Pavlovian conditioned drug effects contribute importantly to critical drug abuse treatment issues of relapse and craving. Application of conditioning principles to treatment are complicated, however, by the fact that drug effects can be conditioned to a wide variety of exteroceptive environmental stimuli associated with drug use and that extinction procedures can only suppress but cannot eliminate the efficacy of the conditioned stimulus (CS) to elicit the conditioned response (CR). In this regard, it is well-established by tests of conditioned effects following extinction in both drug and non-drug models, that CS elicitation of the CR can be reinstated by startle and stress stimuli. Recently, we have found that caffeine could also reactivate an extinguished conditioned dopaminergic drug response. This linkage of caffeine to the modulation of CS efficacy in drug conditioning is important because it creates the possibility of developing a pharmacological identity of the neurochemical mechanisms which modulate conditioned drug effects. Thus, one objective of the present proposal is to relate the modulatory influence of caffeine on drug conditioning processes to caffeine mechanisms; e.g. to adenosine antagonism, norepinephrine release and GABAergic antagonism. Another objective is to examine the influence of over-the counter stimulant drugs (i.e., methylxanthines and phenylethylamines) on the reactivation of an extinguished conditioned dopaminergic drug response. Overall, the objective is to identify, using the unilateral 6-hydroxydopamine rotation and place preference animal models, drug treatments which can facilitate/antagonize CS-efficacy in conditioned drug responses induced by dopaminergic drugs and by drugs with high abuse liability such as amphetamine, cocaine and morphine. The results obtained can provide a basis for pharmacological treatment strategies for clinical control of craving and attendant relapse problems during drug abuse rehabilitation.
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