Behavioral evidence for dopamine receptor subsensitivity following chronic haloperidol.

When treated chronically with haloperidol, rats show progressively enhanced behavioral suppression, mimicking the delay of onset seen clinically with neuroleptics. To investigate potential neurochemical mechanisms underlying this delay, low-dose apomorphine treatment was administered after withdrawal from 21 days of 0.1 mg/kg haloperidol, to probe for depolarization inactivation or autoreceptor supersensitivity. This haloperidol treatment was subthreshold for inducing either dopamine autoreceptor supersensitivity or postsynaptic supersensitivity as evidenced by equivalent metabolic reductions in chronically treated neuroleptic versus vehicle groups, and an absence of stereotypical responding in either condition. However, haloperidol treated rats appeared subsensitive to yawning induced by 0.07 mg/kg apomorphine. This latter response appears to be generated from an as yet unidentified postsynaptic dopaminergic substrate. The present observation suggests that, within a therapeutically relevant dose range, repeated neuroleptic administration induces a complex set of neuroadaptive processes (both up- and down-regulation of pre- and postsynaptic sites) in the underlying substrate for these drugs' behavioral and biochemical effects.