Some behavioral effects of opiates are thought to be mediated by opiate receptors which modulate the neurotransmission of dopamine within the nigrostriatal and mesolimbic systems. The number of opiate receptors may be increased following chronic treatment with opiate antagonists such as naloxone and naltrexone. If chronic antagonist treatment increases the number of brain opiate receptors, then an enhanced effect of morphine on dopamine activity and behavior may also be evident. The present proposal examines that hypothesis. Rats will be implanted with a slow-release pellet of naltrexone for 10 days and then the pellet will be removed. At one of the various different intervals after pellet removal, animals will be sacrificed and different regions of the nigrostriatal and mesolimbic systems will be examined for changes in mu, delta and kappa binding sites. Some animals will also be challenged with an injection of morphine in order to determine whether naltrexone pretreatment alters the functional activity of dopamine neurons within the nigrostriatal and mesolimbic systems. Functional activity will be examined in vivo by measuring turnover of DA and by measuring the spontaneous firing rate of neurons in these dopaminergic subsystems. Correlated with these neurochemical and electrophysiologic changes, morphine-induced changes in antinociception, locomotor activity, and conditioned reinforcement will also be examined. While the results from these experiments may have some potentially significant clinical implications for the treatment of human opiate addiction with opiate antagonists, the long-term objective of the project is to advance our knowledge about the role which opiate receptors normally play in various neurobehavioral processes.
