LIMBIC CIRCUITS AND MONOAMINE RECEPTORS - DISSECTING THE EFFECTS OF ANTIPSYCHOTICS FROM DISEASE PROCESSES

There is considerable evidence for the involvement of brain dopaminerg ic and serotonergic systems in schizophrenia pathology. However, post- mortem studies have been limited by difficulties in separating the eff ects of chronic exposure to antipsychotics from that of the disease pr ocess. Our recent studies directly explored this by comparing groups t hat were free from antipsychotic treatment for up to a year prior to d eath and that were maintained on antipsychotics. We have used this app roach to identify that there are prominent effects of both disease and of antipsychotic treatment. There appears to be a high association fo r schizophrenics between elevations of D3 receptors in target regions of the mesolimbic dopamine (DA) system and elevated numbers of 5-HT1A receptors in prefrontal cortex (PFc). Antipsychotic treatment was corr elated with a reduction of D3 receptors in the ventral striatum and it s output structures. II also led to a reduction in the number of 5-HT2 receptors in some regions of the PFc without modifying the concentrat ion of 5-HT1A receptors. The limbic loop interconnecting the PFc and v entral striatum may be the site of antipsychotic regulation of certain symptoms in schizophrenia, particularly anhedonia and depression. The positive symptoms of schizophrenia are more likely to be associated w ith disturbances in the temporal lobe. However, dopaminergic systems i n the temporal lobe have historically been thought to be underdevelope d compared to that in the basal ganglia and unlikely to be the target of antipsychotics. Our studies of the expression of the DA D2 receptor in the temporal lobe has shown a complex organization in the perirhin al and temporal cortices that is disrupted in schizophrenia. The distu rbances, which might be of neurodevelopmental origin and are unrelated to antipsychotic treatment, include altered laminar distribution of t he D2 receptor and modified modular organization of D2 receptors in th e superior temporal gyrus. We hypothesize that modified expression of D2 receptors in these regions play a key role in the genesis of halluc inations. Treatment with antipsychotics leading to D2 receptor blockad e in temporal cortex may reduce the presence of positive symptoms. (C) 1997 Elsevier Science Ltd.