Opioid dependence is a serious public health problem. Since the neuropharmacology of opioid dependence has been examined primarily in nonhumans, the degree to which pharmacological mechanisms mediating this phenomenon in nonhumans are related to those in humans needs to be determined in order to improve treatment strategies for opioid dependence. Thus, the major aim of this project is to employ an opioid antagonist instructed novel-response drug discrimination procedure in opioid-maintained humans as a human laboratory model of opioid withdrawal, in order to examine the discriminative stimulus, self-reported, and cardiovascular effects of the opioid antagonist as they relate to underlying pharmacological mechanisms thought to mediate this syndrome. In the instructed novel-response drug discrimination procedure, opioid maintained subjects are trained to distinguish between a dose of an opioid antagonist and placebo. Subsequently, the effects of various agents and the antagonist are examined alone and in combination to determine whether these agents produce effects similar to either training condition or neither condition (i.e., 'novel') and whether they alter the antagonist's effects. This procedure allows for simultaneous assessment of objective behavioral measures such as discrimination, self-reports and physiological responses, providing a wide behavioral profile of the opioid withdrawal phenomenon. The novel response procedure will help clarify interpretations of partial generalization and antagonism. The proposed studies focus on 1) verifying the veracity of the instructed novel-response drug discrimination procedure, and 2) examining the utility of the discrimination as a model of withdrawal by assessing the actions of agents acting on noradrenergic/excitatory amino acid systems with the locus coeruleus as the cellular model of opioid withdrawal. In methadone maintained humans trained to discriminate the opioid antagonist naloxone (0.15 mg/7O kg, i.m.) from saline under an instructed novel-response drug discrimination procedure, a series of five studies will examine whether opioid compounds, adrenergic agents, excitatory amino acid antagonists, a glycine agent, and a calcium channel blocker are similar to or alter naloxone's discriminative stimulus, self-reported and physiological effects. This paradigm will potentially provide a sensitive, standard, objective method to assess the behavioral interactions between naloxone and other test compounds which show promise as treatment agents for opioid withdrawal
