EFFECTS OF CHRONIC NEUROLEPTIC TREATMENT ON DOPAMINE RELEASE - INSIGHTS FROM STUDIES USING 3-METHOXYTYRAMINE

Antipsychotic medications appear to exert their therapeutic effects by blocking D2 receptors. While D2 blockade occurs rapidly, reduction in psychotic symptoms is often delayed. This time discrepancy has been a ttributed to the relatively slow development of depolarization inactiv ation (DI) of dopaminergic neurons. The reduced firing rates associate d with DI has been hypothesized to reduce dopamine release and thus ps ychotic symptoms. Studies assessing changes in dopamine release during chronic neuroleptic treatment, using microdialysis and voltammetry, h ave been inconsistent. This may be due to methodological differences b etween studies, the invasive nature of these procedures, or other conf ounds. To investigate the effects of DI on dopamine release: 3-MT accu mulation, an index of dopamine release that does not involve disruptio n of brain tissue: was measured during acute and chronic neuroleptic t reatment. These results are compared with those using other techniques . 3-MT levels remained elevated after chronic treatment: suggesting th at DI does not markedly reduce release. Regulation of dopamine release during DI was examined using two techniques known to block dopamine n euronal impulse flow. 3-MT levels were markedly reduced by both, imply ing that DI does not alter the portion of dopamine release mediated by neuronal impulse flow. Overall, studies to date suggest that the dela yed therapeutic effects of neuroleptics are not due to reductions in i mpulse dependent dopamine release. Recent studies using a neurodevelop mental animal model of schizophrenia have pointed to altered pre- and post-synaptic indices of dopamine neurotransmission. The results sugge st that neuroleptics may exert their therapeutic effects, in part, by limiting the fluctuations in dopamine release, and raise new issues fo r future research.