Stress-induced Relapse to Drug Seeking in the Rat; Role of the Bed Nucleus of the Stria Terminalis and Amygdala

Abstract

There is growing interest in the role that the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA), components of the extended amygdala, play in drug addiction. Within the BNST and CeA, there is an extensive system of intrinsic, primarily GABAergic, interconnections known to synthesize a variety of neuropeptides, including corticotrophin-releasing factor (CRF). The actions of CRF at extrahypothalamic sites,including the BNST and CeA, have been implicated in stress responses and in the aversive effects of withdrawal from drugs of abuse. Most recently, we have shown a critical role for extrahypothalamic CRF in stress-induced reinstatement of drug seeking in rats. In attempting to determine which brain circuitry mediates the effect of stress on relapse and, more specifically, where in the brain CRF acts to initiate the behaviours involved in relapse, we focused on the BNST and CeA. In the present paper, we summarize studies we have conducted that explore the role of these brain sites in stress-induced relapse to heroin and cocaine seeking, and then consider how our findings can be understood within the more general context of what is known about the role of the BNST and CeA in stress-related and general approach behaviours, such as drug seeking.

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

“…One potential site is the bed nucleus of the stria terminalis (BNST). In this brain area, antagonism of either CRF receptors or b adrenoceptors attenuates footshock-stressinduced reinstatement of cocaine seeking (Erb and Stewart, 1999;Erb et al, 2001;Leri et al, 2002). In addition, 6-OHDA lesions of the main input to the BNST, the ventral noradrenergic bundle originating from the lateral tegmental noradrenergic nuclei (Aston-Jones et al, 1999), attenuate footshock-stress-induced reinstatement of heroin seeking (Shaham et al, 2000b); see also Wang et al (2001) for a similar finding using a morphine conditioned place preference model.…”

The Human BNST: Functional Role in Anxiety and Addiction

“…For example, the BNST is involved in the anxiogenic effects of cocaine intoxication (Wenzel et al, 2014). In addition, there is compelling evidence that the BNST mediates stressinduced reinstatement of drug-seeking behavior (Buffalari and See, 2011;Erb et al, 2001;Flavin and Winder, 2013;Jennings et al, 2013a), thus serving an important role in understanding relapse following a period of abstinence. Similar to the light-enhanced startle and CRF-enhanced startle described earlier, withdrawal from drugs of abuse also enhances startle response, providing a model for testing effects of pharmacological agents on withdrawal.…”

“…However, there is some evidence that reinstatement of drug-seeking behavior is uniquely mediated by the BNST (Erb et al, 2001;Lu et al, 2003;Shaham et al, 2003), although many addiction studies find similarities in CeA and BNST response (eg, McFarland et al, 2004). These studies highlight the importance of the BNST for understanding mechanisms underlying addiction.…”

Importance of CRF Receptor-Mediated Mechanisms of the Bed Nucleus of the Stria Terminalis in the Processing of Anxiety and Pain

“…The Function of the CRF Receptors in the BNST AL May be Pathway-Dependent Chronic stress and CRF dysregulation in the BNST have been linked to many traits commonly associated with the amygdala dysfunction including fear (Walker et al, 2003), anxiety (Ventura-Silva et al, 2012), anhedonia (Stout et al, 2000), addiction (Erb et al, 2001), and the emotional component of visceral and somatic pain (Deyama et al, 2007;Tran et al, 2012c). Our investigation focused primarily on anxiety and pain behaviors induced by a chronic repeated psychological stressor.…”