Behavioral and biochemical studies of the scopolamine-induced reversal of neuroleptic activity

Abstract

Scopolamine reversed the reduction in avoidance responding caused by spiperone and antagonized the inhibitory effects of spiperone on the behavioral actions of d-amphetamine or apomorphine. Scopolamine-induced locomotor activity was greater in 6-hydroxydopamine (6-OHDA)-treated animals than in controls. This increase was prevented by administration of α-methyltyrosine, but not by inhibition of dopamine-β-hydroxylase, indicating that this action of scopolamine was associated with presynaptic dopaminergic fibers. Therefore, the possibility that pre-synaptic dopaminergic function was the locus of the antagonism of spiperone by scopolamine was examined using drug interaction studies in 6-OHDA-treated rats. However, when 6-OHDA-treated rats were given α-methyltyrosine, scopolamine still reversed the spiperone blockade of apomorphine-induced locomotion. Although these data provided evidence for a post-synaptic action for this cholinergic blocking agent, scopolamine affected neither dopamine-stimulated adenylate cyclase activity nor ³H-spiperone binding in vitro. Furthermore, scopolamine did not alter the level of specific ³H-spiperone binding found in brain after in vivo administration. This suggests that the postsynaptic mechanism affected by scopolamine is different from the site affected by spiperone. Thus, it is concluded that scopolamine can affect both pre- or post-synaptic events associated with dopaminergic function and that both may contribute to the reversal of the actions of spiperone.