INVOLVEMENT OF THE MESOLIMBIC DOPAMINE SYSTEM IN MEDIATING THE AVERSIVE EFFECTS OF OPIOID ANTAGONISTS IN THE RAT

An unbiased place preference conditioning procedure was used to examin e the neural substrates mediating the aversive effects of opioid antag onists in the rat. Microinjection of the non-selective opioid receptor antagonist naloxone into either the ventral tegmental area (VTA) or t he nucleus accumbens (NAc) produced significant aversions for an envir onment previously paired with its administration. The minimum doses pr oducing these effects were 10.0 and 7.5 mu g, respectively. Microinjec tions into either the caudate/putamen or medial prefrontal cortex were without effect. Place aversions of equivalent magnitude were also obs erved in response to the intra-VTA or intra-NAc administration of the highly selective mu opioid receptor antagonist CTOP. Doses as low as 0 .3 mu g resulted in significant effects. 6-hydroxydopamine lesions of the NAc attenuated the aversive effect of intra-VTA CTOP. Such lesions did not modify the aversive effects of intra-NAc CTOP; they also fail ed to modify the aversive effects of systemically administered naloxon e. These data demonstrate that the blockade of either VTA or NAc mu op ioid receptors is sufficient for the expression of the aversive effect s of opioid antagonists. Furthermore, they suggest that whereas the av ersive effects of intracranially applied opioid antagonists may involv e both a mesolimbic DA-dependent (VTA) and independent (NAc) component , the aversive effects produced by systemically administered opioid re ceptor antagonists are independent of mesolimbic DA neurons.