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  • Neurotransmitters in SchizophreniaDr. Adel El SheshaiProf. Of PsychiatryF.USC., F.APA., F.EAP.

  • Objectives:Neurotransmitters in SchizophreniaDopamineGlutamateSerotoninThe Role of Dopamine in the Phenomenology of Schizophrenia.Atypicality of Antipsychotics.

  • 1 - DOPAMINE

  • Dopaminergic Pathways in the BrainCaudate NucleusPutamenStriatumSubstantia Nigra Pars CompactaNigroStriatal PathwayI - 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 BrainLimbic SystemVentral Tegmental AreaMesolimbic PathwayII - 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 AccambansVentral StriatumAmygdalaPutamen

  • Dopaminergic Pathways in the BrainCortexMesoCortical PathwayIII - MesoCortical Pathway : Is involved in motivation and attention. Mediates the negative and cognitive symptoms of psychosis due to its hypoactivity.Dorso Lat. Pre Frontal CxCingulate CortexMedial Pre Frontal CortexOrbito Frontal CortexVentral Tegmental Area

  • Dopaminergic Pathways in the BrainIV - 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 receptorsThe 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 psychosisThe 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 psychosisKetamine administration usually exacerbates an individuals 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)CortexNMDAD1D2StriatumThalamusPars Compacta Internal Part of G.P.Sub Thalamic N.Pars ReticulataGlutamateGABADopamineSub. Nig

  • Cortico-Thalamo-Cortical PathwaysThese loops have been further classified into :1- Limbic loops : 2- Associative loops :3- Motor Loops :

  • The Limbic loopsMedial prefrontal, and orbitofrontal CortexVentral StriatumMedio dorsal thalamic nuclei Ventral pallidum

  • The associative loopsDorsolateral prefrontal CortexVentral StriatumVentral anterior thalamic nuclei Internal part G.P. / SN reticulata

  • The Motor loopsPremotor and motor CortexPutamen and body of caudateVentral anterior thalamic nuclei Internal part G.P. / SN reticulata

  • The GABAergic filterThalamusCortexNMDAD1D2StriatumPars CompactaInternal Part of Globus PalidusSub Thalamic NucleiiPars ReticulataGlutamateGABADopamineGABAergic filter

  • Glutamate from cortexDA from brain stemSignalSignalCortexThalamus 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 filterNormally

  • Glutamate from cortexDA from brain stemSignalSignalCortexThalamus 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)SignalNoiseIn 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 antipsychotics1) The role of serotonin receptor occupancy2) D2 receptor-affinity3) Regional specificity

  • Atypicality of antipsychotics1) 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 Antipsychotics5HT2AD2Mesocortical pathwayD2Nigrostriatal pathway5HT2CD2MesoLimbic pathwayBlockade of 5HT2A lead to stimulation of DA, so less inhibition of the pathwayImprove negative symptomsImprove positive symptomsLess EPSStimulates DA release by blockade of the more prevalent 5HT2ABlockade of 5HT2c does not lead to stimulation of DA, so the net result is inhibition of the pathway5HT2ABlock 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 SchizophreniaI) The Dopamine Hypothesis.II) Prefrontal DA cortical dysfunction.

  • I ) The Dopamine Hypothesis in Schizophrenia (3 Versions)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, CSF1st Version :

  • 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 de