Extended access cocaine self-administration differentially activates dorsal raphe and amygdala corticotropin-releasing factor systems in rats

Abstract

Cocaine-induced neuroadaptation of stress-related circuitry and increased access to cocaine each putatively contribute to the transition from cocaine use to cocaine dependence. The present study tested the hypothesis that rats receiving extended versus brief daily access to cocaine would exhibit regional differences in levels of the stress-regulatory neuropeptide corticotropin-releasing factor (CRF). A secondary goal was to explore how CRF levels change in relation to the time since cocaine self-administration. Male Wistar rats acquired operant self-administration of cocaine and were assigned to receive daily long access (6 hours/day, LgA, n=20) or short access (1 hour/day, ShA, n=18) to intravenous cocaine self-administration (fixed ratio 1, ~0.50 mg/kg/infusion). After at least 3 weeks, tissue CRF immunoreactivity was measured at one of three timepoints: pre-session, post-session or 3 hours post-session. LgA, but not ShA, rats showed increased total session and first-hour cocaine intake. CRF immunoreactivity increased within the dorsal raphe (DR) and basolateral, but not central, nucleus of the amygdala (BLA, CeA) of ShA rats from pre-session to 3 hours post-session. In LgA rats, CRF immunoreactivity increased from pre-session to 3 hours post-session within the CeA and DR but tended to decrease in the BLA. LgA rats showed higher CRF levels than ShA rats in the DR and, pre-session, in the BLA. Thus, voluntary cocaine intake engages stress-regulatory CRF systems of the DR and amygdala. Increased availability of cocaine promotes greater tissue CRF levels in these extrahypothalamic brain regions, changes associated here with a model of cocaine dependence.

Figure 1

Self-administration of cocaine by rats under a fixed-ratio schedule during the escalation period. Data from the first hour of sessions (a) and from the entire session (b). The data represent least squares mean (±SEM) cocaine intake adjusted for body weight (mg/kg). Filled symbols represent data for rats in 1-hour short-access sessions (ShA, n = 18). Open symbols represent data for rats in 6-hour long-access sessions (LgA, n = 20). Note that error bars in panel b for ShA rats are smaller than the symbol. *P < 0.05, **P < 0.01, ***P < 0.001 versus ShA group and versus baseline (‘B’) first hour intake (a) or session 1 intake (b) (Fisher’s protected LSD tests)

Figure 2

Regional brain corticotropin-releasing factor (CRF) levels in rats receiving daily short-access (1 hour/day, ShA, n = 18) or long-access (6 hours/day, LgA, n = 20) to intravenous cocaine self-administration. Panels show CRF concentrations in the (top) central nucleus of the amygdala (CeA), (middle) basolateral nucleus of the amygdala (BlA) or (bottom) dorsal raphe (DR). The data represent least squares mean (±SEM) CRF immunoreactivity normalized for total protein content (pg/mg) across the following 3 timepoints of observation (n = 6–7 per timepoint): the time of day the self-administration would otherwise occur (pre-session), immediately following the completion of the self-administration session (post-session), or 3 hours following the completion of the self-administration session (3 hours post). Note scale differences across regions. **P < 0.01 versus other timepoints, # P < 0.05 versus respective ShA group (Fisher’s protected LSD tests)