Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats

229

176

Conditioned stimuli are important for nicotine dependence and may trigger craving and relapse after prolonged nicotine abstinence. However, little is known about the pharmacology of this process. Among the systems that have been shown to play a role in drugseeking behavior is the endocannabinoid transmission. Therefore, the present study examined the resistance to extinction of drugseeking behavior elicited by nicotine-associated environmental stimuli and the effects of the selective CB 1 cannabinoid antagonist rimonabant (SR141716) on the reinforcing effects of nicotine-related stimuli. Rats were trained to self-administer nicotine (0.03 mg/kg/ injection, i.v.) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and stimuli (light and tone). After self-administration acquisition, nicotine was withdrawn and lever pressing was only reinforced by contingent presentation of the audiovisual stimuli. Under such a condition, responding persisted for 3 months, following which nonpresentation of the cues produced a progressive extinction of responding. As expected, rats trained to lever-press for saline injections paired with the audiovisual stimuli did not acquire the self-administration. These findings indicate that the cues required learned association with nicotine to acquire reinforcing properties and to function as conditioned reinforcers. When administered 1 month following nicotine withdrawal, rimonabant (1 mg/kg, i.p.) decreased conditioned behavior. These results showing the persistence of a nicotine-conditioned behavior are congruent with the role of nicotine-related environmental stimuli in nicotine craving in abstinent smokers. Rimonabant, which has been shown previously to reduce nicotine self-administration, may be effective not only as an aid for smoking cessation but also in the maintenance of abstinence.

Section: Discussioncontrasting

confidence: 46%

Nicotine-Associated Cues Maintain Nicotine-Seeking Behavior in Rats Several Weeks after Nicotine Withdrawal: Reversal by the Cannabinoid (CB1) Receptor Antagonist, Rimonabant (SR141716)

Cohen

Perrault

Griebel

et al. 2004

229

176

“…We are not familiar with studies that have systematically evaluated the motivational value of reward cues as a function of the duration of training. However, results from several recent studies indicate that reward seeking induced by cues progressively increases after withdrawal from heroin (Shalev et al, 2001;Di Ciano and Everitt, 2004), cocaine (Neisewander et al, 2000;Grimm et al, 2001;Lu et al, 2005), or sucrose Di Ciano and Everitt, 2004;Lu et al, 2004). Perhaps most relevant here, as we have found progressive within-subject increases in timeout lever responses, is the recent finding of Di Ciano and Everitt (2004).…”

Section: Progressive Increase In Food-taking Behavior During Trainingsupporting

confidence: 52%

The Anxiogenic Drug Yohimbine Reinstates Palatable Food Seeking in a Rat Relapse Model: a Role of CRF1 Receptors

Ghitza

Gray

Epstein

et al. 2005

Self Cite

143

156

The major problem in treating excessive eating is high rates of relapse to maladaptive eating habits during diet treatments; this relapse is often induced by stress or anxiety states. Preclinical studies have not explored this clinical problem. Here, we adapted a reinstatement model (commonly used to study relapse to abused drugs) to examine the role of stress and anxiety in relapse to palatable food seeking during dieting. Rats were placed on restricted diet (75-80% of daily standard food) and for 12 intermittent training days (9 h/day, every other day) lever-pressed for palatable food pellets (25% fat, 48% carbohydrate) under a fixed ratio 1 (20-s timeout) reinforcement schedule. Subsequently, the rats were given 10 daily extinction sessions during which lever presses were not reinforced, and were then injected with yohimbine (an a-2 adrenoceptor antagonist that induces stress and anxiety in humans and non-humans) or given a single food pellet to assess reinstatement of food seeking. The rats rapidly learned to lever press for the palatable pellets and across the training days the ratio of timeout nonreinforced lever presses to reinforced lever presses progressively increased more than three-fold, suggesting the development of compulsive eating behavior. After extinction, yohimbine injections and pellet priming reliably reinstated food seeking. The corticotropin-releasing factor 1 (CRF 1 ) receptor antagonist antalarmin attenuated the reinstatement induced by yohimbine, but not pellet priming. Antalarmin also reversed yohimbine's anxiogenic effects in the social interaction test. These data suggest that CRF is involved in stress-induced relapse to palatable food seeking, and that CRF 1 antagonists should be considered for the treatment of maladaptive eating habits.

“…The decrease in CRF mRNA in the BNST in response to restraint in vehicle-treated rats is different from the increase observed in response to acute stressors in naïve rats (Makino et al, 1999) and rats undergoing 1-and 6-day heroin withdrawal (Shalev et al, 2001). The differences in the types of stressors, the opioid dependence paradigms, and interval between exposure to stress/ withdrawal and tissue collection probably contributed to these discrepancies.…”

Section: Hpa Activitymentioning

confidence: 74%

“…In humans, the majority of relapses occur during states of stress (Koob and Le Moal, 2001;Kreek and Koob, 1998). Similarly, in animal models, stressors also reinstate opioid self-administration (Shaham et al, 1997(Shaham et al, , 1998Shalev et al, 2001). Furthermore, induction of a 'stress-like' state by intracerebroventricular injection of corticotropin-releasing factor (CRF) reinstates heroin seeking (Shaham et al, 1997), whereas CRF receptor antagonists attenuate stress-induced relapse to drug seeking in heroin-trained rats (Shaham et al, 1997(Shaham et al, , 1998).…”

Section: Introductionmentioning

confidence: 99%

Intermittent Morphine Administration Induces Dependence and is a Chronic Stressor in Rats

Houshyar

Gómez

Manalo

et al. 2003

Although constant treatment with morphine (implanted pellets) does not activate the hypothalamic-pituitary-adrenal (HPA) axis, intermittent injections of morphine may constitute a chronic stressor in rats. To test this hypothesis, we compared the effects of morphine in escalating doses (10-40 mg/kg, s.c.) or saline injected twice daily for 4 days on energy balance, hormones, HPA responses to novel restraint and central corticotropin-releasing factor (CRF) mRNA 12 h and 8 days after the last morphine injection in adult male Sprague-Dawley rats. Weight gain stopped at the onset of morphine, weight loss was marked 36 h postmorphine; thereafter, body weight gain paralleled saline controls. At 12 h, insulin, leptin, and testosterone concentrations were reduced but normalized by 8 days. Restraint and tail nicks caused facilitated ACTH responses at 12 h, under-responsiveness at 8 days. CRF mRNA, measured only at 12 h, was increased in the paraventricular (PVN) and Barrington's nuclei (BAR), decreased in the bed nuclei of the stria terminalis (BNST) and unchanged in the amygdala (CeA) in morphine-treated rats. After stress, CRF mRNA increased in PVN in both groups, increased in BAR and decreased in BNST in saline but not morphine groups, and was unchanged in CeA in both groups. Results from all variables characterize intermittent morphine injections as a chronic stressor. In contrast to constant treatment, injected morphine probably allows some withdrawal during each 12 h interval, causing repeated stress. Drug addicts treat themselves intermittently, and stress causes relapse after withdrawal. Thus, intermittent morphine, itself, may promote relapse.