CP-154,526, a selective, non-peptide antagonist of the corticotropin-releasing factor 1 receptor attenuates stress-induced relapse to drug seeking in cocaine- and heroin-trained rats

Abstract

We have found that peptide antagonists of corticotropin-releasing factor (CRF) receptors attenuate reinstatement of heroin and cocaine seeking induced by footshock. Here we examined the effect of a nonpeptide, selective CRF1 receptor antagonist, CP-154,526, on reinstatement of heroin and cocaine seeking induced by footshock. Rats were trained to self-administer heroin or cocaine (0.1 and 1.0 mg/kg per infusion, i.v., respectively) for 9-12 days. Extinction sessions were given for up to 14 days, during which saline was substituted for the drugs. Tests for reinstatement were then conducted after exposure to intermittent footshock (10 or 15 min, 0.5 mA). The footshock stressor reliably reinstated extinguished cocaine- and heroin-taking behavior. Pretreatment with CP-154,526 (15 and 30 mg/kg, s.c.) significantly attenuated the reinstatement effect of the stressor in both heroin- and cocaine-trained rats. CP-154,526, administered in the absence of the footshock stressor, did not affect extinguished drug seeking. In addition, in a separate experiment, CP-154,526 was shown not to alter high rates of lever pressing for a 10% sucrose solution, suggesting that the suppression of lever pressing in stress-induced reinstatement is not caused by a performance deficit. These results extend previous reports on the role of CRF in reinstatement of drug seeking induced by stressors. The present data also suggest that, to the extent that exposure to environmental stressors provoke relapse to drug use in humans, systemically effective CRF receptor antagonists may be of use in the treatment of relapse to drug use.

Repeated Stimulation of CRF Receptors in the BNST of Rats Selectively Induces Social but not Panic-Like Anxiety

“…It is well established that the activation of central CRF system is essential for stress-induced reinstatement of drug-seeking behavior (Shaham et al, 1997;Le et al, 2000;Shalev et al, 2006), and CRF receptor antagonism blocks this stress effect (Shaham et al, 1998). Identifying the BNST as a key structure for mediating this phenomenon, Erb and Stewart reported that stress-induced reinstatement of drugseeking behavior is mimicked by an intra-BNST injection of CRF and blocked by an intra-BNST injection of a CRF antagonist, D-Phe CRF (Erb and Stewart, 1999).…”

Elevation of Glucocorticoids is Necessary but not Sufficient for the Escalation of Cocaine Self-Administration by Chronic Electric Footshock Stress in Rats

“…Although SAinduced increases in plasma CORT were less pronounced than those evoked by EFS, the observed elevation of CORT in the absence of increased SA provides further evidence that elevated CORT alone is insufficient to produce escalation and suggests that CORT is exerting its permissive effects on neurobiological systems that are directly responsive to stressors and not cocaine. Although it is not clear exactly which glucocorticoid-dependent stressor-responsive target is responsible for the escalating effects of EFS, a strong case can be made for corticotropin releasing factor (CRF), which has been identified as a mediator of EFSinduced but not cocaine-induced reinstatement of extinguished cocaine-seeking behavior Shaham et al, 1998 andsee Sarnyai et al, 2001 for review).…”

Altered HPA Axis Responsivity to Metyrapone Testing in Methadone Maintained Former Heroin Addicts with Ongoing Cocaine Addiction

“…The HPA axis hyper-responsivity to metyraponeinduced removal of glucocorticoid negative feedback in the present study suggests that endogenous opioidergic dysfunction may be involved in the mechanism of perpetuation of, and relapse to, cocaine addiction, and reinforces lines of inquiry into novel pharmacological treatments. Corticotropin-releasing factor antagonists have been demonstrated to attenuate stress-induced drug-seeking behavior (Shaham et al 1998) as well as IV cocaine self-administration (Goeders and Guerin 1998) in animal models. In addition, kappa opioid agonists, which may be acting to modulate cocaine-associated alterations in dopaminergic function, as well as alterations in HPA axis function, have been shown to affect cocaine self-administration and reinstatement of self-administration stimulated by cocaine exposure after a period of abstinence (Schenk et al 1999).…”