Increased sensitivity to the locomotor depressant effect of a dopamine receptor antagonist during cocaine withdrawal in the rat

The effect of a dopamine receptor antagonist on locomotor activity was exam ined during withdrawal from either self-administered or experimenter-admini stered cocaine. In the self-administration experiment, the locomotor respon se to a challenge injection of cis-flu-penthixol was assessed in photocell cages at 4 h after the cessation of a 12-h cocaine self-administration sess ion. Rats which had self-administered cocaine, and were challenged with cis -flupenthixol (0.05 mg/kg), were found to be hypoactive relative to control s. In the experimenter-administered cocaine experiment, animals were given eight IP injections of 15 mg/kg cocaine over a 9.5-h period, for a total of 120 mg/kg. At 4, 8, and 24 h (tested in three separate groups of rats) aft er cessation of the eight injections, the locomotor response to a challenge injection of saline or cis-flupenthixol was tested. Cocaine-treated animal s displayed a dose-dependent, heightened sensitivity to the locomotor depre ssant effects of 0.05 mg/kg and 0.2 mg/kg cis-flupenthixol 4 h post-cocaine , whereas they did not show increased sensitivity to 0.05 mg/kg cis-flupent hixol 8 or 24 h post-cocaine. However, cocaine-treated animals displayed a mild hypoactivity 8 h post-cocaine. In a separate group of animals, a dose- response experiment was performed which indicated that a dose of cis-flupen thixol as high as 0.2 mg/kg was required to produce locomotor depression in cocaine-naive rats. The results of this study support clinical observation s of dopamine antagonist-precipitated motor dysfunction in abstinent cocain e abusers, and lend further support to the hypothesis that alterations in d opaminergic neurotransmission consequent to prolonged cocaine exposure are partly responsible for some of the symptoms of cocaine withdrawal.