Kappa-opioid receptor activation prevents alterations in mesocortical dopamine neurotransmission that occur during abstinence from cocaine

In vivo microdialysis was used to characterize basal dopamine dynamics and cocaine-evoked dopamine levels in the medial prefrontal cortex of male Spra gue-Dawley rats that had previously received once daily injections of cocai ne (days 1-5; 20 mg/kg, i.p.) in combination with the selective kappa-opioi d receptor agonist U-69593 (days 3-5; 0.32 mg/kg, s.c.) or its vehicle. The influence of these treatments on [H-3]dopamine uptake in medial prefrontal cortex synaptosomes was also determined. Three days following the cessatio n of drug treatment, animals with prior history of cocaine administration e xhibited enhanced psychomotor stimulation in response to a subsequent cocai ne challenge. This effect was not apparent in animals that had previously r eceived the cocaine treatment regimen in combination with the kappa-opioid receptor agonist U-69593. Cocaine challenge increased prefrontal dopamine l evels in all pretreatment groups, but cocaine-pre-exposed animals had lower cocaine-evoked dopamine levels and higher basal in vivo extraction fractio n, indicative of an increase in basal dopamine uptake relative to controls. Pretreatment with U-69593 prevented these effects of cocaine. Measurement of [H-3]dopamine uptake in synaptosomes revealed a significant increase in uptake three days after the cessation of cocaine treatment. No increase in uptake was observed in animals that had received the cocaine treatment regi men in combination with U-69593. These results demonstrate that the early phase of abstinence from cocaine i s associated with marked alterations in medial prefrontal cortex dopamine n eurotransmission and that these neuroadaptations are prevented by the activ ation of kappa-opioid receptors. Furthermore, they raise the possibility th at mesocortical dopamine neurons may be an important neural substrate upon which kappa-opioid agonists act to prevent the development of cocaine-induc ed behavioral sensitization. (C) 2000 IBRO. Published by Elsevier Science L td. All rights reserved.