pituitaryanterior pituitary secretes six secretes six hormones, most of which have hormones, most of which have tropic tropic properties properties (i.e., they have an affinity for a (i.e., they have an affinity for a specific target gland). Its hormones include:specific target gland). Its hormones include:

(a)(a) ACTH ACTH (b)(b) GH GH (c)(c) TSH TSH

(d)(d) LH LH (e)(e) FSH FSH (f)(f) Prolactin Prolactin

(2)(2) The The posterior pituitary posterior pituitary secretes vasopressin and secretes vasopressin and oxytocin.oxytocin.

(3)(3) The The intermediate lobeintermediate lobe is vestigial in adult is vestigial in adult humans. MSH is believed to be secreted from this humans. MSH is believed to be secreted from this part of the pituitary gland in animals, but possibly part of the pituitary gland in animals, but possibly from the anterior pituitary in humans.from the anterior pituitary in humans.

b. Hypothalamic hormones,b. Hypothalamic hormones, or releasing factors, or releasing factors, control the release of anterior pituitary hormones. control the release of anterior pituitary hormones. The anterior pituitary hormones control the release The anterior pituitary hormones control the release of hormones from target endocrine glands.of hormones from target endocrine glands.

c. Pineal hormones:c. Pineal hormones: Melatonin is synthesized in the Melatonin is synthesized in the pineal glandpineal gland

2. ACTH2. ACTH ( (corticotrophincorticotrophin) is found in the limbic ) is found in the limbic system, brain stem, and thalamus and may be system, brain stem, and thalamus and may be important in learning, memory, and attention. important in learning, memory, and attention.

- ACTH regulates the release of ACTH regulates the release of cortisol;cortisol; ACTH ACTH is regulated by the is regulated by the CRF.CRF.

- The levels of both ACTH and cortisol exhibit a The levels of both ACTH and cortisol exhibit a diurnal variation, and cortisol levels peak at diurnal variation, and cortisol levels peak at approximately 7 A.M.approximately 7 A.M.

a. Excess amounts of cortisol are seen in a. Excess amounts of cortisol are seen in Cushing’s syndrome,Cushing’s syndrome, which may be associated which may be associated with depression, mania, hallucinations, with depression, mania, hallucinations, delusions, and delirium.delusions, and delirium.

b. A deficit of cortisol is seen in Addison’s b. A deficit of cortisol is seen in Addison’s disease, disease, which may be accompanied by which may be accompanied by depression, lethargy, and fatigue.depression, lethargy, and fatigue.

c. A subset of patients with endogenous c. A subset of patients with endogenous depression have: depression have:

--- high cortisol levels,--- high cortisol levels,

--- loss of the normal diurnal variation in cortisol --- loss of the normal diurnal variation in cortisol levels,levels,

--- and “early escape” from suppression of cortisol --- and “early escape” from suppression of cortisol secretion following administration of secretion following administration of dexamethasone in the dexamethasone in the dexamethasone dexamethasone suppression test.suppression test.

Some patients with mania, schizoaffective, Some patients with mania, schizoaffective, bulimia, or anorexia nervosa may also exhibit bulimia, or anorexia nervosa may also exhibit these findings. Suppression of cortisol levels these findings. Suppression of cortisol levels during the dexamethasone suppression test, during the dexamethasone suppression test, however, indicate the presence of antidepressant-however, indicate the presence of antidepressant-responsive endogenous depressive illness.responsive endogenous depressive illness.

3. GH3. GH ( (somatotropinsomatotropin) increases protein synthesis, ) increases protein synthesis, decreases the utilization of carbohydrates, and decreases the utilization of carbohydrates, and facilitates the mobilization of fats. facilitates the mobilization of fats.

--- GH secretion and synthesis are controlled by --- GH secretion and synthesis are controlled by GH-RF and GH-release inhibiting factor GH-RF and GH-release inhibiting factor (somatostatin). (somatostatin).

