Development of behavioral sensitization to cocaine: influence of kappa opioid receptor agonists

The effects of acute or repeated administrations of the selective kappa opioid receptor agonists U-69593 and U-50488H on cocaine-induced locomotor stimulation were examined in the rat. Acute administration of cocaine (10-30 mg/kg i.p.) produced a dose-dependent increase in locomotor activity. A single injection of U-69593 (0.04-0.32 mg/kg s.c.) or U-50488H (2.5-7.5 mg/kg s.c.) administered 15 min before cocaine did not modify the effects of an acute cocaine challenge. In contrast, repeated administration of U-69593 or U-50488H in combination with saline for 3 days prevented the acute locomotor-activating effects of cocaine. Repeated administration of cocaine (10-30 mg/kg i.p.) for 3 days resulted in an enhancement of its locomotor-activating effects, i.e., sensitization. No such sensitized responses were observed in animals that had received U-69593 or U-50488H in combination with the cocaine treatment regimen. Repeated administration of U-69593 (0.16 mg/kg s.c.) for 3 days failed to block the acute locomotor-activating effects of nicotine (0.6 mg/kg s.c.). Furthermore, when U-69593 was given in combination with nicotine, sensitized motor responses to a subsequent nicotine challenge were still observed. These data demonstrate that the repeated activation of kappa opioid receptors prevents the locomotor activation that occurs in response to an acute cocaine challenge as well as the sensitized motor responses that develop after the repeated administration of cocaine.