Dopaminergic dysfunction has long been implicated in the pathophysiology of schizophrenia, although its precise role is unclear. Normal brain maturational processes occurring during adolescence, including those involving dopamine (DA) and related systems, have led researchers to hypothesize how such processes and/or disruptions of such processes may be related to the typical age of schizophrenia onset.
Dopamine (DA)-Related Systems Implicated in Schizophrenia
Accumulating findings implicating the involvement of numerous brain regions and other neurotransmitter systems in schizophrenia have led researchers to expand their scope of inquiry to other systems that may also interact with DA, such as the glutamate system and the hypothalamic-pituitary-adrenal (HPA) axis. Several findings suggest that glutamate dysfunction has been strongly implicated in schizophrenia. When administrating antagonists of the yV-methyl-D-aspartate (NMDA) receptor subtype of glutamate such as phencyclidine (PCP) or ketamine to stabilized patients, idiosyncratic schizophrenia symptoms will reemerge. MDA receptor antagonists are thought to produce effects that more closely mimic the symptoms of schizophrenia than DA agonists. Moreover, clinical trials suggest that agents that facilitate glutamate transmission at the NMDA receptor may modestly improve negative and possibly cognitive symptoms of schizophrenia in patients also receiving antipsychotic medication.
The Prefrontal Cortex (PFC) and Mesocortical DA activity in Schizophrenia
Dysfunction of the prefrontal cortex (PFC) is a central feature of many psychiatric disorders. Cytoarchitectural abnormalities of the PFC also have been demonstrated in patients with schizophrenia, including lower PFC levels of the presynaptic marker synaptophysin. DA actions in the PFC are complex. DA projections from the ventral tegmental area (VTA) interact with both the glutamatergic pyramidal cells and local GABAergic interneurons of the PFC. Research suggests that DA modulates pyramidal cell excitability via direct actions on pyramidal neurons and indirectly via interneurons. For example, experimentally reducing DA input to the PFC or injecting a D1 antagonist into the PFC results in decreased working memory performance in nonhuman primates.
Numerous findings have also suggested that prefrontal DA may play a role in regulating subcortical DA activity. In rats, chemical lesions of mesoprefrontal DA terminals enhanced responsivity of the subcortical DA system as assessed both behaviorally and biochemically in the striatal region, including the nucleus accumbens. Furthermore, enhancing monoaminergic activity in the PFC via DA agonists was found to reduce subcortical DA release.
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