Effects of the dopamine release inhibitor, CGS 10746B, on the locomotor stimulant and discriminative stimulus effects of cocaine and methamphetamine.

CGS 10746B or 5-(4-methyl-1 piperazinyl)-imadazo[2,1-b]1,3,5]benzothiadiazepine maleate is a clozapine analog that, unlike clozapine, produces decreases in neostriatal dopamine release without changing dopamine metabolism or occupying D2 receptors. CGS 10746B also blocks neuronal impulse flow. The ability of this atypical antipsychotic candidate to alter the discriminative stimulus effects induced by cocaine or methamphetamine in rats or the stimulation of locomotor activity in mice was evaluated. A range of doses of CGS 10746B was tested against maximally effective doses of the psychomotor stimulants. Although CGS 10746B completely blocked the locomotor stimulant effects of cocaine and methamphetamine, it also decreased spontaneous activity in mice over the same dose range. Rats were trained to discriminate 10 mg/kg cocaine or 1 mg/kg methamphetamine from saline. The discriminative stimulus effects of cocaine or methamphetamine were not blocked by CGS 10746B. Thus, in contrast to other potential atypical antipsychotic compounds (e.g., D1 receptor antagonists), CGS 10746B does not appear to produce selective blockade of these behavioral effects of psychomotor stimulant compounds.