Schizophrenia Integrated Dopamine Hypothesis

may be involved in sleep & arousal

mechanisms

function underinvestigation

arises out of multiple sites:periaqueductal gray matter,

ventral mesencephalon, hypothalamic nuclei & lateral

parabrachial nucleus

thalamic dopaminepathway

untreated schizophrenia =

preserved function of this pathway

causing galactorrhea ,amenorrhea & sexual

dysfunction

blockade of D2 receptors by

antipsychotics = elevated prolactin

levels to the anterior

pituitary

from dopaminergic cell bodies ( locatedin the hypothalamus)

tuberoinfundibular dopamine pathway

chronic blockade of D2 receptors =

neuroleptic -inducedtardive dyskinesia

chorea, dyskinesias & tics

hyperactivity =hyperkinetic

movement disorders

parkinsonismw /tremor, rigidity &

akinesia /bradykinesia

hypoactivity = movement disorders

to basal ganglia orstriatum

from dopaminergic cell bodies (located

in substantia nigra of brainstem)

nigrostriatal dopamine pathway

hypoactivity = negative & affectivesymptoms

ventromedial prefrontal cortex

hypoactivity = negative & cognitivesymptoms

dorsolateral prefrontal cortex

to areas of prefrontal cortex

from dopaminergic cell bodies (located

in ventral tegmental area of brainstem)

mesocortical dopamine pathway

mesocorticaldopaminehypothesis

possibly why higher use of nicotine &

substance abuse ofstimulants

possible role inaggressive/hostile

symptoms

delusions &hallucinations

hypoactive = negative symptoms

& malfunctioning reward systems

hyperactivity = positive psychotic

symptoms to axon terminals

(located in nucleusaccumbens in the

ventral striatum of limbic system)

from dopaminergic cell bodies (located

in ventral tegmental area of brainstem)

mesolimbic dopamine pathway

mesolimbicdopaminehypothesis

IntegreatedDopamineHypothesis

Schizophrenia

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Schizophrenia NMDA Receptor Hypofunction Hypothesis

Corticothalamic Glutamate Pathways

cortical manifestations of hallucinations as well as

cognitive, affective & negative symptoms of

schizophrenia

excess sensory information overwhelms

cortex

thalamic sensory filterfails

add in excessive dopamine drive from

mesolimbic neurons

reduced excitatory driveon GABA neurons that

create thalamic sensoryfilter

NMDA receptorhypofunction in

descending corticostriatal glutamate pathway

abnormal functioning =

thalamocortical glutamate pathways

project limited sensory information back tocortex

where GABA creates sensory filter projecting to thalamus terminating on GABA

neurons to striatum or nucleus

accumbens

descending from pyramidal neurons in

lamina 5

corticostriatal glutamatepathways

behavioral and functional outputs are appropriate

limited sensory information delivered

back to cortex

thalamic sensory filtercreated normal functioning =

Cortico -Striatal -Thalamic -Cortical ( CSTC ) Loop

malfunctioning glutamate input from one

glutamatergic pyramidal cell to

another (within thecortex)

NMDA receptorhypofunction

OFC to DLPFC

partialhyperactivation &

partialhypoactivation

VMPFC to OFChyperactivation of entire loop

DLPFC to VMPFChypoactivation of entire loop

abnormal functioning =

communication between pyramidal neurons within the

cortex via glutamate

Corticocortical Glutamate Pathways

NMDA hypofunction may cause sensory

overload

represents some of sensory input via glutamate neurons

to the thalamus

provides sensory & other types of input

projects directly tothalamus

from lamina 6 (located in cortex)

causing cognitive, negative & affective

symptoms ofpsychosis

mesocortical dopamine pathway

becomes hypoactive

tonic excitation islost

NMDA receptorshypoactive abnormal function =

This pathway acts as an accelerator on

mesocortical dopamine pathway

mesocortical dopamine pathway

functioningpreserved

tonic excitation ofmesocortical

dopamine neurons normal function =NMDA receptors

located within pathway that

communicate directly with

mesocorticaldopamine neurons

NMDA receptors located within pathway that communicate with

mesolimbicdopamine neurons

via GABAinterneuron

to brainstemneurotransmitter

centers ( raphe ,locus coeruleus ,

ventral tegmental area & substantia

nigra)

causing positive symptoms of

psychosis

mesolimbic dopamine pathway

becomeshyperactive

tonic inhibition ofmesolimbic pathway

does not occur

NMDA receptorhypoactive abnormal function =

this pathway acts as a brake on mesolimbic

dopamine pathway

mesolimbic dopamine pathway function

preserved

GABA inhibits release of dopamine from

mesolimbic dopaminepathway

GABA released (aninterneuron in ventral

tegmental area)

excitatoryglutamate

stimulates NMDAreceptors

normal function =

from cortical pyramidal neurons

(mostly located in the lamina)

Corticobrainstem Glutamate Pathways

NMDA ReceptorHypofunction

Hypothesis(Glutamate)

Schizophrenia

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