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

Neuropsychopharmacology (2008) 33, 814–826 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 www.neuropsychopharmacology.org 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 John R Mantsch*,1, David A Baker1, Joseph P Serge1, Michael A Hoks1, David M Francis1 and Eric S Katz1 1 Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA 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. Neuropsychopharmacology (2008) 33, 814–826; doi:10.1038/sj.npp.1301464; published online 30 May 2007 Keywords: addiction; neuroplasticity; corticosterone; escalation; relapse; cocaine INTRODUCTION The unpredictable relapse of cocaine use that occurs even after extended periods of drug abstinence is the primary obstacle to the effective management of cocaine addiction. This chronically relapsing nature of cocaine addiction is likely attributable to long-lasting, if not permanent, neuroplasticity that emerges as a consequence of repeated drug use. Understanding the neuroplasticity that determines susceptibility to drug relapse is essential for the development of new and more effective therapeutic interventions aimed at minimizing the risk that renewed drug use will occur following detoxification. One approach that has been used to investigate cocaineinduced neuroplasticity that is pathogenic for addiction has *Correspondence: Dr JR Mantsch, Department of Biomedical Sciences, Marquette University, Schroeder Health Complex, PO Box 1881, Milwaukee, WI 53201, USA, Tel: + 1 414 288 2036, Fax: + 1 414 288 6564, E-mail: Received 25 September 2006; revised 26 April 2007; accepted 27 April 2007 involved the study of rats provided chronic daily prolonged access to cocaine for self-administration (SA). Rats provided long access to cocaine for SA each day (longaccess; LgA rats), but not rats provided shorter drug access (short-access; ShA rats), display a progressive escalation of cocaine intake suggested to be related to the loss of control over drug use that is central to human cocaine addiction (Ahmed and Koob, 1998, 1999). We and others have demonstrated that LgA rats also display greater reinstatement following administration of cocaine (Mantsch et al, 2004; Ahmed and Cador, 2006), cocaine-associated cues (Kippin et al, 2006), and a stressor (electric footshock; unpublished observation) when measured several weeks after SA testing compared to ShA rats. Thus, cocaine SA appears to produce long-term neuroadaptations that lead to a heightened susceptibility to engage in cocaine-seeking behavior and emerge in an intake-dependent manner. Glucocorticoids secreted as a consequence of activation of the stressor-responsive hypothalamic–pituitary–adrenal (HPA) axis play a critical role in physiological processes that enable organisms to effectively adapt to and cope with Adrenal regulation of cocaine-induced neuroplasticity JR Mantsch et al 815 stressors (de Kloet et al, 2005; McEwen, 2005). Although elevated glucocorticoids are of short-term benefit to an organism, prolonged and/or repeated elevations of glucocorticoids during periods of chronic stress are maladaptive and lead to a number of pathological conditions, some of which may contribute to the addiction process. For example, it has been reported that elevated corticosterone (CORT) during periods of chronic or repeated stress is involved in the stressor-induced facilitation of cocaine SA (Goeders and Guerin, 1996a, b; Mantsch et al, 1998; Campbell and Carroll, 2001) and in the stressor-induced sensitization of the locomotor stimulating effects of cocaine (Prasad et al, 1998; Rouge-Pont et al, 1995). More recently, we have demonstrated that daily exposure to a stressor, uncontrollable electric footshock stress, at the time of SA testing produces a progressive escalation of cocaine SA that is dependent on elevated glucocorticoids, suggesting that the neuroplasticity that contributes to heightened drugseeking behavior in cocaine addicts may be glucocorticoid dependent (Mantsch and Katz, 2007). Like stressors, self-administered cocaine increases glucocorticoid secretion in rats (Galici et al, 2000), nonhuman primates (Broadbear et al, 1999), and human cocaine addicts (Ward et al, 1999; Ghitza et al, 2007). When rats self-administer cocaine during LgA sessions, increases in plasma CORT are greater and more persistent than they are in ShA rats (Mantsch et al, 2003) and physiological signs of increased glucocorticoid secretion (eg reductions in thymus weight and adrenal hypertrophy) are exaggerated (unpublished observation). Thus, any contribution of elevated glucocorticoids to cocaine-induced neuroplasticity should be particularly pronounced in rats self-administering cocaine under LgA conditions. The goal of the present study was to investigate how elevation of glucocorticoids as a consequence of cocaine SA under LgA conditions contributes to addiction-related neuroplasticity expressed as escalating patterns of cocaine intake and augmented cocaine-induced reinstatement. The role of elevated glucocorticoids was examined by surgically adrenalectomizing rats and then providing them with hormone replacement using a protocol that maintains di (...truncated)