Research ReportDaily cocaine self-administration under long-access conditions augments restraint-induced increases in plasma corticosterone and impairs glucocorticoid receptor-mediated negative feedback in rats
Introduction
A role for stress in cocaine addiction has been established (Sinha, 2001). In addition to findings that stress promotes cocaine-seeking behavior, it has been reported that stress responses emerge or are exaggerated as a result of prior cocaine exposure, suggesting that the relationship between stress and cocaine abuse represents a self-perpetuating cycle within which stress serves as both a precipitating factor for and consequence of drug use.
This complex relationship between stress and cocaine addiction likely involves the hypothalamic–pituitary–adrenal (HPA) axis. Increases in circulating glucocorticoid levels as a consequence of stressor-induced activation of the HPA axis appear to promote cocaine-seeking behavior (Goeders, 2002, Marinelli and Piazza, 2005). The HPA axis is also stimulated by cocaine in rats (Moldow and Fischman, 1987, Rivier and Vale, 1987), monkeys (Sarnyai et al., 1996, Broadbear et al., 1999) and humans (Mendelson et al., 1992, Baumann et al., 1995) through a mechanism dependent on the release of the peptide corticotropin-releasing hormone (CRH) from the terminals of parvocellular neurons originating in the paraventricular nucleus (PVN) of the hypothalamus (Rivier and Vale, 1987, Sarnyai et al., 1992). The effects of cocaine on the HPA axis are dependent upon the contingency of drug delivery. When cocaine is self-administered, its effects on plasma adrenocorticotropic hormone (ACTH) and cortisol in monkeys (Broadbear et al., 1999) or corticosterone (CORT) in rats (Galici et al., 2000) are different than those produced by non-self-administered cocaine delivered under otherwise identical conditions. For this reason, the use of self-administration (SA) procedures is likely more appropriate for examination of alterations in HPA function associated with cocaine use.
With repeated cocaine administration, adaptive changes in the HPA axis emerge and can be observed as disrupted basal HPA function during drug withdrawal in cocaine-dependent individuals (Vescovi et al., 1992, Buydens-Branchey et al., 2002, Contoreggi et al., 2003) and in rats (Sarnyai et al., 1998, Zorrilla et al., 2001, Zhou et al., 2003). Less is known about how the response of the HPA axis to stressors is altered as a consequence of prior cocaine use. Preclinical studies examining withdrawal from repeated experimenter-delivered psychomotor stimulant drug administration have reported either no change in (Levy et al., 1994, Sarnyai et al., 1998) or an augmentation of (Mantsch et al., 2007, Barr et al., 2002) the stressor-induced CORT and/or ACTH response. These effects appear to depend on the pattern and/or amount of drug exposure as well as the duration of withdrawal. Notably, similar discrepancies have been found when examining the effects of repeated drug exposure on the HPA response to cocaine, with no changes in (Borowsky and Kuhn, 1991, Levy et al., 1992), augmentation of (Schmidt et al., 1995), or attenuation of (Zhou et al., 1996) the HPA response reported, depending on the treatment parameters used.
A clearer understanding how HPA reactivity is altered in cocaine addiction will likely be facilitated by examination of stressor-induced HPA activation in rats self-administering cocaine under conditions that produce levels and patterns of drug exposure as well as behavioral profiles that better resemble those associated with use by human addicts. For this reason, we chose to examine the impact of cocaine SA on stressor-induced HPA activation using rats provided extended (i.e., 6 h) daily access to cocaine. We and others have shown that rats self-administering under long-access conditions display a number of behavioral responses thought to be related to human cocaine addiction, including a progressive escalation of cocaine intake (Ahmed and Koob, 1998) and a persistently heightened susceptibility to reinstatement in response to a cocaine challenge (Mantsch et al., 2004, Ahmed and Cador, 2006), cocaine-associated cues (Kippin et al., 2006), and stressors (unpublished data). Repeated extended-access (i.e., 10 h) cocaine SA also produces persistent changes in basal HPA function, including a reduction in basal CORT levels and anterior pituitary POMC mRNA expression (Mantsch et al., 2003). Although it is possible that the observed reductions in basal HPA function may reflect a general attenuation of HPA responsiveness that would also include reduced activity in response to stressors, it is also possible that changes in basal activity augment HPA reactivity to stressors by removing negative feedback exerted by basal CORT and/or producing adaptations in the HPA axis that render it more sensitive to stimulation. This possibility is highlighted by recent findings by Fox et al. (2005) who demonstrated that stressor-induced craving, anxiety, and physiological responses are magnified in high-frequency cocaine users compared to individuals with a lower frequency of cocaine use. Thus, stressor responsiveness appears to increase with the severity of cocaine addiction.
The first goal of this study was to examine persistent changes in basal and stressor-induced HPA activity resulting from cocaine SA under conditions of daily extended drug access. It was hypothesized that, despite previously characterized reductions in basal CORT levels, cocaine SA would result in an intensified HPA response. The second goal of the study was to examine potential neurobiological mechanisms through which HPA responsiveness is altered as a result of cocaine SA. Since glucocorticoid receptors (GR) in the brain and pituitary gland serve as critical negative feedback regulators of HPA function, we chose to examine the effects of cocaine SA on the ability of the GR agonist, dexamethasone (DEX), to suppress plasma CORT levels and on brain and pituitary GR protein expression. Impaired GR-mediated negative feedback would remove inhibitory constraint from the HPA axis, thus augmenting the glucocorticoid response to stressors.
Section snippets
Cocaine SA
Alterations in HPA function were examined using rats permitted to self-administer cocaine under daily long-access conditions for 14 days and saline self-administering controls. Cocaine and saline intake across the 14 days of SA testing is shown in Fig. 1. Since no differences in cocaine SA were observed between rats used for Experiments #1 and #2, SA data from these experiments were combined for statistical analyses. Two-way repeated measures ANOVA showed significant effects of SA condition
Discussion
The primary finding of the present study is that cocaine SA under long-access conditions produces persistent changes in the activity of the HPA axis, including a reduction in basal plasma CORT levels, an augmentation of the CORT response to restraint, and impaired negative feedback regulation of HPA function that may be partially attributable to reduced hypothalamic GR expression. Surprisingly, the exaggerated CORT response to restraint following cocaine SA was not accompanied by an
Subjects
Seventy-four adult male Sprague-Dawley rats (Harlan Laboratories, Inc., St. Louis, MO), approximately 90 days old (325 g) were used for the study. All rats were housed individually in a temperature- and humidity-controlled, AAALAC-accredited animal facility under a 12 h/12 h reversed light/dark cycle (lights on at 6:00 p.m.) and had access to food and water at all times, except when in the experimental chambers. All procedures were carried out in accordance with the Guide for the Care and Use
Acknowledgments
This work was supported by NIDA grant number DA15758 to JRM. The authors would like to thank Joseph Serge, David Francis, and Tanveer Sajan for their technical assistance and Dr. Pastor Couceyro for his guidance with the in situ hybridization experiment.
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