In vivo CRF release in rat amygdala is increased during cocaine withdrawal in self-administering rats

Abstract

Previous studies have suggested a role for corticotropin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) in the aversive and anxiogenic effects of withdrawal from opiates and ethanol. To test whether this role of CRF extends to cocaine withdrawal as well, the release of CRF in rat amygdala was monitored by intracranial microdialysis during a 12-hour session of intravenous cocaine self-administration and subsequent 12-hour cocaine withdrawal period. Cocaine self-administration tended to lower dialysate CRF concentrations to approximately 75% of CRF levels in controls. In contrast, subsequent cocaine withdrawal produced a profound increase in CRF release, which reached peak levels of approximately 400% of baseline between 11 and 12 hours post-cocaine. These results provide evidence that cocaine withdrawal activates CRF neurons in the amygdala, a site that has been implicated in emotional and anxiogenic effects of stress and drug withdrawal syndromes.

Effects of acute ethanol on opioid peptide release in the central amygdala: an in vivo microdialysis study

“…One such site is the basolateral amygdala where opioid receptors are more abundant (Paden et al 1987;Ding et al 1996) and may also mediate ethanol reinforcement (Hyytiä and Kiianmaa 2001). However, we hypothesized that we would observe ethanol-induced increases in opioid peptides in the CeA and we used established coordinates to do so (Merlo-Pich et al 1995;Richter and Weiss 1999;Roberto et al 2004). Thus, a significant amount of our sampling was in the CeA and any one dose group was ensured not to have probes that deviated predominantly from the target site according to our histological assessment.…”

CRF1 receptor antagonists attenuate escalated cocaine self-administration in rats

“…Research substantiating this hypothesis includes findings that extracellular CRF levels are increased in the central amygdala during cocaine, ethanol, cannabinoid, and opioid withdrawal in rats (Richter and Weiss 1999;Merlo-Pich et al 1995;Rodriguez de Fonseca et al 1997;Weiss et al 2001, respectively) and that tissue content levels of CRF in the amygdala are depleted during withdrawal from cocaine or ethanol Funk et al 2006). CRF antagonists have been found to reduce negative emotional states during withdrawal from cocaine (Basso et al 1999, Przegalinski et al 2005, methamphetamine (Moffet and Goeders 2007), nicotine (Bruijnzeel et al 2007), and ethanol (Baldwin et al 1991, Rassnick et al 1993Menzaghi et al 1994).…”

“…Thus, one may speculate that the loading phase is more sensitive than the maintenance phase of the 1-h test session, as presumably, the loading phase would reflect an attempt to reverse the hypothesized increase in CRF activity observed during cocaine withdrawal (Richter and Weiss 1999). However, further analysis of the effect of the CRF 1 antagonists on cocaine intake by LgA rats during the loading and the maintenance phases showed no significant interaction between the antagonist dose and phase intake in LgA rats.…”

“…The hypothesis that CRF may be involved in withdrawal-induced anxiety-like responses is supported by research showing an association between cocaine withdrawal and increased extracellular CRF levels in the amygdala, as well as depleted amygdala CRF tissue content (Richter and Weiss 1999;Zorrilla et al 2001). Intracranial administration of a peptide CRF receptor antagonist blocks cocaine withdrawal-induced anxiety-like behavior in rats (Basso et al 1999).…”

Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented following long-access cocaine self-administration by rats

“…The role of regional changes in CRF actions in this apparent shift remains to be determined. In contrast to stressor-induced reinstatement which appears to involve CRF in the VTA and/or BNST, CRF in the central nucleus of the amygdala, which is markedly elevated during acute withdrawal (Richter and Weiss 1999;Zorrilla et al 2001;Zhou et al 2003), appears to underlie the anxiety associated with acute withdrawal (Sarnyai et al 1995;Basso et al 1999). Therefore, it is possible that distinct CRF systems subserving aversive vs appetitive functions are differentially regulated by repeated cocaine in a way that contributes to the temporally dynamic profile of stressor responsiveness during withdrawal.…”