Neurotransmitters

in SchizophreniaDr. Adel El SheshaiProf. Of Psychiatry

F.USC., F.APA., F.EAP.

Objectives:

• Neurotransmitters in Schizophrenia– Dopamine– Glutamate– Serotonin

• The Role of Dopamine in the Phenomenology of Schizophrenia.

• Atypicality of Antipsychotics.

1 - DOPAMINE

Dopaminergic Pathways in the Brain

Caudate Nucleus

Putamen

Striatum

Substantia Nigra Pars Compacta

NigroStriatal Pathway

I - Nigrostriatal Pathway :I - Nigrostriatal Pathway :

It is a part of extrapyramidal system involved in cognitive integration, habituation, sensory-motor coordination and initiation of movement.

Dopaminergic Pathways in the Brain

Limbic System

Ventral Tegmental

Area

Mesolimbic Pathway

II - Mesolimbic Pathway :II - Mesolimbic Pathway :

Involved in pleasure, reward and reinforcing behavior and many drug of abuse interact here. Its over-activity lead to production of positive symptoms.

Nucleus Accambans

Ventral Striatum

Amygdala Putamen

Dopaminergic Pathways in the BrainCorte

x

MesoCortical Pathway

III - MesoCortical Pathway :III - MesoCortical Pathway :

Is involved in motivation and attention. Mediates the negative and cognitive symptoms of psychosis due to its hypoactivity.

Dorso Lat. Pre Frontal Cx

Cingulate Cortex

Medial Pre Frontal Cortex

Orbito Frontal Cortex

Ventral Tegmental

Area

Dopaminergic Pathways in the Brain

IV - Tubero infandibular Pathway :IV - Tubero infandibular Pathway :

Where Dopamine is responsible of inhibition of the release of prolactin.

Dopamine receptors :• D1- like receptors family :

– D1 receptors has a wide spread neocortical distribution including the PFC, and also in the striatum.

– D5 receptors are concentrated in the Hippocampus and entorhinal cortex.

• D2- like receptors family : – D2 receptors are concentrated in the striatum, with low densities in

medial temporal structures (Hippocampus, entorhinal cortex, amygdala) and thalamus. The density of the D2 in the PFC is extremely low.

– D3 receptors are present in the striatum more in ventral part.

– D4 receptors are present in the PFC and Hippocampus, but not in the striatum

Dopaminergic receptors

• The action of DA on target neurons should not be viewed in terms of simple excitation or inhibition ... but stimulation of DA G-protein linked receptors induce a cascade of intracellular signaling that results in modifying the response of the cells to OTHER neurotransmitters.

• Thus DA is not “inhibitory” nor excitatory, but its action will depend on the state of the neurons at the time of stimulation.

2 - Glutamate

• Glutamate the major excitatory transmitter in the CNS may be at least as important as DA in the pathophysiology of Schizophrenia

NMDA receptor antagonists and experimental psychosis

• The first psychotomimetic to be evaluated was phencyclidine (PCP) , it can induce the clinical picture of schizophrenia in normal individuals and exacerbate that of schizophrenics.

• PCP was subsequently demonstrated to be an antagonist to the NMDA glutamate receptor.

• Since then, other NMDA receptor antagonists such as ketamine have also been shown to induce experimental psychosis.

NMDA receptor antagonists and experimental psychosis

• Ketamine administration usually exacerbates an individual’s symptom profile . Because Ketamine alter neuronal firing in limbic gray matter regions (hippocampus and anterior cingulate), this is probably mediated by alterations in the activity of the limbic system.

• This implies that glutamate may modulate the expression of psychosis.

Cortico-Thalamo-Cortical loops

(Cortex - B.G. - Thalamus)

CortexNM

DA

D1

D2

Striatum

Thalamus

Pars Compacta

Internal Part of G.P. Sub Thalamic N.

