Alpha-2 Adrenergic Receptor Agonists Block Stress-Induced Reinstatement of Cocaine Seeking

Abstract

The alpha -2 adrenergic receptor agonists, clonidine, lofexidine and guanabenz, blocked stress-but not cocaineinduced reinstatement of cocaine seeking at doses that suppressed footshock-induced release of noradrenaline in prefrontal cortex and amygdala. Rats were trained to selfadminister cocaine (0.5 mg/kg/infusion, i.v; 10-12 days) and, after a drug-free period (7-13 days), were returned to the selfadministration chambers for daily extinction and reinstatement test sessions. Both intermittent footshock (15 min, 0.6 mA) and cocaine priming (20 mg/kg, i.p.) reinstated extinguished drug seeking. Pretreatment with eitherclonidine (20, or 40 g/kg, i.p.) or lofexidine (50, 100, 150, or 200 g/kg, i.p.) (e.g. Jaffe 1985) and reinstate drug-seeking in monkeys and rats with a history of drug self-administration (e.g., Stretch and Gerber 1973;de Wit and Stewart 1981). Another factor thought to be important to relapse in humans is stress (Kreek and Koob 1998). In a recent laboratory study, Sinha and colleagues (1999) found that induction of psychological stress provoked craving for drug in cocaine addicts. Using an animal model of stress-induced relapse, we and others have found in rats that exposure to brief intermittent footshock stress reliably reinstates heroin seeking (Shaham and Stewart 1995), cocaine seeking (Erb et al. 1996;Ahmed and Koob 1997;Mantsch and Goeders 1999), nicotine seeking (Buczek et al. 1999), and alcohol seeking (Lê et al. 1998).In a search for neurotransmitter systems involved in stress-induced relapse, and for pharmacological manipulations that might prevent it, we explored in the present set of experiments the role of the noradrenergic (NE) system, comprised of a dorsal stream of neurons originating in the locus-coeruleus and a ventral stream of neurons originating in the lateral tegmental nuclei (Aston-Jones et al. 1995;Moore and Bloom 1979). Although the stress-related functions of the ventral projections have been only partially characterized (Cole and Robbins 1987;Hansen et al. 1980), NE projections from the LC have been directly implicated in a number From the Center for Studies in Behavioral Neurobiology (SE, PKH, HR, DM, JS), Department of Psychology, Concordia University, Montreal, Quebec, Canada; Behavioral Neuroscience Department(YS), IRP/NIDA, Baltimore, MD.Address correspondence to: Dr. Jane Stewart, Center for Studies in Behavioral Neurobiology, Department of Psychology, 1455 de Maisonneuve Blvd. W., Montreal, Quebec, Canada H3G 1M8 Tel: 514-848-2193, Fax: 514-848-2817, E-mail: Stewart@CSBN.concordia.ca. Received September 20, 1999 revised December 21, 1999; accepted December 28, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 2 alpha -2 Agonists and Relapse to Cocaine Seeking 139 of stress-related responses. For example, electrical stimulation of the LC has been found to induce anxiety and to result in activation of the autonomic nervous system, whereas local injections of the alpha-2 adrenergic receptor agonist clonidine, which acts to inhibit NE cell fi...

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

“…Yohimbine increases central release of noradrenaline, which previous studies have shown to play a critical role in footshock stress-induced reinstatement of drug seeking (Erb et al, 2000;Shaham et al, 2000b;Leri et al, 2002). Thus, we interpret the present data to indicate that brain noradrenaline is involved in yohimbine-induced reinstatement of palatable food seeking.…”

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

“…Similar to the present findings, manipulations of either the CRF or adrenergic neurotransmitter systems blocked stress-induced reinstatement and failed to alter drug-priming-induced reinstatement. The CRF antagonist D-Phe-CRF (Erb et al 1998), the alpha-2 adrenoreceptor agonists clonidine, lofexidine, and guanabenz (Erb et al 2000), as well as a mixture beta-1 and beta-2 adrenoreceptor antagonists (Leri et al 2002) were able to attenuate footshock-induced but not cocaine-induced reinstatement. It seems reasonable then that a mechanism for stress-induced reinstatement of drug-seeking behavior may involve not only the dynorphin/kappa system but also an interaction between the kappa opioid, CRF, and/or adrenergic neurotransmitter systems.…”

Involvement of Arginine Vasopressin and V1b Receptor in Heroin Withdrawal and Heroin Seeking Precipitated by Stress and by Heroin

“…In addition, both the basolateral and central nucleus of the amygdala receive NA projections that are sensitive to stress and to adrenergic manipulations (Quirarte et al, 1998). Exposure to foot shock, for example, increases NA release in these regions (Quirarte et al, 1998;Hatfield et al, 1999;Erb et al, 2000). Also, partial 6-hydroxydopamine lesions of the ventral NA bundle projecting to the amygdala attenuate foot shock-induced reinstatement of heroin seeking (Shaham et al, 2000b), and blockade of beta-NA receptors within the central amygdala block the stress-induced reinstatement (Leri et al, 2002).…”