The Possible Future Role of a Serotonergic Crug in the Treatment of Schizophrenia: The Effects of a 5-HT6 Antagonist (PNU-33696A) on Local Cerebral Glucose Utilizaiton
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Drug therapy for schizophrenia is problematic in that side effects are unavoidable. Typical antipsychotic drugs such as haloperidol enervate into the extrapyramidal region of the brain, causing extrapyramidal side effects (EPS), similar to symptoms of Parkinson's disease. Atypical drugs such as clozapine cause agranulocytosis, a major breakdown of the immune system. Many theories of causation have been proposed in order to suggest mechanisms of therapy, including the "dopamine hypothesis," which states that schizophrenia is a result of altered dopamine levels in the brain. Recent research show that other neurotransmitters may play a role in schizophrenia. In this study 5- hydroxytryptamine's (5-HT or serotonin) role in schizophrenia is investigated, in particular at the 5-HT6 receptor. PNU-33696A is the first selective 5-HT6 antagonist and was the focus of this study. The [14C]-2-deoxyglucose (2-DG) autoradiography procedure of Sokoloff et ala (1977) was used to evaluate the effects of PNU-33696A on amphetamine- and haloperidol-treated rats. The resulting local cerebral glucose utilization (LCGU) values showed a loss of amphetamine's effect when treated with PNU-33696A in the cortical, limbic, and brainstem areas. No effect was seen in the extrapyramidal regions. Together these results suggest that PNU-33696A may be effective in treating the symptoms of schizophrenia while not affecting the extrapyramidal regions, decreasing the chance of causing EPS. There was also an indication that serotonin may somehow modulate the activity of dopamine.