Pars Reticulata

Glutamate

GABA

Dopamine

Su

b. N

ig

Cortico-Thalamo-Cortical Pathways

These loops have been further classified into :

1- Limbic loops :

2- Associative loops :

3- Motor Loops :

The Limbic loops

Medial prefrontal, and orbitofrontal Cortex

Ventral Striatum

Medio dorsal thalamic nuclei

Ventral pallidum

The associative loops

Dorsolateral prefrontal Cortex

Ventral Striatum

Ventral anterior thalamic nuclei

Internal part G.P. / SN reticulata

The Motor loops

Premotor and motor Cortex

Putamen and body of caudate

Ventral anterior thalamic nuclei

Internal part G.P. / SN reticulata

The GABAergic filter

ThalamusCortex NMDA

D1

D2

Striatum

Pars Compacta

Internal Part of Globus Palidus

Sub Thalamic Nucleii

Pars Reticulata

Glutamate

GABA

Dopamine

GlutamatGlutamatee

DADA

GABAergic filter

Glutamate from Glutamate from cortexcortex

DA from brain stemDA from brain stem

Signal

Noise

Noise

Noise

Noise

SignalCortex

Thalamus

Both an elevation of DA function in striatum or a decrease in glutamate function (PCP) would lead to relief of striatal inhibition of the thalamus and opening the filter leading to cortical overload (psychosis)

Both an elevation of DA function in striatum or a decrease in glutamate function (PCP) would lead to relief of striatal inhibition of the thalamus and opening the filter leading to cortical overload (psychosis)

GABAergic filter

Normally

Glutamate from Glutamate from cortexcortex

DA from brain stemDA from brain stem

Signal

Noise

Noise

Noise

Noise

SignalCortex

Thalamus

In Schizophrenia, a hypoactivity in glutamate function will lead to relief of striatal inhibition of the thalamus and opening the filter leading to cortical overload (psychosis)

In Schizophrenia, a hypoactivity in glutamate function will lead to relief of striatal inhibition of the thalamus and opening the filter leading to cortical overload (psychosis)

Sign

alNoise

Noise

Noise

Noise

Noi

se

In Schizophrenia

• Evidence:-– In post mortum studies of schizophrenics:

• NMDA receptors were less in number than normal.

• NMDA receptors showed functional abnormalities, although the NMDA coding gene was apparently normal.

• A future challenge :-– To develop a partial agonist on NMDA

glutamate receptors such as : D-serine and D-cycloserine. They are currently used as augmentation for novel antipsychotics.

3 - SEROTONIN

• Interest in 5HT in the pathophysiology of Schizophrenia has been stimulated largely by the observation that many atypical antipsychotic drugs also bind with high affinity to certain Serotonin receptors

Serotonin receptors in Schizophrenia:

• 5 HT 2A :– Concomitant blokade of 5 HT2A and D2

receptors may cause a relative stimulation of mesocortical dopamine pathway with respect to the Nigrostriatal pathway and mesolimbic pathways. Which explains why atypical antipsychotics effects at doses which do not produce Extrapyramidal side effects.

Serotonin receptors in Schizophrenia:

• 5 HT 2C :– 5HT2c receptor is present in both cell bodies and terminal fields of

dopaminergic neurons of nigrostriatal and mesolimbic systems.

– It exerts a tonic and phasic facilitatory control on basal DA efflux in the striatum, where in the VTA this receptor subtype appear to mediate the tonic inhibitory serotonergic tone on DA neurons.

• 5 HT 1A :– This receptor subtype can be considered as functionally

antagonistic to 5HT2A, both at the presynaptic and post synaptic levels .

Atypicality of antipsychotics

1) The role of serotonin receptor occupancy

2) D2 receptor-affinity3) Regional specificity

Atypicality of antipsychotics

1) The role of serotonin receptor occupancy:

Theory :Generally Serotonin inhibit the Dopamine

release both at the level of DA cell bodies and axon terminals.

A) In the Mesolimbic pathway:

• Serotonin 2A antagonism fortunately fails to reverse D2 antagonism in mesolimbic system.

B) In the nigrostriatal pathway :• When DA release is enhanced by an

atypical antipsychotic via blockade of 5HT2A, this allow extra dopamine to compete with atypical antipsychotic to reverse blockade of D2 ... Leading to fewer EPS.

C) In the Mesocortical pathway :• There is preponderance of 5HT2A receptors

over D2 receptors in many parts of cerebral cortex.

• Thus in mesocortical DA pathway, atypical antipsychotics with Serotonin-Dopamine-Antagonistic properties have a more profound effect in blocking densely populated cortical 5HT2A receptors, hence stimulating the pathway, and improving negative symptoms.

D) In the Tuberoinfundibular pathway:

• Dopamine inhibit prolactine release by stimulating D2 receptors while serotonin promotes prolactin release by stimulating 5HT2A receptors, hence less Hyperprolactinemia with novel antipsychotics.

