Footshock stress can reinstate cocaine-seeking behavior through a central action of the stress-associated neurohormone corticotropinreleasing factor (CRF). Here we report (1) that footshock stress releases CRF in the ventral tegmental area (VTA) of the rat brain, (2) that, in cocaine-experienced but not in cocaine-naive rats, this CRF acquires control over local glutamate release, (3) that CRF-induced glutamate release activates the mesocorticolimbic dopamine system, and (4) that, through this circuitry, footshock stress triggers relapse to drug seeking in cocaine-experienced animals. Thus, a long-lasting cocaine-induced neuroadaptation, presumably at the level of glutamate terminals in the VTA, appears to play an important role in stress-induced relapse to drug use. Similar neuroadaptations may be important for the comorbidity between addiction and other stress-related psychiatric disorders.

Initiation of cocaine self-administration in rats was associated with release of glutamate in the ventral tegmental area (VTA). The glutamate release was transient, despite continued cocaine intake. Similar glutamate release was seen in rats earning, for the first time, unexpected saline rather than expected cocaine. VTA glutamate release was not seen in similarly trained rats earning saline instead of cocaine for the 13th time. VTA glutamate release was also seen in similarly trained rats that received yoked rather than earned cocaine injections on test day. VTA glutamate release was not seen in a group of rats that had never earned cocaine but had received yoked injections during the training period. Glutamate release was also not seen in a group of rats that received yoked injections but had no previous experience with cocaine. VTA GABA levels did not fluctuate during any aspect of cocaine seeking. Blockade of VTA glutamate receptors appeared to attenuate the rewarding effects of intravenous cocaine injections and blocked almost completely the conditioned responding normally seen during extinction trials. These findings indicate that VTA glutamate release is a conditioned response dependent on an associative process and is not a simple consequence of previous cocaine exposure. The findings implicate glutamate as at least one of the sources of VTA signals from reward-associated environmental stimuli.

Subsecond fluctuations in dopamine (dopamine transients) in the nucleus accumbens are often time-locked to rewards and cues and provide an important learning signal during reward processing. As the mesolimbic dopamine system undergoes dynamic changes during adolescence in the rat, it is possible that dopamine transients encode reward and stimulus presentations differently in adolescents. However, to date no measurements of dopamine transients in awake adolescents have been made. Thus, we used fast scan cyclic voltammetry to measure dopamine transients in the nucleus accumbens core of male rats (29 -30 days of age) at baseline and with the presentation of various stimuli that have been shown to trigger dopamine release in adult rats. We found that dopamine transients were detectable in adolescent rats and occurred at a baseline rate similar to adult rats (71 -72 days of age). However, unlike adults, adolescent rats did not reliably exhibit dopamine transients at the unexpected presentation of visual, audible and odorous stimuli. In contrast, brief interaction with another rat increased dopamine transients in both adolescent and adult rats. While this effect habituated in adults at a second interaction, it persisted in the adolescents. These data are the first demonstration of dopamine transients in adolescent rats and reveal an important divergence from adults in the occurrence of these transients that may result in differential learning about rewards.

Microdialysis was used to assess the contribution to cocaine seeking of cholinergic input to the mesocorticolimbic dopamine system in ventral tegmental area (VTA). VTA acetylcholine (ACh) was elevated in animals lever pressing for intravenous cocaine and in cocaineexperienced and cocaine-naive animals passively receiving similar "yoked" injections. In cocaine-trained animals, the elevations comprised an initial (first hour) peak to ϳ160% of baseline and a subsequent plateau of 140% of baseline for the rest of the cocaine intake period. In cocaine-naive animals, yoked cocaine injections raised ACh levels to the 140% plateau but did not cause the initial 160% peak. In cocaine-trained animals that received unexpected saline (extinction conditions) rather than the expected cocaine, the initial peak was seen but the subsequent plateau was absent. VTA ACh levels played a causal role and were not just a correlate of cocaine seeking. Blocking muscarinic input to the VTA increased cocaine intake; the increase in intake offset the decrease in cholinergic input, resulting in the same VTA dopamine levels as were seen in the absence of the ACh antagonists. Increased VTA ACh levels (resulting from 10 M VTA neostigmine infusion) increased VTA dopamine levels and reinstated cocaine seeking in cocaine-trained animals that had undergone extinction; these effects were strongly attenuated by local infusion of a muscarinic antagonist and weakly attenuated by a nicotinic antagonist. These findings identify two cholinergic responses to cocaine self-administration, an unconditioned response to cocaine itself and a conditioned response triggered by cocaine-predictive cues, and confirm that these cholinergic responses contribute to the control of cocaine seeking.

Introduction The opioid receptor antagonist naltrexone (NTX) reduces goal-directed alcohol drinking in rats presumably by blunting alcohol reward. However, different operant conditioning behavior can be produced by different reinforcement schedules, with goal-directed operant behavior being more sensitive to changes in reward value than less flexible, habit-associated models. Objectives We tested the hypothesis that NTX more effectively reduces alcohol drinking and seeking in a goal-directed than in a habit-associated operant model, and more effectively reduces alcohol versus sucrose self-administration, consistent with diminished alcohol reward. Materials and Methods Rats were trained to self-administer 10% alcohol or 1.5% sucrose in a lever-press task and then underwent a within-subject assessment of NTX (0.1–1mg/kg) effects on operant behavior. A fixed-ratio (FR5) reinforcement schedule was used to model goal-directed behavior and a variable-interval (VI30) schedule was used to model habitual behavior. Results As predicted, NTX reduced fluid deliveries earned by the FR5-alcohol group significantly more than all other groups. However, NTX reduced lever presses during self-administration sessions in VI30-trained rats without reducing earned deliveries, due to the low contingency between rate of pressing and fluid deliveries under that schedule. Interestingly, when fluid delivery was withheld (extinction), NTX reduced reward-seeking in all rats. Finally, NTX blocked reinstatement of reward-seeking upon presentation of 0.2ml alcohol or sucrose and associated cues in the FR5-trained but not VI30-trained rats. Discussion NTX reduced goal-directed alcohol drinking compared to other operant conditions. In addition, NTX blocked reinstatement of reward-seeking in rats trained on the goal-directed FR5 reinforcement schedule but not in rats trained on the habit-like VI30 reinforcement schedule. However, NTX also exerted nonspecific effects on reward-seeking that were revealed under low-effort contingency conditions or absence of reward. Together, the data support the hypothesis that NTX is less effective in conditioning models that are more habit-associated.