Pharmacological Blockade of α2-Adrenoceptors Induces Reinstatement of Cocaine-Seeking Behavior in Squirrel Monkeys

Abstract

Converging evidence suggests a role for noradrenergic mechanisms in stress-induced reinstatement of cocaine seeking in animals. Yohimbine, an a 2 -adrenoceptor antagonist, is known to be anxiogenic and induce stress-related responses in humans and animals. Here, we tested the ability of yohimbine to reinstate cocaine-seeking behavior and induce behavioral and physiological signs characteristic of stress in squirrel monkeys. Monkeys were trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Drug seeking subsequently was extinguished by substituting saline for cocaine injections and omitting the cocaine-paired stimulus. The ability of yohimbine and the structurally distinct a 2 -adrenoceptor antagonist RS-79948 to reinstate cocaine-seeking behavior was assessed by administering priming injections immediately before test sessions in which the cocaine-paired stimulus was either present or absent. Priming injections of yohimbine (0.1-0.56 mg/kg, i.m.) or RS-79948 (0.01-0.1 mg/kg, i.m.) induced dose-related reinstatement of cocaineseeking behavior. The magnitude of yohimbine-induced reinstatement was similar regardless of the presence or absence of the cocainepaired stimulus. Yohimbine also significantly increased salivary cortisol levels, a physiological marker of stress, as well as scratching and selfgrooming, behavioral markers of stress in nonhuman primates. In drug interaction experiments, pretreatment with the a 2 -adrenoceptor agonist clonidine (0.1-0.3 mg/kg, i.m.) dose-dependently inhibited yohimbine-induced reinstatement of cocaine seeking. In contrast, pretreatment with the dopamine receptor antagonist flupenthixol failed to inhibit yohimbine-induced reinstatement of cocaine seeking. The results show that pharmacological blockade of a 2 -adrenoceptors can induce reinstatement of cocaine-seeking behavior and characteristic stress responses in squirrel monkeys, providing a potentially useful model of stress-induced relapse to drug seeking.

The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

“…Consistent with previous work (Lee et al, 2004;Le et al, 2005;Shepard et al, 2004) the results of Experiment 2 show that the pharmacological stressor yohimbine reinstated responding following extinction of self-administration. This response-reinstating effect of yohimbine was blocked dose dependently by Ro60-0175.…”

“…Opioid-dependent patients exhibit anxiety-like responses and withdrawal symptoms following treatment with yohimbine, and these states are accompanied by drug cravings (Stine et al, 2002). In animals, yohimbine reinstates responding for cocaine (Lee et al, 2004) methamphetamine (Shepard et al, 2004), and alcohol (Le et al, 2005). Second, we examined the ability of Ro60-0175 to attenuate responding induced by contextual cues previously associated with cocaine self-administration (Crombag et al, 2002).…”

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

“…Reinstatement of drug seeking is also obtained with administration of the α-2 adrenoreceptor antagonist yohimbine, which, by increasing brain noradrenaline cell firing (Aghajanian and VanderMaelen 1982) and release (Abercrombie et al 1988), acts as a pharmacological stressor (Bremner et al 1996a,b;Charney et al 1983;Holmberg et al 1962;Lee et al 2004;Lê et al 2000Lê et al , 2005. These two methods were used to investigate the effect of URB597 on stress-induced alcohol seeking.…”

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

“…Other pharmacological stressors, including corticotropin-releasing factor (CRF) and yohimbine administration, have also been found to reinstate cocaine-seeking behaviors, indicating a role for the CRF and adrenergic neurotransmitter systems in mediating stressinduced relapse (Erb et al 2001;Erb and Stewart 1999;Lee et al 2004;Leri et al 2002). The relationship between the CRF, adrenergic, and dynorphin systems in stress-induced reinstatement has not been resolved; however, we recently reported that CRF-induced place aversion was mediated by dynorphin-dependent KOR activation (Land et al 2008).…”