--- GH exhibits a diurnal pattern of --- GH exhibits a diurnal pattern of release, with higher levels secreted release, with higher levels secreted during sleep. during sleep.

a.a. The The somatic effects of GHsomatic effects of GH appear to appear to requirerequire the involvement of a family of the involvement of a family of polypeptides called polypeptides called somatomedins.somatomedins.

b.b. Norepinephrine, dopamine, and Norepinephrine, dopamine, and serotonin alter GH concentrations, and serotonin alter GH concentrations, and stress causes increased release of GH.stress causes increased release of GH.

4. TSH4. TSH ( (thyrotropinthyrotropin) causes the release of the ) causes the release of the thyroid hormones T3 and T4. The release of thyroid hormones T3 and T4. The release of TSH is controlled by TSH is controlled by TRH.TRH.

a.a. TRH is localized in the dorsomedial and TRH is localized in the dorsomedial and periventricular nuclei of the hypothalamus.periventricular nuclei of the hypothalamus.

b.b. TRH is inhibitory to postsynaptic neurons TRH is inhibitory to postsynaptic neurons and, apart from its effects on thyroid function, and, apart from its effects on thyroid function, is involved in is involved in mood and behavior.mood and behavior.

Some patients with major depression show a Some patients with major depression show a blunted TSH response to intravenous infusion blunted TSH response to intravenous infusion of TRH, which suggests hypothalamic-of TRH, which suggests hypothalamic-pituitary dysfunction in major depression.pituitary dysfunction in major depression.

5. LH and FSH5. LH and FSH regulate ovarian follicle regulate ovarian follicle growth, spermatogenesis, and testosterone growth, spermatogenesis, and testosterone secretion. Release of LH and FSH from the secretion. Release of LH and FSH from the anterior pituitary is regulated by GnRH.anterior pituitary is regulated by GnRH.

a.a. GnRH injection in males causes an increase GnRH injection in males causes an increase in sexual arousal, and injections have been in sexual arousal, and injections have been used with some success to treat delayed used with some success to treat delayed puberty.puberty.

b.b. GnRH may function as a neurotransmitter as GnRH may function as a neurotransmitter as well as a hormone, and it may be excitatory or well as a hormone, and it may be excitatory or inhibitory.inhibitory.

6. Prolactin6. Prolactin is controlled by PIF and PRF. is controlled by PIF and PRF.

a.a. Prolactin regulates the activity of the mammary Prolactin regulates the activity of the mammary glands during lactation. Sleep, exercise, pregnancy, glands during lactation. Sleep, exercise, pregnancy, and breast-feeding increase circulatory levels of and breast-feeding increase circulatory levels of prolactin.prolactin.

b. Dopamineb. Dopamine may function physiologically as may function physiologically as PIF.PIF. Most neuroleptic medications block dopamine Most neuroleptic medications block dopamine receptors in the tuberoinfundibular dopamine tract, receptors in the tuberoinfundibular dopamine tract, causing an increase in circulating prolactin and causing an increase in circulating prolactin and therefore inducing beast enlargement and lactation. therefore inducing beast enlargement and lactation. This is a common side effect of neuroleptics in This is a common side effect of neuroleptics in women – which can also occur in men.women – which can also occur in men.

7. Vasopressin and oxytocin7. Vasopressin and oxytocin are formed are formed from larger precursor hormones known as from larger precursor hormones known as neurophysins.neurophysins.

a. Synthesis and releasea. Synthesis and release

They are synthesized in large neurons in the They are synthesized in large neurons in the supraoptic, & paraventricular nuclei of the supraoptic, & paraventricular nuclei of the hypothalamus.hypothalamus.

(1)(1) The neurons from the supraoptic and The neurons from the supraoptic and paraventricular nuclei project to the paraventricular nuclei project to the posterior pituitary, where the hormones are posterior pituitary, where the hormones are released into the circulation.released into the circulation.

(2)(2) The release of vasopressin ( The release of vasopressin (ADH)ADH) is is increased by stress, pain, exercise, and a increased by stress, pain, exercise, and a variety of drugs (e.g., morphine, nicotine, variety of drugs (e.g., morphine, nicotine, barbiturates). Alcohol decreases its barbiturates). Alcohol decreases its release, resulting in diuresis.release, resulting in diuresis.

