It is well-established that drugs can act as unconditioned stimuli and induce Pavlovian conditioned effects on autonomic system responses. More recently, however, it has been shown that behavioral processes such as hedonic states, motoric activation, craving and behavioral drug sensitization/tolerance can be impacted by drugs of abuse through Pavlovian conditioning mechanisms. Since Pavlovian conditioning is a primitive, involuntary form of learning this expansion of the domain of Pavlovian conditioning to include complex biochemical and behavioral processes which can be activated by drugs of abuse has important implications for the understanding and treatment of drug abuse problems. While Pavlovian conditioning is widely acknowledged to be an important factor in drug abuse, to date, it has not been systematically studied in animal models. In addition, the neural mechanisms which mediate Pavlovian conditioned drug effects appear to be separate from those which mediate the drug induced effects and are therefore unknown. The drug conditioning methodology we have recently developed, however, provides a unique opportunity to establish an experimental foundation for this important but underdeveloped area within behavioral pharmacology. The overall objective of the present research proposal is to use our newly developed animal behavior methodology to identify the critical variables and neurobiological mechanisms by which Pavlovian drug conditioning processes link drug effects to exteroceptive stimuli. The identification of important variables is guided by Pavlovian conditioning principles and incudes drug dose (i.e., Unconditioned Stimulus intensity), extinction and spontaneous recovery. One series of studies will systematically manipulate these variables with selected drugs of abuse. Initially, cocaine will be investigated and subsequently the analysis will be extended to include caffeine and morphine. The second series of studies are guided by our and others very recent observations which implicate several neurobiological systems (e.g., NMDA and opioid receptors, corticosterone and the medial prefrontal cortex) in the mediation of cocaine conditioning and/or sensitization processes. This series of experiments will provide critical information for the identification of neural mechanisms which underlie cocaine conditioning. Additionally, since the cocaine manipulations involve repeated treatments, possible changes in the regional distribution of cocaine in brain will be examined. Altogether, the proposed research will develop a broad empirical base upon which the relationship between Pavlovian conditioning and drugs of abuse can be better understood and subsequently applied to the improvement of treatment modalities for drug abuse therapy.
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