Differential Effects of Classical and Atypical Antipsychotic Drugs on A9 and A10 Dopamine Neurons

Abstract

Prolonged treatment with classical antipsychotic drugs decreased the number of spontaneously active dopamine neurons in both the substantia nigra (A9) and the ventral tegmental area (A10) of the rat brain. In contrast, treatment with atypical antipsychotic drugs selectively decreased the number of A10 dopamine neurons. Related drugs lacking antipsychotic efficacy failed to decrease dopamine activity. These findings suggest that the inability of atypical antipsychotic drugs to decrease A9 dopamine neuronal activity may be related to their lower potential for causing tardive dyskinesia and that the inactivation of A10 neurons may be involved in the delayed onset of therapeutic effects during treatment.

Tyrosine Augments Acute Clozapine- but not Haloperidol-Induced Dopamine Release in the Medial Prefrontal Cortex of the Rat An in vivo Microdialysis Study

“…The atypical and clinically superior antipsychotic drug, clozapine, has already been demonstrated to preferentially release DA in the prefrontal cortex of the rat (Moghaddam and Bunney 1990; Pehek and Yamamoto 1994;Yamamoto and Cooperman 1995) as well as of the non-human primate (Youngren et al 1999) and to preferentially activate DA neurons projecting to cortical regions (White and Wang 1983;Goldstein et al 1993). Accordingly, we postulated that the co-administration of tyrosine and clozapine would potentiate MPFC DA synthesis.…”

“…Intriguingly, in rats pretreated with FG-7142, a beta-carboline known to preferentially increase MPFC synthesis, utilization and release Roth 1985, 1990;Bradberry et al 1991), administration of tyrosine robustly enhances MPFC DA synthesis (Tam et al 1990). We postulated that such precursor dependence would also be established by other drugs which activate mesocortical dopaminergic activity.The atypical and clinically superior antipsychotic drug, clozapine, has already been demonstrated to preferentially release DA in the prefrontal cortex of the rat (Moghaddam and Bunney 1990; Pehek and Yamamoto 1994;Yamamoto and Cooperman 1995) as well as of the non-human primate (Youngren et al 1999) and to preferentially activate DA neurons projecting to cortical regions (White and Wang 1983;Goldstein et al 1993). Accordingly, we postulated that the co-administration of tyrosine and clozapine would potentiate MPFC DA synthesis.…”

“…Such data suggested that whereas precursor dependence was not a constant feature of mesocortical DA neurons, their high basal electrophysiological activity notwithstanding, precursor dependence did become evident when these DA neurons were activated above baseline levels. The typical antipsychotic drug, haloperidol, increases the firing rate of DA neurons originating in regions A9 and A10 (Bunney and Grace 1978; White and Wang 1983) whereas clozapine may preferentially activate DA neurons originating in A10 (White and Wang 1983;Goldstein et al 1993, but see also Chiodo and Bunney 1983). Terminal DA release within the striatum at least, is impulse dependent (Gonon and Buda 1985).…”

Effects of Atypical Antipsychotic Drug Treatment on Amphetamine-Induced Striatal Dopamine Release in Patients with Psychotic Disorders

“…Preclinical models have focused on striatal dopamine systems to account for the favorable EPS profile (Chiodo 1988). Both atypical and typical neuroleptics inhibit firing rates of ventral tegmental area (VTA) neurons (i.e., A-10 neurons) that innervate limbic and cortical regions (Skarsfeldt 1992;Stockton and Rasmussen 1996a;Chiodo andBunney 1983, 1985;White and Wang 1983;Chiodo 1988), an action hypothesized to account for antipsychotic efficacy (Bunney 1992). In contrast, typical but not atypical agents inhibit firing rates of substantia nigra pars compacta (SNC) dopamine neurons (i.e., A-9 neurons) that innervate dorsal striatum, and action suggested to account for the differential EPS profile of these agents (Chiodo andBunney 1983, 1985;White and Wang 1983;Chiodo 1988).…”

“…Both atypical and typical neuroleptics inhibit firing rates of ventral tegmental area (VTA) neurons (i.e., A-10 neurons) that innervate limbic and cortical regions (Skarsfeldt 1992;Stockton and Rasmussen 1996a;Chiodo andBunney 1983, 1985;White and Wang 1983;Chiodo 1988), an action hypothesized to account for antipsychotic efficacy (Bunney 1992). In contrast, typical but not atypical agents inhibit firing rates of substantia nigra pars compacta (SNC) dopamine neurons (i.e., A-9 neurons) that innervate dorsal striatum, and action suggested to account for the differential EPS profile of these agents (Chiodo andBunney 1983, 1985;White and Wang 1983;Chiodo 1988). Also, traditional antipsychotics induce greater early gene expres-sion (i.e., C-FOS) is dorsal striatum than atypical drugs which is suggestive of differential EPS effects (Deutch et al 1992;Nguyen et al 1992;Robertson and Fibiger 1992).…”