Blockade of Stress-Induced But Not Cocaine-Induced Reinstatement by Infusion of Noradrenergic Antagonists into the Bed Nucleus of the Stria Terminalis or the Central Nucleus of the Amygdala

Abstract

Experiments in our laboratory have shown that central noradrenergic (NA) activation plays a major role in stress-induced reinstatement of drug seeking in rats. In the present experiments, we investigated the effects of blockade of beta-NA adrenoceptors in the bed nucleus of the stria terminalis (BNST) and in the region of the central nucleus of the amygdala (CeA) on footshock- and cocaine-induced reinstatement. Rats were trained to self-administer cocaine (0.5 mg/kg, i.v.) for 9 d and, after a 5-7 d drug-free period, were given extinction sessions followed by a test for footshock stress-induced (15 min of intermittent footshock, 0.8 mA) or cocaine-induced (20 mg/kg, i.p.) reinstatement. Before the test, different groups of rats were given bilateral infusions of one of four doses of a mixture of the beta(1)- and beta(2)-receptor antagonists betaxolol and ICI-118,551 (vehicle, 0.25, 0.5, and 1 nmol of each compound in 0.5 microliter) into either the BNST or CeA. We observed a dose-dependent reduction of stress-induced reinstatement after infusions into the BNST and a complete blockade of stress-induced reinstatement after infusions into the CeA at all doses tested. The same treatments did not block cocaine-induced reinstatement when given at either site. These data suggest that stress-induced NA activation in the BNST and in the region of the CeA is critical to relapse to drug seeking induced by stress but not to relapse induced by priming injections of cocaine, and we hypothesize that NA activity leads to activation of corticotropin-releasing factor neurons in these regions.

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

“…Using procedures such as these, the a 2 -adrenoceptor agonist clonidine has been shown to inhibit footshock-induced reinstatement of cocaine seeking in rats . In addition, a mixture of b 1 -and b 2 -adrenoceptor antagonists betaxolol and ICI-118,551, when injected into the bed nucleus of the stria terminalis or the central nucleus of the amygdala, can inhibit footshock-induced reinstatement of cocaine-seeking behavior in this species (Leri et al, 2002). These results suggest that modulation of central noradrenergic systems may play a role in stress-induced reinstatement of cocaine-seeking behavior.…”

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.…”

“…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).…”

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

“…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). In the present studies, we found that the AVP mRNA levels were enhanced by foot shock in the amygdala of rats withdrawn from heroin self-administration but not in the amygdala of the heroin naïve rats.…”