Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that stress may "set the stage" for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction. Exposure of rats to acute electric footshock stress did not by itself reinstate drug-seeking behavior but potentiated reinstatement in response to a subthreshold dose of cocaine. This effect of stress was not observed in adrenalectomized animals, and was reproduced in nonstressed animals by administration of corticosterone at a dose that reproduced stress-induced plasma levels. Pretreatment with the glucocorticoid receptor antagonist RU38486 did not block the corticosterone effect. Corticosterone potentiated cocaine-induced increases in extracellular dopamine in the nucleus accumbens (NAc), and pharmacological blockade of NAc dopamine receptors blocked corticosterone-induced potentiation of reinstatement. Intraaccumbens administration of corticosterone reproduced the behavioral effects of stress and systemic corticosterone. Corticosterone treatment acutely decreased NAc dopamine clearance measured by fast-scan cyclic voltammetry, suggesting that inhibition of uptake 2 -mediated dopamine clearance may underlie corticosterone effects. Consistent with this hypothesis, intra-accumbens administration of the uptake 2 inhibitor normetanephrine potentiated cocaine-induced reinstatement. Expression of organic cation transporter 3, a corticosterone-sensitive uptake 2 transporter, was detected on NAc neurons. These findings reveal a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake.

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, ip) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and re-established by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim; FS; 20–25°C water), or administration of the alpha-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, ip) or BRL44408 (5, 10 mg/kg, ip). To investigate the role of ARs, mice received the non-selective beta AR antagonist, propranolol (5, 10 mg/kg, ip), the alpha-1 AR antagonist, prazosin (1, 2 mg/kg, ip), or the alpha-2 AR agonist, clonidine (0.03, 0.3 mg/kg, ip) prior to reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting involvement of beta ARs. The beta-2 AR antagonist ICI-118551 (1 mg/kg, ip), but not the beta-1 AR antagonist, betaxolol (10 mg/kg, ip) also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through beta-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate.

The ventral bed nucleus of the stria terminalis (vBNST) has been implicated in stress-induced cocaine use. Here we demonstrate that, in the vBNST, corticotropin releasing factor (CRF) is expressed in neurons that innervate the ventral tegmental area (VTA), a site where the CRF receptor antagonist antalarmin prevents the reinstatement of cocaine seeking by a stressor, intermittent footshock, following intravenous self-administration in rats. The vBNST receives dense noradrenergic innervation and expresses ␤ adrenergic receptors (ARs). Footshock-induced reinstatement was prevented by bilateral intra-vBNST injection of the ␤-2 AR antagonist, ICI-118,551, but not the ␤-1 AR antagonist, betaxolol. Moreover, bilateral intra-vBNST injection of the ␤-2 AR agonist, clenbuterol, but not the ␤-1 agonist, dobutamine, reinstated cocaine seeking, suggesting that activation of vBNST ␤-2 AR is both necessary for stress-induced reinstatement and sufficient to induce cocaine seeking. The contribution of a ␤-2 AR-regulated vBNST-to-VTA pathway that releases CRF was investigated using a disconnection approach. Injection of ICI-118,551 into the vBNST in one hemisphere and antalarmin into the VTA of the contralateral hemisphere prevented footshock-induced reinstatement, whereas ipsilateral manipulations failed to attenuate stressinduced cocaine seeking, suggesting that ␤-2 AR regulate vBNST efferents that release CRF into the VTA, activating CRF receptors, and promoting cocaine use. Last, reinstatement by clenbuterol delivered bilaterally into the vBNST was prevented by bilateral vBNST pretreatment with antalarmin, indicating that ␤-2 AR-mediated actions in the vBNST also require local CRF receptor activation. Understanding the processes through which stress induces cocaine seeking should guide the development of new treatments for addiction.

The bed nucleus of the stria terminalis was first described nearly a century ago and has since emerged as a region central to motivated behavior and affective states. The last several decades have firmly established a role for the BNST in drug-associated behavior and implicated this region in addiction-related processes. Whereas past approaches used to characterize the BNST have focused on a more general role of this region and its subnuclei in behavior, more recent work has begun to reveal its elaborate circuitry and cellular components. Such recent developments are largely owed to methodological advances, which have made possible efforts previously deemed intractable, such as tracing of long-range cell-type specific projections and identifying functional efferent and afferent connections. In this review, we integrate earlier foundational work with more recent and advanced studies to construct a broad overview of the molecular neurocircuitry of the BNST in drug-associated behavior and affect.

These findings suggest that stress-induced increases in corticosterone promote cocaine seeking by mobilizing 2-arachidonoylglycerol in the PL, resulting in CBR-mediated attenuation of inhibitory transmission in this brain region.

