The basic objectives of this research project remain as they were: 1) to study the mode of action of antipsychotic drugs on dopamine (DA) systems, and 2) to elucidate and charcterize the factors (e.g. neurotransmitters) regulating or modulating DA and non-DA neurons in the midbrain ventral tegmental area (VTA or A10) and the substantia nigra pars compacta (SNC or A9). The goal is to develop new antipsychotic drugs (APDs) with minimum neurological side effects. According to the DA hypothesis of schizophrenia, a hyperactive DA system is responsible for at least some of the symptoms associated with this disease. Recent evidence indicates that the therapeutic actions of APDs may be related to the time-dependent reduction of DA activity in the A10 mesolimbic and mesocortical regions rather than in the A9 nigrostriatal area. The latter may be involved primarily in the extrapyramidal side effects (EPS) and tardice dyskinesia (TD) caused by APDs. Therefore, the ability of potential APDs to reduce activity in A10 and A9 cell groups during chronic administration may serve as a valuable model for predicting clinical and EPS liability, respectively. To test the validity of our model, the chronic effects of several potential new APDs on DA cells will be examined; the results will be compared with clinical studies. Moreover, evidence indicates that the primary sites of action for APDs are on DA receptive neurons. Therefore, studies for elucidating the long-term effects of typical and atypical APDs on DA receptive neurons in the neostriatum and the limbic and cortical regions will be carried out by using electrophysiological, biochemical and behavioral approaches. On the other hand, psychotic abnormalities may reflect dysfunction in the DA neurons themselves and/or in a neuronal system or systems controlling DA activity. Therefore, new APDs and adjunct therapy might be developed by pharmacological manipulation of afferent inputs to identified DA neurons. By using combinations of physiological pharmacological and histochemical techniques, DA and non-DA neurons in the VTA and SNC have been identified. Results to date show that psychotomimetic drugs such as amphetamines and LSD and specific neurotransmitter systems such as DA, norepinephrine, enkephalins have marked effects on the physiological activity of identified DA cells.
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