No abstract

We have shown that intracerebroventricular administration of the corticotropin-releasing factor (CRF) receptor antagonist D-Phe CRF(12-41), blocks footshock-induced reinstatement of drug seeking in cocaine-trained rats. We now report that D-Phe acts in the bed nucleus of the stria terminalis (BNST), and not in the amygdala, to block footshock-induced reinstatement of cocaine seeking. In addition, CRF injections in the BNST, and not in the amygdala, are sufficient to reinstate cocaine seeking. Rats were trained to self-administer cocaine intravenously on a fixed ratio (FR-1) schedule of reinforcement. After 5 drug-free days, animals were returned to the self-administration chambers and given daily extinction and reinstatement test sessions. To test the effects of D-Phe CRF(12-41) on stress-induced reinstatement, rats were pretreated with vehicle or D-Phe in either the BNST (10 or 50 ng per side) or amygdala (50 or 500 ng per side) before being exposed to 15 min of intermittent footshock stress. To test whether injections of CRF itself could induce reinstatement, rats were given vehicle or CRF in either the BNST (100 or 300 ng per side) or amygdala (300 ng per side) 15 min before the session. Injections of D-Phe into the BNST completely blocked footshock-induced reinstatement of cocaine seeking; injections of CRF itself in this structure induced reinstatement. Injections of these compounds into the amygdala were without effect. These findings suggest that activation of CRF receptors in the BNST, but not in the amygdala, is critical for footshock-induced reinstatement of cocaine seeking.

We showed previously that brief footshock stress and priming injections of heroin reinstate heroin-seeking after prolonged drug-free periods. Here, we examined whether the adrenal hormone, corticosterone, and brain corticotropin-releasing factor (CRF) were involved in such reinstatement. We tested the effects of adrenalectomy, chronic exposure to the corticosterone synthesis inhibitor metyrapone (100 mg/kg, s.c., twice daily), acute exposure to metyrapone, acute intracerebroventricular injections of CRF (0.3 and 1.0 microgram), and intracerebroventricular injections of the CRF antagonist alpha-helical CRF (3 and 10 micrograms). Rats were trained to self-administer heroin (100 micrograms/kg/infusion, i.v.) for 12-14 d. Extinction sessions were given for 4-8 d (saline substituted for heroin). Tests for reinstatement were given after priming injections of saline and of heroin (0.25 mg/kg, s.c.), and after intermittent footshock (15 or 30 min, 0.5 mA). Adrenalectomy (performed after training) did not affect reinstatement by heroin but appeared to potentiate the reinstatement by footshock. Chronic exposure to metyrapone (from the beginning of extinction) or an acute injection of metyrapone (3 hr before testing) did not alter the reinstatement of heroin-seeking induced by footshock or heroin. Acute exposure to metyrapone alone potently reinstated heroin-seeking. In addition, acute exposure to CRF reinstated heroin-seeking, and the CRF antagonist alpha-helical CRF attenuated stress-induced relapse. The effect of the CRF antagonist on reinstatement by heroin was less consistent. These results suggest that CRF, a major brain peptide involved in stress, contributes to relapse to heroin-seeking induced by stressors.

We have shown previously, using an animal model of relapse, that acute exposure to intermittent footshock stress induces reinstatement of heroin-taking behavior in rats. Here we report that in rats trained to self-administer cocaine, exposure to acute intermittent footshock stress induces reinstatement of cocaine-taking behavior after prolonged extinction sessions and after a 4- to 6-week drug-free period; an effect comparable to that induced by a priming injection of cocaine. Animals were initially allowed to self-administer cocaine HCl (1.0 mg/kg per infusion, i.v.) during one 3-h session/day for 12 days. Subsequently, extinction conditions were introduced by substituting saline for cocaine so that lever-pressing resulted in i.v. infusions of saline rather than of drug. Extinction conditions were maintained until animals made 15 responses or less in the 3 h, after which animals were given saline infusions at the start of each daily session to establish baseline responding of ten responses or less. Subsequently, animals were tested for reinstatement of responding for saline infusions following a non-contingent injection of cocaine (2.0 mg/kg, i.v.) and exposure to intermittent footshock (10 min, 0.5 mA, 0.5 s on, mean off period of 40 sec). After an additional 4- to 6-week drug-free period, tests for reinstatement were repeated. Reinstatement of cocaine-taking behavior was observed in both sets of tests in response to footshock and cocaine. These results extend previous reports from this laboratory that footshock stress is an effective stimulus for reinstatement of drug-taking behavior in the rat.

Studies on the neurocognitive effects of cocaine abuse are equivocal with respect to the specific types of deficits observed, although the vast majority of studies indicate that at least some deficits in certain broad functions such as attention, learning and memory, executive functions, and response speed exist. All of these studies based their results on null hypothesis statistical significance testing (NHSST). It is argued that effect size analysis, which provides information about the magnitude of difference, offers a more valid index of cognitive impairments in a population when compared to NHSST. Accordingly, the objective of the current study was to conduct an effect size analysis (or a meta-analysis in cases where the same test measure was utilized in more than one study) to determine the type and the magnitude of the specific cognitive deficits found as a result of cocaine use. Effect sizes were calculated for each test variable across 15 empirical studies that met inclusion criteria. The results from 481 cocaine users and 586 healthy normal controls revealed that cocaine use had the largest effect on several measures of attention (0.40 < d < 1.10). Moderate to large effect sizes (d > 0.50) were also obtained on tests of visual memory and working memory. Minimal effect sizes (d < 0.30) were obtained on tests of verbal fluency and other language functions and sensory-perceptual functions. Tests of executive functioning produced mixed findings and were interpreted in terms of degree rather than nature of impairment. The results are consistent with findings from neuroimaging and neurochemical studies that have found cocaine use to be associated with dysfunctions in the anterior cingulate gyrus and orbitofrontal cortex; these regions are highly implicated in the mediation of attentional and executive functions, respectively. Methodological limitations of the empirical studies included in the analysis are discussed.