some controversy……

some controversy……..

some controversy……..

Muscarinic agonists –Muscarine

some controversy……..Muscarinic agonists –Muscarine

Muscarinic antagonistsSynthetic and natural-

• DA – dopamine• NE – norepinephrine• 5HT - serotonin

monoamines

• NE and E are synthesized from their precursor DA with the appropriate enzymes present

catecholamines

tyrosine hydroxylase-rate limiting step

tyrosine hydroxylase

DA decarboxylase

tyrosine hydroxylase

DA decarboxylase

DA β hydroxylase

PNMT

• CNS - reward, movement, motivated behaviors, executive function?

• numerous DA pathways in CNS of importance for psychotropics…..

DA (dopamine)

• DA receptor subtypes– 2 major families – D1 and D2 families

DA receptor subtypes

• In CNS- arousal; role in depression, possible role in spinal analgesia, possible motivated behaviors such as hunger, thirst, sex, anxiety, drug reward?

• NE is in both the CNS and PNS

NE (norepinephrine)

• receptor subtypes– alpha 1 and 2; β 1 – 3

NE receptor subtypes

• Catecholamines removed by reuptake:– DAT – DA transporter– NET – NE transporter

How are catecholamines taken removed from the synapse?

• metabolism –– far slower than ACh by AChE

metabolism

• metabolism –– far slower than ACh by AChE– MAO enzymes (monoamine oxidase)

metabolism

• metabolism –– far slower than ACh by AChE– MAO enzymes (monoamine oxidase)

• MAOA AND MAOB enzymes• MAO A – more selective for NE and 5HT

metabolism

• metabolism –– far slower than ACh by AChE– MAO enzymes (monoamine oxidase)

• MAOA AND MAOB enzymes• MAO A – more selective for NE and 5HT• MAO B- more selective for DA

metabolism

• Major metabolites:– Important when trying to study potential

differences

– DA - dopac and HVA– NE - MHPG -(3-methoxy-4-hydroxy-

phenethyleneglycol)

Tyrosine

Tyrosine hydroxylase (rate limiting step)TH

DOPA

DA-β-hydroxylase

Dopamine (DA)

Norepinephrine (NE) Epinephrine (E)

Aromatic acid decarboxylase

maohomovanillic acid (HVA)

pnmt

catecholamines

MHPGmao

• more recent in our history of studying NT• similarity to LSD• found early in high concentrations in the gut• found in many non neuronal cells (only ~ 1 – 2% of 5HT in

whole body is in brain)• cannot cross bbb so……

5HT

• behavioral role (CNS): sleep, aggressive behavior

• abnormal function implicated in:– schizophrenia, depression, phobic disorders, OCD,

eating disorders, migraine, etc

5HT

• synthesis– amino acid precursor – tryptophan

5HT

• synthesis– amino acid precursor – tryptophan

– elimination of dietary tryptophan can significantly lower brain 5HT levels

5HT

• synthesis– amino acid precursor – tryptophan

– elimination of dietary tryptophan can significantly lower brain 5HT levels

– foods high in tryptophan;• nuts (ie walnuts, almonds), tofu, milk, eggs, certain

cheeses, turkey, seafood, seeds

5HT

• receptor subtypes-many – at least 18 subtypes have been identified

- probably best way to group 5HT1 and 5HT2 families;

- some are metabotropic; some ionotropic

5HT

• reuptake main mechanism for terminating– SSRIs

• breakdown – major metabolite 5HIAA

5HT

• pervasive throughout the brain• classified into 2 general categories

– excitatory (glutamate, aspartate)– inhibitory (GABA, glycine)

• amino acids are more difficult to classify as nt

amino acid neurotransmitters

• first identified in leg of lobster• causes hyperpolarization of neurons• highest concentrations in brain and spinal

cord and virtually absent in peripheral nerve or other organs

• does not cross bbb easily

GABA

• stored in synaptic vesicles (like other nt)• usually removed from synapse via transporter

(GAT)• GABA also found in glia• receptor subtypes:

– GABA A – ionotropic – clinically important– GABA B - metabotropic

GABA

• mediates anxiolytic, sedative, anticonvulsant, muscle-relaxant and amnesic activity

• subunit compositions appear to vary from one brain region to another and even between neurons within a given region

• linked to chloride channel

GABA A

modulatory effects

• found in high concentrations in brain• serves many functions• GAD (enzyme – can convert glutamate to

