Changes in levels of regional CRF-like-immunoreactivity and plasma corticosterone during protracted drug withdrawal in dependent rats

Rationale: Despite prolonged abstinence, prior drug dependence is accompanied by lasting changes in physiology, psychosocial functioning and vulnerability to relapse. One proposed mechanism for these alterations is dysregulation of corticotropin-releasing factor (CRF) neurocircuitry. Objectives: To determine regional brain CRF content and HPA-axis activity during protracted cocaine and ethanol withdrawal in dependent rats. Methods: To study protracted ethanol withdrawal, rats (n=22) were fed a nutritionally complete, ethanol (10% v/v) liquid diet for 3-4 weeks. Controls (n=12) were pair-fed an isocaloric, ethanol-free formulation. To study protracted cocaine withdrawal, rats (n=23) self-administered cocaine (0.25 mg/infusion; FR-5) daily for 3 weeks during 3-h sessions and subsequently were allowed to self-administer cocaine during two 12-h binge sessions. Controls (n=6) received yoked saline infusions. Regional brain CRF-like-immunoreactivity (CRF-LI), plasma ACTH-LI and CORT-LI levels were determined from 1 day to 6 weeks post-withdrawal. Results: Both ethanol- and cocaine-withdrawn rats initially exhibited reduced CRF-LI content in the amygdala followed by a progressive increase culminating in elevated levels 6 weeks post-withdrawal. Ethanol-withdrawn rats also initially had reduced hippocampal, frontal cortical and hypothalamic CRF-LI levels and time-dependent reductions in basal CORT levels. Cocaine-withdrawn rats showed time-dependent elevations in frontal cortical CRF-LI and basal CORT levels. Conclusions: Protracted withdrawal from ethanol or cocaine is associated with altered limbic CRF-LI and circulating CORT levels beyond the detoxification stage. The delayed nature of some changes suggests that they may not represent residual effects of acute withdrawal, but rather emerging manifestations of a separate process, such as allostatic load.