Dopaminergic neurons in the brain are thought to play an important role in the etiology of schizophrenia. The chronic intake of amphetamine, a dopamine releasing drug, can produce clinical symptoms similar to paranoid schizophrenia, whereas the drugs that are used therapeutically to alleviate the symptoms of schizophrenia are predominantly dopamine receptor blockers. These observations imply that schizophrenia or at least some of the symptoms of this disorder are due to an excess of dopamine in certain areas of the brain. Three major dopaminergic neuronal systems have been described in the brain that may be related to the disorder of schizophrenia; the mesocortical system, the mesolimbic system and the nigrostriatal system. The studies outlined in this proposal will evaluate and compare the regulation of dopamine release from tissue minces and synaptosomes obtained from these three areas of the rat brain. The areas of the brain that will be examined include the dopaminergic nerve terminal regions; the olfactory tubercle (mesolimbic), prefrontal cortex (mesocortical) and striatum (nigrostriatal), and the cell body regions that project to one or more of these areas; the ventral tegmental area (mesocortical and mesolimbic areas) and the substantia nigra (nigrostriatal). Initial studies will be performed to characterize the basal and potassium stimulated release of endogenous dopamine form these brain areas. Then experiments will be performed to evaluate the presynaptic autoreceptor regulation of dopamine release in these five brain regions by performing dose response curves with the D2 selective dopamine agonists, pergolide and quinpirole; the D1 selective dopamine agonist SKF 38393; the non- selective dopamine antagonist, haloperidol; the D2 selective agonists, sulpiride, the D1 selective antagonist, Schering 23390 and the dopamine releasing drug, d-amphetamine. A second series of studies will evaluate the effects of chronic drug treatments on dopamine release from the five brain areas. The drugs that will be administered chronically include, the direct acting dopamine agonists, pergolide (D2), SKF 38393 (D1) and apomorphine (D1,D2); the nonselective dopamine antagonist haloperidol, the D2 selective antagonist sulpride, the D1 selective antagonist Schering 23390 and the dopamine releasing drug, amphetamine. Following the chronic administration of these compounds the autoreceptor regulation of the release of endogenous dopamine in the five dopaminergic brain regions will be evaluated. Evaluating the autoreceptor control of dopamine release in selective areas of the brain should expand our knowledge on the possible biochemical dysfunctions and treatments of the disorder schizophrenia.
| Huettl, P; Gerhardt, G A; Browning, M D et al. (1991) Effects of dopamine receptor agonists and antagonists on catecholamine release in bovine chromaffin cells. J Pharmacol Exp Ther 257:567-74 |
