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 in modulating the transition from goal-directed to habitual cocaine seeking. Preliminary results suggest that kappa opioid receptors within the dorsolateral striatum are necessary for the expression of habitual cocaine seeking. Currently we are comparing the role of kappa and mu opioid receptors in goal directed and habitual cocaine seeking. In addition, we have started to investigate how the propensity to develop habitual cocaine seeking correlates with other behavioral phenotypes implicated in addiction (i.e. impulsivity, compulsivity, escalation of drug intake, reinstatement). 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).
