Anomalies in prefrontal cortex (PFC) function are posited to underpin difficulties in learning to suppress drug-seeking behavior during abstinence. As Group1 metabotropic glutamate receptors (mGluRs) regulate drug-related learning, we assayed the consequences of extended access to intravenous cocaine (6 hrs/day; 0.25 mg/infusion for 10 days) upon the PFC expression of Group1 mGluRs and the relevance of observed changes for cocaine-seeking. Following protracted withdrawal, cocaine-experienced animals exhibited a time-dependent intensification of cue-induced cocaine-seeking behavior and an impaired extinction of this behavior. These behavioral phenomena were associated with a time-dependent reduction in mGluR1/5 expression within ventromedial PFC (vmPFC) of cocaine-experienced animals exposed to extinction testing, but not in untested ones. Interestingly, pharmacological manipulations of vmPFC mGluR1/5 produced no immediate effects upon cue-induced cocaine-seeking behavior, but produced residual effects on a subsequent test for cocaine-seeking. At 3 days withdrawal, cocaine-experienced rats infused intra-vmPFC with mGluR1/5 antagonists, either before or after an initial test for cocaine-seeking, persisted in their cocaine-seeking akin to cocaine-experienced rats in protracted withdrawal. Conversely, cocaine-experienced rats infused with an mGluR1/5 agonist before the initial test for cocaine-seeking at 30 days withdrawal exhibited a facilitation of extinction learning. These data indicate that cue-elicited deficits in vmPFC Group1 mGluR function mediate resistance to extinction during protracted withdrawal from a history of extensive cocaine self-administration and pose pharmacological stimulation of these receptors as a potential approach to facilitate learned suppression of drug-seeking behavior which may aid drug abstinence.

BackgroundAdministration of psychomotor stimulants like amphetamine facilitates behavior in the presence of incentive distal stimuli, which have acquired the motivational properties of primary rewards through associative learning. This facilitation appears to be mediated by the mesolimbic dopamine system, which may also be involved in facilitating behavior in the presence of distal stimuli that have not been previously paired with primary rewards. However, it is unclear whether psychomotor stimulants facilitate behavioral interaction with unconditioned distal stimuli.Principal FindingsWe found that noncontingent administration of amphetamine into subregions of the rat ventral striatum, particularly in the vicinity of the medial olfactory tubercle, facilitates lever pressing followed by visual signals that had not been paired with primary rewards. Noncontingent administration of amphetamine failed to facilitate lever pressing when it was followed by either tones or delayed presentation or absence of visual signals, suggesting that visual signals are key for enhanced behavioral interaction. Systemic administration of amphetamine markedly increased locomotor activity, but did not necessarily increase lever pressing rewarded by visual signals, suggesting that lever pressing is not a byproduct of heightened locomotor activity. Lever pressing facilitated by amphetamine was reduced by co-administration of the dopamine receptor antagonists SCH 23390 (D1 selective) or sulpiride (D2 selective).ConclusionsOur results suggest that amphetamine administration into the ventral striatum, particularly in the vicinity of the medial olfactory tubercle, activates dopaminergic mechanisms that strongly enhance behavioral interaction with unconditioned visual stimuli.

Rationale-Responding for a drug-or sucrose-paired cue increases over forced abstinence (incubation of craving). If the incentive value of a cue depends on the incentive value of the primary reward, devaluing the primary reward should reduce cue reactivity.Objectives-We investigated whether conditioned taste aversion (CTA) to sucrose would transfer to a sucrose-paired cue after 1 or 30 days of forced abstinence and whether CTA after 1 day of forced abstinence would affect incubation of craving.Materials and methods-Rats self-administered 10% sucrose paired with a tone + light cue for 10 days. After 1 (Exp.1) or 30 (Exp.2) days of forced abstinence, rats received two home-cage pairings of sucrose with either LiCl (65 mg/kg, IP) to produce CTA or saline as a control. Two days later, rats responded for the cue alone. The following day, sucrose consumption was assessed in the same operant conditioning chamber. Exp.1 rats were tested again 1 month later to determine if CTA would affect incubation of craving.Results-Exp.1: CTA after 1 day of forced abstinence did not attenuate cue reactivity when tested immediately after CTA, nor did the treatment affect incubation of craving or incubation of sucrose consumption. Exp.2: CTA after 1 month of forced abstinence resulted in a significant reduction in cue reactivity. Conclusion-The incentive values of sucrose and the conditioned representation of sucrose increase over an extended period of forced abstinence. This incubation appears to facilitate the transfer of an aversion to the primary reward to the conditioned cue.