Regulation of CRF mRNA in the Rat Extended Amygdala Following Chronic Cocaine: Sex Differences and Effect of Delta Opioid Receptor Agonism

BACKGROUND: Cocaine withdrawal activates stress systems. Females are more vulnerable to relapse to cocaine use and more sensitive to withdrawal-induced negative affect. Delta opioid receptors modulate anxiety-like behavior during cocaine withdrawal in rats. This study measured the time course of gene regulation of one of the main stress peptides, corticotropin-releasing factor (CRF), and its type 1 receptor in male and female rats as well as the ability of the delta opioid receptor agonist SNC80 to normalize cocaine withdrawal-induced changes in CRF mRNA. METHODS: Rats were injected with cocaine or saline 3 times daily for 14 days. Brains were collected 30 minutes, 24 hours, 48 hours, 7 days, and 14 days following the last injection. The paraventricular nucleus of the hypothalamus, central amygdala, and bed nucleus of the stria terminalis were processed for quantitative reverse transcriptase PCR measurement of CRF and CRFR1 mRNA. Additional rats received SNC80 during early cocaine withdrawal, and CRF mRNA was measured in the central amygdala. RESULTS: CRF mRNA was elevated in the central amygdala at 24 hours and the paraventricular nucleus at 48 hours of cocaine withdrawal in males and females. Significant sex differences in cocaine-induced CRF upregulation were found in the bed nucleus of the stria terminalis at 30 minutes and 24 hours. SNC80 administration attenuated the increase in CRF mRNA in the central amygdala of female rats only. CONCLUSIONS: CRF mRNA regulation during cocaine withdrawal is sex, time, and brain region dependent. Administration of a delta opioid receptor agonist during early withdrawal may ameliorate stress-related negative affect in females by abrogating the induction of CRF mRNA.