(3)(3) The release of oxytocin is stimulated by The release of oxytocin is stimulated by estrogens, vaginal and breast stimulation, estrogens, vaginal and breast stimulation, and psychic stress. and psychic stress.

-- Oxytocin release is inhibited by severe -- Oxytocin release is inhibited by severe pain, increased temperature, and loud pain, increased temperature, and loud noise.noise.

b. Effectsb. Effects

(1) Vasopressin(1) Vasopressin is mainly inhibitory and may be is mainly inhibitory and may be important in important in learning, memory,learning, memory, and and attention.attention. Treatment with vasopressin Treatment with vasopressin improves memory in patients with dementia improves memory in patients with dementia and brain damage. and brain damage.

(2) Oxytocin(2) Oxytocin

(a) (a) The The main peripheral effects of oxytocin main peripheral effects of oxytocin include stimulation of the myoepithelial cells include stimulation of the myoepithelial cells lining ducts of the beast – causing lining ducts of the beast – causing expression expression of milkof milk – and inducing – and inducing contraction of uterine contraction of uterine smooth muscles during parturition.smooth muscles during parturition.

(b)(b) Centrally, oxytocin may be an inhibitory Centrally, oxytocin may be an inhibitory neurotransmitter or neuromodulators and may neurotransmitter or neuromodulators and may act in a way opposite to vasopressin in terms act in a way opposite to vasopressin in terms of its effects on memory, actually causing of its effects on memory, actually causing amnesia.amnesia.

8. MSH8. MSH is structurally similar to ACTH. Its is structurally similar to ACTH. Its release is regulated by dopamine and possibly release is regulated by dopamine and possibly by MSH-inhibiting factor and MSH-releasing by MSH-inhibiting factor and MSH-releasing factor.factor.

a.a. MSH is found in the pituitary gland as well as MSH is found in the pituitary gland as well as a number of other brain area, including the a number of other brain area, including the hypothalamus, and cerebral cortex.hypothalamus, and cerebral cortex.

MSH is important in the control of pigmentation MSH is important in the control of pigmentation in animals. It may have a role in learning and in animals. It may have a role in learning and memory. MSH and MSH-inhibiting factor have memory. MSH and MSH-inhibiting factor have both been reported to have antidepressant both been reported to have antidepressant effects.effects.

9. Melatonin9. Melatonin is synthesized from serotonin in the is synthesized from serotonin in the pineal gland.pineal gland.

a. a. Melatonin has important neuroendocrinologic Melatonin has important neuroendocrinologic effects. It is involved in the regulation of effects. It is involved in the regulation of circadian rhythms. Melatonin synthesis is circadian rhythms. Melatonin synthesis is regulated by the day-night or light-dark cycle, regulated by the day-night or light-dark cycle, and levels are increased during darkness.and levels are increased during darkness.

b.b. Because the pineal gland can transform information Because the pineal gland can transform information contained in light into chemical information contained in contained in light into chemical information contained in melatonin, the pineal gland has been called a melatonin, the pineal gland has been called a “neuroendocrine transducer”.“neuroendocrine transducer”.

c.c. Some depressed patients show low nocturnal melatonin Some depressed patients show low nocturnal melatonin levels.levels.

d.d. In In seasonal mood disorder,seasonal mood disorder, affected individuals have affected individuals have regularly occurring seasonal depressions, usually in the regularly occurring seasonal depressions, usually in the fall and winter. Early morning therapy with bright light fall and winter. Early morning therapy with bright light (phototherapy) has shown benefit and may be associated (phototherapy) has shown benefit and may be associated normalization of the so-called dim-light onset of normalization of the so-called dim-light onset of melatonin secretion. The role of melatonin is seasonal melatonin secretion. The role of melatonin is seasonal mood disorder, however, is far from clear.mood disorder, however, is far from clear.

Health & Medicine

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