GABA)

glutamate

• found in high concentrations in brain• serves many functions• GAD (enzyme – can convert glutamate to

GABA)• receptor subtypes:

– tremendous work done in recent years

glutamate

• receptor subtypes:– NMDA, ionotropic, various other receptors

including metabotropic GLU R (mGLUR) – families within these– role of neuromodulators

• current potential interests– reducing neurotoxicity, psychiatric disorders,

substance use disorders, Alzhemiers Disease?

glutamate

memantine

• 2005 – first non AChE inhibitor for treating AD• Only approved for advanced (not early stage)• uncompetitive low-to-moderate affinity

NMDA receptor antagonist• Multiple other uses possible

– acts as a neurotransmitter; also released during immune response; also found in gut

– antihistaminergic effects: • drowsiness, dry mouth, dizziness, sleepiness, upset

stomach, decreased coordination, fatigue, weight gain, dry mouth and throat, upset stomach, fluttery heartbeat, loss of appetite, hives, sleepiness, vision problems

More about histamine

• Overview of nervous system

PNS - peripheral nervous system2 components- autonomic and somatic

1. autonomic nervous system

- “involuntary”- role in emotion and stress- controls smooth muscles, cardiac

muscles and glands

1. Sympathetic NS“fight or flight”activated during emergencies, stress and/or arousal

Autonomic NS has two components

• Maintain homeostasis, energy restoration– physiological changes:

2. Parasympathetic nervous system

• voluntary nervous system– sensory and motor nerves

– connection between all motor nerves and muscle (NMJ – neuromuscular junction) are nicotinic ACh synapses

2nd part of the PNS is the somatic nervous system

• CNS – Central Nervous System– brain, spinal cord

• PNS – Peripheral Nervous System– Somatic, autonomic

2 divisions of the nervous system

• 3 main divisions of brain

– hindbrain; midbrain; forebrain

brain

hindbrain

Medulla

• medulla– Contains part of the reticular formation – (nuclei

involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness)

hindbrainhindbrain

• medulla– Contains part of the reticular formation – (nuclei

involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness) as well as

– Nuclei important for vital functions

hindbrainhindbrain

• medulla– Contains part of the reticular formation – (nuclei

involved in integration of information from senses, attention, arousal, and control of sleep and wakefulness) as well as

– Nuclei important for vital functions

– Various ascending and descending pathways

hindbrainhindbrain

medulla

hindbrain

• pons– Contains part of the reticular formation

• Nuclei important for sleep and arousal

hindbrainhindbrain

• pons– Contains part of the reticular formation

• Nuclei important for sleep and arousal

– Specific nuclei include• Raphe (5HT) – sleep and dreaming• Locus coerulus (NE) - arousal

hindbrainhindbrain

• pons– Contains part of the reticular formation

• Nuclei important for sleep and arousal

– Specific nuclei include• Raphe (5HT) – sleep and dreaming• Locus coerulus (NE) - arousal

• Cerebellum

hindbrainhindbrain

• Sensory information– reticular formation

• movement– substantia nigra -

midbrainmidbrain

• cortical and subcortical structures

forebrain

frontal

parietal

temporal occipital

4 lobes of cerebral cortex

• Frontal– Motor function– Prefrontal – higher “executive function”

4 lobes of cerebral cortex• Frontal

– Motor function• Prefrontal – higher “executive function”

• Parietal– Somatosensory function

• Temporal– Audition– emotion

• Occipital– vision

Prefrontal cortex

Prefrontal cortex

• thalamus

Some subcortical structures

The thalamus communicates with much of the cerebral cortex - serving as a sensory and motor information relay.

• thalamus • hypothalamus

Some subcortical structures

• thalamus • hypothalamus• limbic system

Some subcortical structures

• thalamus • hypothalamus• limbic system• basal ganglia

Some subcortical structures

Some major nt pathways

• Mesolimbic/cortical – – Involved in reward, possible role in schizophrenia

• Projects to nucleus accumbens and parts of the limbic system

• nigrostriatal – – Important in initiation of movement; system that

degenerates in Parkinsons disease• projections from the substantia nigra to the basal ganglia

• tuberofundibular – – Important for hormonal release via hypothalamus and

pituitary gland

3 major DA fiber tracts

Peptides• Opioids

– Mu– Delta– Kappa– Endorphins and

enkephalins are opioids

• Substance P

Neurotransmitters and Receptors