Stress can trigger the relapse of drug use in recovering cocaine addicts and reinstatement in rodent models through mechanisms that may involve norepinephrine release and ␤-adrenergic receptor activation. The present study examined the role of ␤-adrenergic receptor subtypes in the stressor-induced reinstatement of extinguished cocaine-induced (15 mg/kg i.p.) conditioned place preference in mice. Forced swim (6 min at 22°C) stress or activation of central noradrenergic neurotransmission by administration of the selective ␣ 2 adrenergic receptor antagonist 2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole (BRL-44,408) (10 mg/kg i.p.) induced reinstatement in wild-type, but not ␤-adrenergic receptor-deficient Adrb1/Adrb2 double-knockout, mice. In contrast, cocaine administration (15 mg/kg i.p.) resulted in reinstatement in both wild-type and ␤-adrenergic receptor knockout mice. Stress-induced reinstatement probably involved ␤ 2 adrenergic receptors. The ␤ 2 adrenergic receptor antagonist -(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol (ICI-118,551) (1 or 2 mg/kg i.p.) blocked reinstatement by forced swim or BRL-44,408, whereas administration of the nonselective ␤-adrenergic receptor agonist isoproterenol (2 or 4 mg/kg i.p.) or the ␤ 2 adrenergic receptor-selective agonist clenbuterol (2 or 4 mg/kg i.p.) induced reinstatement. Forced swim-induced, but not BRL-44,408-induced, reinstatement was also blocked by a high (20 mg/kg) but not low (10 mg/kg) dose of the ␤ 1 adrenergic receptor antagonist betaxolol, and isoproterenol-induced reinstatement was blocked by pretreatment with either ICI-118,551 or betaxolol, suggesting a potential cooperative role for ␤ 1 and ␤ 2 adrenergic receptors in stress-induced reinstatement. Overall, these findings suggest that targeting ␤-adrenergic receptors may represent a promising pharmacotherapeutic strategy for preventing drug relapse, particularly in cocaine addicts whose drug use is stress related.

Levo-tetrahydropalmatine (l-THP) is an alkaloid found in many traditional Chinese herbal preparations and has a unique pharmacological profile that includes dopamine receptor antagonism. Previously we demonstrated that l-THP attenuates fixed-ratio (FR) cocaine selfadministration (SA) and cocaine-induced reinstatement in rats at doses that do not alter food-reinforced responding. This study examined the effects of l-THP on cocaine and food SA under progressive-ratio (PR) schedules of reinforcement and the discriminative stimulus effects of cocaine. In adult male Sprague-Dawley rats self-administering cocaine (0.5 or 1.0 mg/kg/inf), l-THP significantly reduced breaking points at the 1.875, 3.75 and 7.5 mg/kg doses. l-THP also reduced the breaking points and response rates for PR SA of sucrose-sweetened food pellets, although the decrease was significant only at the 7.5 mg/kg l-THP dose. In rats trained to discriminate cocaine (10 mg/kg, ip) from saline, l-THP (1.875, 3.75 and 7.5 mg/kg) produced a rightward shift in the dose-response curve for cocaine generalization. During generalization testing, l-THP reduced response rate, but only at the 7.5 mg/kg dose. l-THP also prevented substitution of the dopamine D2/D3 receptor agonist, (+/−) 7-OH-DPAT, for cocaine suggesting a potential role for antagonism of D2 and/or D3 receptors in the effects of l-THP. These data further demonstrate that l-THP attenuates the reinforcing and subjective effects of cocaine at doses that do not produce marked motor effects and provide additional evidence that l-THP may have utility for the management of cocaine addiction.

Rationale Under some conditions stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a sub-threshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well-defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior. Objectives To test the hypothesis that cannabinoid receptor 1 (CB1R) signaling is required for stress-potentiated reinstatement of cocaine seeking in rats. Methods Following i.v. cocaine self-administration (2 hr access/day) and extinction in male rats, footshock stress alone does not reinstate cocaine seeking, but reinstatement is observed when footshock is followed by an injection of an otherwise subthreshold dose of cocaine (2.5 mg/kg, i.p.). CB1R involvement was tested by systemic administration of the CB1R antagonist AM251 (0, 1, or 3 mg/kg, i.p.) prior to testing for stress-potentiated reinstatement. Results Stress-potentiated reinstatement was blocked by both 1 and 3 mg/kg AM251. By contrast, AM251 only attenuated food-reinforced lever pressing at the higher (i.e., 3 mg/kg) dose and did not affect locomotor activity at either dose tested. Neither high-dose cocaine-primed reinstatement (10 mg/kg, i.p.) nor footshock stress-triggered reinstatement following long-access cocaine self-administration (6 hr access/day) were affected by AM251 pretreatment. Footshock stress increased concentrations of both endocannabinoids, N-arachidonylethanolamine and 2-arachidonoylglycerol, in regions of the prefrontal cortex. Conclusions These findings demonstrate that footshock stress increases prefrontal cortical endocannabinoids and stress-potentiated reinstatement is CB1R-dependent, suggesting that CB1R is a potential therapeutic target for relapse prevention, particularly in individuals whose cocaine use is stress-related.