Surgical Adrenalectomy with Diurnal Corticosterone Replacement Slows Escalation and Prevents the Augmentation of Cocaine-Induced Reinstatement in Rats Self-Administering Cocaine Under Long-Access Conditions

Abstract

The loss of control over cocaine use and persistently heightened susceptibility to drug relapse that define human cocaine addiction are consequences of drug-induced neuroplasticity and can be studied in rats self-administering cocaine under conditions of daily long access (LgA) as escalating patterns of drug intake and heightened susceptibility to reinstatement. This study investigated the potential contribution of elevated glucocorticoids at the time of LgA cocaine self-administration (SA) to these behavioral indices of addictionrelated neuroplasticity. Rats provided 14 days of 6-h access (LgA) to cocaine showed a progressive escalation of SA and were more susceptible to cocaine-induced reinstatement (10 mg/kg, i.p.) compared to rats self-administering under short-access (ShA; 2 h) conditions. A surgical adrenalectomy and corticosterone replacement (ADX/C) regimen that eliminated SA-induced increases in corticosterone (CORT) while maintaining the diurnal pattern of secretion failed to alter SA or reinstatement in ShA rats but slowed escalation and attenuated later reinstatement in LgA rats when applied before but not after chronic LgA SA testing. Although the contribution of other adrenal hormones cannot be ruled out, these data suggest that elevated glucocorticoids at the time of cocaine exposure may be required for the effects of LgA SA on cocaine intake and later reinstatement. The inability of daily CORT administration before daily ShA SA, at a dose that reproduced the response during LgA SA, to mimic the effects of LgA SA suggests that elevated glucocorticoids during SA may play a permissive role in cocaine-induced neuroplasticity that contributes to addiction.

Adrenal Activity during Repeated Long-Access Cocaine Self-Administration is Required for Later CRF-Induced and CRF-Dependent Stressor-Induced Reinstatement in Rats

“…We have reported that an intact adrenal response at the time of earlier drug SA is necessary for the establishment of neuroadaptations that lead to heightened cocaine seeking Mantsch et al, 2008b). Our findings are consistent with previous reports that eliminating cocaine-induced adrenal responses during the induction phase prevents the later expression of stress-and cocaine-induced sensitization (Rouge-Pont et al, 1995;Prasad et al, 1996Prasad et al, , 1998Przegaliński et al, 2000;de Jong et al, 2007).…”

“…It has been suggested that escalated SA reflects the loss of control over drug use that is central to human cocaine addiction. As reported previously Mantsch et al, 2008b), ADX/C failed to alter SA before escalation (ie, on the first day of testing), consistent with reports in monkeys and human addicts that increased glucocorticoid secretion by cocaine is not necessary for its acute reinforcing effects (Broadbear et al, 1999b;Ward et al, 1999). Others have shown that complete elimination of glucocorticoids by surgical or pharmacological ADX in the absence of corticosterone replacement attenuates cocaine SA in rats (Goeders and Guerin, 1996;Deroche et al, 1997).…”

“…CRF is also augmented following long-access SA (Mantsch et al, 2008a). Cocaine SA under long-access conditions produces robust and prolonged increases in plasma corticosterone (Mantsch et al, 2003, and elimination of the adrenal response to long-access SA attenuates later cocaine-induced reinstatement (Mantsch et al, 2008b). In this paper, we show that CRF-dependent stress-induced reinstatement and reinstatement by CRF also rely on an intact adrenal response at the time of earlier long-access SA.…”

“…Like stress, cocaine SA elevates circulating glucocorticoid levels in rats (Galici et al, 2000;Mantsch et al, 2003), monkeys (Broadbear et al, 1999a), and human addicts (Ward et al, 1999). Not surprisingly, when rats self-administer cocaine under long-access conditions, the increase in corticosterone is prolonged, matching the duration of drug exposure and potentially rendering these rats more susceptible to later cocaine seeking (Mantsch et al, 2003(Mantsch et al, , 2008b.…”

“…and xylazine (2 mg/kg, i.p.) anesthesia (Mantsch et al, 2008b). Catheters were connected to back-mounted cannulae (Plastics One, Roanoke, VA) attached using dental acrylic to pieces of polypropylene monofilament surgical mesh (Atrium Medical, Hudson, NH) to permit connection of polyurethane delivery lines (0.51 mm i.d.…”