Effect of cocaine and sucrose withdrawal period on extinction behavior, cue-induced reinstatement, and protein levels of the dopamine transporter and tyrosine hydroxylase in limbic and cortical areas in rats

Abstract

Lever pressing during tests for resistance to extinction and cue-induced reinstatement of cocaine seeking in rats progressively increases over the first 2 months of withdrawal. In the present report, we investigated the generality of these findings in rats trained to self-administer sucrose, a non-drug reinforcer. We also examined whether the time-dependent changes in cocaine seeking correlate with the levels of the dopamine transporter (DAT) and tyrosine hydroxylase (TH) proteins in the amygdala, nucleus accumbens, prefrontal cortex and orbitofrontal cortex. Rats were trained to selfadminister cocaine (0.5 mg/kg/i.v. infusion) or 10% sucrose (0.2 ml/infusion into a liquid drop receptacle) for 10 days (6 h/day); each reward delivery was paired with a tone+light cue. Tests for cocaine seeking were conducted following 1 or 15 reward-free days. On the test day, rats were initially tested for resistance to extinction during 6-7 60-min extinction sessions in the absence of the tonelight cue, until they reached the extinction criterion of less than 15 responses/60 min. Subsequently, rats were tested for cue-induced reinstatement during a 60-min session in which each lever press led to a contingent presentation of the tone-light cue. Lever pressing during the tests for reward seeking was significantly greater on day 15 than on day 1 following withdrawal from both cocaine and sucrose self-administration training. The levels of DAT, but not TH, were greater in the prefrontal cortex of cocaine-trained rats than in sucrose-trained rats on both days 1 and 15 of withdrawal. The levels of DAT and TH in other brain areas were not altered following withdrawal from cocaine or sucrose self-administration. These data suggest that the withdrawal period can modulate reward seeking of both drug and non-drug reinforcers, and that alterations in DAT and TH levels in the brain regions examined do not mediate this effect.

Differential Effects of σ1 Receptor Blockade on Self-Administration and Conditioned Reinstatement Motivated by Cocaine vs Natural Reward

“…While SCM conditioning sessions were restricted to 20 min to avoid satiety and, thus, shorter than cocaine conditioning sessions, the number of responses per session was considerably higher in the SCM than in the cocaine group such that these animals experienced a greater number of reinforcer presentations in the presence of the SCM S + compared to the cocaine S + condition. Nonetheless, as in previous reports where stimuli conditioned to conventional reinforcers were less effective in eliciting reward-seeking than cocaineassociated stimuli (Baptista et al, 2004;Grimm et al, 2002), the SCM S + produced weaker reinstatement than the cocaine S + . Moreover, the SCM S + induced and maintained responding only during the first 10-20 min of the reinstatement test, whereas the cocaine S + produced strong and sustained responding throughout the 60 min session.…”

Dissecting motivational circuitry to understand substance abuse

“…Clearly, our electrophysiological recordings support this view. Similar increases in sucrose-seeking behavior have been observed following sucrose abstinence (Grimm et al, 2002). Conversely, we failed to observe similar increased responding or an enhancement in NAc cell firing properties following abstinence from sucrose reinforcement .…”

A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior

“…Significant studies have shown that cue-induced drug-seeking increases over time during abstinence, leading to the concept of 'incubation of craving' (Grimm et al, 2001). This is a robust phenomenon that has been observed across a number of different drug classes in rats (Di Ciano and Everitt, 2004;Grimm et al, 2002;Shalev et al, 2001;Lu et al, 2007). Moreover, this type of delayed onset craving can be present in human cocaine users (Kosten et al, 2005).…”