Novel Antipsychotics

5HT2A

D2

Mesocortical pathway

D2

Nigrostriatal pathway

5HT2C D2

MesoLimbic pathway

Blockade of 5HT2A lead to stimulation of DA, so less inhibition of the pathway

Improve negative symptoms

Improve positive symptoms

Less EPS

Stimulates DA release by blockade of the more prevalent 5HT2A

Blockade of 5HT2c does not lead to

stimulation of DA, so the net result is

inhibition of the pathway

5HT2A

Block both 5HT and DA receptors

2) D2 receptor-affinity:• The hypothesis that can account for

atypicity is ; faster dissociation rate “K-off” from D2 receptors, which results in a lower overall affinity for D2 receptors.

Minimal EPS or prolactin elevation, decreased cognitive impairment, and perhaps greater improvement of secondary negative symptoms

3) Regional Specificity:• Recent reports suggest that atypical

antipsychotics show a preferential blockade of the cortical D2 receptors as opposed to striatal D2 receptors, whereas haloperidol shows equal occupancies in the 2 regions.

The Role of Dopamine in the phenomenology of Schizophrenia

I) The Dopamine Hypothesis.II) Prefrontal DA cortical dysfunction.

I ) The Dopamine Hypothesis in Schizophrenia (3 Versions)

1st Version :

• Proposed that DA levels were increased in patients with schizophrenia but efforts were not confirmatory of increased DA levels, turnover or metabolism by measuring DA and metabolites in peripheral fluids. e.g. : blood, urine, CSF

2nd Version :

• There might be increased number of DA receptors in the striatum, primarily D2 receptors, the target of antipsychotics. But the majority of studies of D2 receptors ligand binding both in post mortum tissue and in vivo with PET found no evidence of increased abundance of D2 receptors.

3rd Version : • DA neuronal activity might be abnormal as a

downstream effect of a primary cortical abnormality.• Proof:-

– Decreased prefrontal cortical DA activity has been found in imaging studies of living subjects and decreased prefrontal DA enervation has been observed in post mortum tissue.

– Diminished prefrontal DA signaling is one of the factors that lead to a downstream upregulation of striatal DA activity.

II ) Prefrontal DA cortical dysfunction

Prefrontal Cortex is involved in :-• Context updating• Inhibition of reflexive drive

directed behavior• Planning• Decision making• Motivation and emotion• Rule detection

• One of the functions of the frontal lobes is to find regularities in whatever input patterns arrive from lower level cortical areas.

• However if something unexpected happens, it may be dangerous (Negative) or rewarding (positive).

• These two types of evaluations are performed by different brain systems.

• Negative aspects of incoming information are quickly relayed to the Amygdala where they are associated with fear and anxiety (fight, flight and fright).

• Whenever something happens that is better than expected then the Dopaminergic reward system becomes activated

Frontal Cortex

Input patterns arrive from lower cortical areas

Positive Negative

AmygdalaReward system

Fight, Flight, Fright

If signal was Unexpected

Detects regularities in the input signal

(Good event) (Bad event)

DA function

• The Dopaminergic neurons signal the importance and rewordness of the stimulus regardless of its nature.

• All organisms are bombarded with a large number of stimuli and have to sort out the few that are important from the many that are unimportant. The Dopamine system is thus the signal that become attached to the stimuli when the “sorting out” function is applied.

Dopamine, reward and salience :-

• Salience :-– A process in which the events and thoughts come to grab

attention, drive action and influence goal directed behavior due to their association with reword or punishment.

– The mesolimbic DA system is a critical component in the attribution of Salience.

• In schizophrenia, the DA system is dysfunctional in that it is no longer appropriately fine tuned, becoming either hyperactive in the acute phase of the illness or hypoactive during more chronic states.

Dopamine, reward and salience :-

• Aberrant salience experiences (Noises) reaching the cortex are cognitively explained in the form of delusions.

• Since delusions are constructed by the individual they are colored by the psychodynamic themes relevant to the individual and his cultural background.

• This explains how the same neurochemical dysregulation lead to variable phenomenological expression.

In acute phase : Delusions :-

• A hyperactive DA system no longer produces much (or any) meaningful experience. Even stimuli which are normally meaningful and worth further consideration, such as social interactions become uninteresting and boring and hence don’t capture cognitive resources.

• This process could be the biological correlate of certain of the core negative symptoms of schizophrenia such as blunted affect and social withdrawal.

In the chronic state :-

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