Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2

Abstract

Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 μg/side) or antisauvagine-30 (ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1-dependent regulation of addiction-related neurocircuitry in the VTA.

Figure 1.

A–C, Injection sites within the VTA for the following: LgA rats (triangles), ShA rats (squares), and Sal rats (circles) (A); LgA rats tested for CRF-induced reinstatement following CP-376395 (triangles), ASV-30 (circles), antalarmin (diamonds), and astressin-2B (squares), or LgA rats tested for footshock-induced reinstatement (stars) (B); and rats tested for effects on food-reinforced responding (open circles) and LgA rats tested for reinstatement by CRF receptor agonists (closed circles) (C).

Figure 2.

Self-administration, extinction, and reinstatement of cocaine seeking by intra-VTA injections of CRF in ShA (14 × 2 h/d) and LgA (14 × 6 h/d) rats and in saline self-administration control rats. A, Data represent the daily mean hourly numbers of self-administered infusions (±SE) in ShA, LgA, and Sal rats across the 14 day test period. Escalation was observed in LgA, but not ShA or Sal rats (**p < 0.05 overall effect), and self-administration was increased in LgA rats compared with ShA (and Sal) rats on days 5 and 9–14 of self-administration (*p < 0.05). The cumulative total cocaine intake (in milligrams per kilogram ± SE) in ShA and LgA rats is shown in the inset in A. Intake was markedly and significantly increased in LgA rats (**p < 0.001 vs ShA rats). B, Responding (±SE) during the final self-administration session (represented as the 2 h mean in LgA rats) and the 10 consecutive 2 h extinctions sessions is shown. Significant differences in extinction responding between ShA and LgA rats were not found. C, Significant intra-VTA CRF-induced reinstatement was observed in LgA but not ShA rats, and CRF-induced responding was significantly higher in LgA rats compared with ShA rats and Sal controls at both doses tested (*p < 0.05), and increased compared with vehicle at the 500 ng/side (but not the 250 ng/side) CRF dose (^#p < 0.05). D, Effects on responding on the previously inactive lever during reinstatement testing were not found.

Figure 3.

Effects of intra-VTA injections of CRF-R1 antagonists on reinstatement by intra-VTA CRF delivery and footshock stress in LgA rats. A, B, Data represent the effects of bilateral injections of antalarmin (A, 500 ng/side; n = 7), CP-376395 (B, 500 ng/side; n = 6), or vehicle on reinstatement by bilateral intra-VTA delivery of CRF (500 ng/side) and the effects of bilateral injections of antalarmin (500 ng/side) on reinstatement (responses/2 h session ± SE) by electric footshock (C, n = 6). In all cases, significant reinstatement was observed in rats pretreated with vehicle [*p < 0.05 vs extinction (Ext)] but not CRF-R1 antagonists, and responding during reinstatement was significantly lower following administration of CRF-R1 antagonists compared with vehicle (^#p < 0.05 vs Veh).

Figure 4.

Effects of intra-VTA injections of CRF-R2 antagonists on reinstatement by intra-VTA CRF delivery and footshock stress in LgA rats. A, B, Data represent the effects of bilateral injections of astressin-2B (A, 500 ng and 1 μg/side; n = 6), ASV-30 (B, 500 ng/side; n = 6), or vehicle on reinstatement by bilateral intra-VTA delivery of CRF (500 ng/side) and the effects of bilateral injections of astressin-2B (500 ng/side) on reinstatement (responses/2 h session ± SE) by electric footshock (C, n = 8). In all cases, significant reinstatement was observed in rats pretreated with vehicle or CRF-R2 antagonists [*p < 0.05 vs extinction (Ext)], while CRF-R2 antagonist pretreatments failed to attenuate reinstatement by intra-VTA CRF or shock.

Figure 5.

Reinstatement by intra-VTA administration of the CRF-R1-selective agonist cortagine and the CRF-R2-selective agonist rUCN II in LgA rats (n = 5). Cortagine (100 ng/side), but not UCN II (250 ng/side) or vehicle, reinstated extinguished cocaine seeking (*p < 0.05 vs vehicle and the preceding extinction session). The data represent responding on the cocaine lever (responses/2 h session ± SE) during extinction or following bilateral intra-VTA cortagine or Veh treatment.