Habit learning processes are implicated in the transition from recreational drug use to the compulsive drug seeking that characterizes addiction. Lesions of the dorsal striatum, an area necessary for habit learning, attenuate cue controlled drug seeking and nigrostriatal dopamine lesions disrupt habit formation. Moreover, prior repeated psychostimulant administration facilitates habitual responding for food reinforcers suggesting that their self-administration accelerates habit development. Studies assessing the development of habitual drug seeking are limited. Using outcome devaluation procedures by satiation or pairing of oral reinforcers with sickness induced by a drug (e.g. lithium), two laboratories demonstrated habitual drug seeking of orally administered drug reinforcers. However, studies of intravenous drug administration have been hampered by difficulties inherent in adapting standard devaluation procedures for natural reinforcers to intravenous administered drug. In contrast to natural reinforcers, this route of administration is not associated with an obvious consummatory response and psychostimulants such as cocaine have unconditioned, behaviorally activating effects, that can affect responding. To circumvent these issues, we have used a heterogenous chained schedule of intravenous cocaine administration in which habitual cocaine-seeking is tested by devaluing the final link of a drug seeking/taking chained schedule. In this procedure, responding on the designated drug seeking lever provides access to a drug taking lever, rather than to cocaine itself. Responses on the drug taking lever result in a cocaine infusion. The effects of devaluation of the drug taking link (by extinction) is assessed once performance under the chained schedule has stabilized. Decreased responding during the drug seeking link is indicative of behavior that is goal-oriented. Responding that is insensitive to devaluation is evidential of the development of habitual drug-seeking. Other rats underwent the same protocol except that after completing the cocaine seeking test, an additional 36 sessions were conducted to provide an extended drug seeking history. Given the documented role of the dorsolateral striatum in stimulus-response associations, the influence of inactivation of this brain area was assessed in animals with a prolonged history of cocaine seeking and taking. In rats with limited cocaine access, devaluation of the outcome of the drug seeking link by extinction significantly decreased drug seeking indicating that behavior is goal-oriented rather than habitual. Importantly, however, examination of each animals data revealed that whereas drug seeking was clearly attenuated by outcome devaluation in eight animals, responding of six animals after devaluation was greater than 80% of that under the revalued condition, indicating poor sensitivity to devaluation in these animals. Thus, in this subset of animals, cocaine seeking was not goal-oriented but already habitual in nature. With, however, more prolonged drug experience, all animals transitioned to habitual cocaine seeking. Thus, cocaine-seeking became insensitive to outcome devaluation. Moreover, when the dorsolateral striatum, an area implicated in habit learning, was transiently inactivated, outcome devaluation was again effective in decreasing drug-seeking indicating that responding was no longer habitual but had reverted to control by the goal-oriented system. These studies provide direct evidence that cocaine seeking becomes habitual with prolonged drug experience and describe a rodent model with which to study the neural mechanisms underlying the transition from goal-oriented to habitual drug-seeking. On-going studies are using this model to examine the role of the dynorphin/k-opioid receptor system (see: DA000538-04) in modulating the transition from goal-directed to habitual cocaine seeking.Stimuli associated with drug use not only contribute to the maintenance of habitual drug seeking but their presentation precipitates relapse in abstinent subjects. Second order schedules of drug self administration have been used extensively to study control of drug seeking by drug associated stimuli. In this schedule, responses on the drug lever are maintained for prolonged periods of time by discrete presentations of a cocaine associated stimulus before any drug is infused. Responding during the first component of the schedule, before the first drug infusion, provides a measure of drug seeking exclusively under the control of drug-associated stimuli. As such, it is not confounded by the unconditioned effects of a drug. Responses during the second and subsequent components reflect control of behavior by both the conditioned and unconditioned effects of a drug. Furthermore, in contrast to fixed ratio schedules of drug self-administration, the extended training required for acquisition of behavior in a second order schedule is thought to promote the transition from goal-oriented to habitual (stimulus-response) drug seeking. During the past year, we have established this procedure for cocaine. Furthermore, we have begun to examine whether drugs currently under evaluation for the treatment of cocaine addiction affect drug-seeking under the control of conditioned stimuli. Our studies have focused on kappa opioid receptor antagonists since kappa opioid receptor antagonists are in Phase I testing for preventing stress-induced relapse to cocaine addiction. We found that in rats actively taking drug, the selective and long-acting kappa opioid receptor antagonist, nor-binaltorphimine, exacerbates cocaine-seeking maintained by a conditioned stimulus. In contrast, cocaine-taking is unaltered. Kappa opioid receptor blockade does not affect taking or seeking of a natural reinforcer (e.g. sucrose). Furthermore, it does not attenuate the spontaneous reinstatement of cocaine taking and seeking that occurs in animals in which self-administration was terminated several weeks prior to testing. Kappa opioid receptor antagonists attenuate stress-induced potentiation of cocaine place conditioning and stress induced reinstatement of cocaine seeking in abstinent animals. These effects have been attributed to blockade of increased kappa opioid receptor activation resulting from stress-evoked increases in dynorphin. We previously reported that kappa opioid receptor antagonists do not prevent (or even potentiate) relapse to drug seeking induced by a cocaine priming injection;and enhance behavioral sensitization to cocaine. These findings and those regarding their effects on cocaine-seeking maintained by conditioned stimuli suggests that the utility of these agents for preventing relapse in abstinent addicts may depend on the predominant factor (i.e. context, stress, unconditioned drug effects, etc) which precipitate drug-seeking and taking in a particular individual. Furthermore, they suggest that kappa opioid receptor blockade may promote drug seeking in non-abstinent individuals by increasing the ability of conditioned stimuli to control drug seeking. Future studies seek to delineate the role of the kappa opioid receptor/dynorphin system during various stages of the addiction cycle and in modulating processes within the brain that underlie control of behavior by conditioned stimuli.We have also begun to characterize the use of confocal fiberoptic microscopy to assess brain activity in vivo. We have used AAV-directed expression of GCamp3, a fluorescent calcium-binding, to measure intracellular calcium transients in VTA neurons. Initial pharmacological characterization show transient responses to NMDA or morphine. We have also observed transient responses to a painful stimulus (tail-pinch).

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National Institute on Drug Abuse
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