Behavioral and biochemical evidence of opioidergic involvement in cocaine sensitization.

Chronic administration of cocaine produces sensitization to its behavioral effects in humans and experimental animals. In the present study, rats treated with cocaine (10 mg/kg, i.p.) once daily for 10 days showed an enhancement in the acute drug stimulation of locomotor activity and stereotypy. Biochemical analysis in the nucleus accumbens of chronic cocaine-treated animals indicated that sensitization of D1 dopamine (DA) receptors had also developed. In fact, stimulation of adenylyl cyclase activity by DA was increased in nucleus accumbens membranes from sensitized rats. Our findings suggest that a novel postsynaptic mechanism, i.e., an increased DA-D1 receptor function, may play a role in the sensitization. A causal relationship between the two events is supported by the observation that neither motor behavioral sensitization nor DA-dependent adenylyl cyclase hyperactivity developed when the opiate antagonist naltrexone (2 mg/kg, s.c.) was given daily for 10 days before cocaine. When given alone, naltrexone was inactive in all respects, which rules out any unspecific action and suggests that its effects may be due to competition at receptors with endogenous opioids mobilized by cocaine. This was indirectly supported by the finding that desensitization of opioid inhibition of adenylyl cyclase developed in nucleus accumbens membranes of cocaine-sensitized rats. Chronic blockade of opioid receptors by naltrexone also counteracted the reinforcing properties of cocaine; conditioned place preference, clearly displayed by cocaine-treated animals, was antagonized in a dose-related manner. Overall, these results confirm that endogenous opioid peptides play an important role in cocaine addiction.