Brain corticotropin-releasing factor mediates 'anxiety-like' behavior induced by cocaine withdrawal in rats

Anxiety is a key symptom of the cocaine withdrawal syndrome in human addicts, and it is considered to be one of the major factors in precipitating relapse to chronic cocaine abuse. Corticotropin-releasing factor (CRF) plays an important role in the pathophysiology of anxiety and depression, and it may also be involved in the acute behavioral and neuroendocrine actions of cocaine. The role of endogenous CRF in cocaine withdrawal-induced anxiety was investigated in the present study. Animals were subjected to chronic cocaine (20 mg/kg, intraperitoneally, once a day for 14 days) administration. Rats tested 30 min after the last cocaine injection did not show withdrawal anxiety on the elevated plus maze or any alterations in brain CRF levels. Withdrawal (48 h) from chronic cocaine administration produced an intense anxiety-like behavior characterized by decreased open arm exploration. Immunoreactive CRF (CRF-LI) levels were selectively altered in the hypothalamus, in the amygdala and in the basal forebrain structures at the time of the behavioral anxiety, reflecting an increased activity of brain CRF systems. Daily intracerebroventricular (i.c.v.) pretreatment with an immunoserum raised against CRF completely prevented the development of anxiety induced by cocaine withdrawal. These data suggest that extrahypothalamic-limbic CRF hypersecretion may be involved in the development of anxiety related to cocaine withdrawal and that the CRF system may be a useful target for new pharmacotherapies for cocaine withdrawal and relapse.     

Drug-induced reinstatement to heroin and cocaine seeking: A rodent model of relapse in polydrug use.

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 μg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine-associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The consequences of different "lapses" on relapse to heroin seeking in rats.

Although human studies have shown that a lapse, the first violation of abstinence, often induces resumption of drug taking, or relapse, it is not known what aspect of a lapse is critical to relapse or whether this phenomenon can be studied in other species. Rats were trained to self-administer heroin accompanied by a discrete light stimulus. After extinction, different groups experienced different "lapses." Twenty-four hours later, all groups received a test for relapse. It was found that a lapse during which heroin was self-administered, or was presented in close temporal contiguity with lever pressing, induced subsequent heroin seeking. Simple exposure to heroin, or to heroin-related stimuli, during the lapse had little effect on responding in the test for relapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reduction of cocaine seeking by a food-based inhibitor in rats.

Environmental stimuli can exert a powerful influence over drug seeking and taking. For example, previous experiments found that combining multiple drug-related stimuli tripled drug seeking and doubled drug intake (L. V. Panlilio, S. J. Weiss, & C. W. Schindler, 1996, 2000), whereas a signal for the absence of cocaine (i.e., a drug-related inhibitor) dramatically reduced cocaine seeking in rats by over 90% (D. N. Kearns, S. J. Weiss, C. W. Schindler, & L. V. Panlilio, 2005). In the present experiment, a signal for the absence of food created through the A+/AB- conditioned inhibition paradigm also suppressed responding for cocaine by approximately 90%. Symmetrically, a signal for the absence of cocaine (i.e., a cocaine-based inhibitor) suppressed food seeking to a similar degree. These findings, consistent with the appetitive-aversive interaction theory of motivation, suggest that using inhibitors based on nondrug appetitive reinforcers might be a practical method of reducing drug seeking in human drug abusers and should be seriously considered for clinical test and application. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of cocaine preexposure on the acquisition of cocaine-induced taste aversions

OBJECTIVES: This study investigated the role of programmed ventricular stimulation (PVS) for arrhythmia risk prediction in patients with idiopathic dilated cardiomyopathy (IDC) and spontaneous nonsustained ventricular tachycardia (VT). BACKGROUND: Nonsustained VT in patients with IDC has been associated with a high incidence of sudden cardiac death. METHODS: Over the course of 4 years, 34 patients with IDC, a left ventricular (LV) ejection fraction < or = 35%, and spontaneous nonsustained VT underwent PVS. All patients were prospectively followed for 24+/-13 months. RESULTS: Sustained ventricular arrhythmias were induced in 13 patients (38%). Sustained monomorphic VT was induced in three patients (9%), and polymorphic VT or ventricular fibrillation (VF) in another 10 patients (29%). No sustained ventricular arrhythmia could be induced in 21 study patients (62%). Prophylactic implantation of third-generation defibrillators (ICDs) with electrogram storage capability was performed in all 13 patients with inducible sustained VT or VF, and in nine of 21 patients (43%) without inducible sustained VT or VF. There were no significant differences between the additional use of amiodarone, d,I-sotalol, and beta-blocker therapy during follow-up in patients with and without inducible VT or VF. During 24+/-13 months of follow-up, arrhythmic events were observed in nine patients (26%) including sudden cardiac deaths in two patients and ICD shocks for rapid VT or VF in seven patients. Arrhythmic events during follow-up occurred in four of 13 patients with inducible ventricular arrhythmias compared with five of 21 patients without inducible ventricular arrhythmias at PVS (31% vs. 24%, p=NS). CONCLUSION: PVS does not appear to be helpful for arrhythmia risk stratification in patients with IDC, a left ventricular ejection fraction < or =35%, and spontaneous nonsustained VT. Due to the limited number of patients, however, the power of this study is too small to exclude moderately large differences in outcome between patients with IDC with and without inducible VT or VF.     

Differential effects of chronic antidepressant treatment on swim stress- and fluoxetine-induced secretion of corticosterone and progesterone

Hypersecretion of cortisol occurs in numerous patients with major depression and normalizes with clinical recovery during the course of chronic antidepressant treatment. These clinical data suggest that investigation of the effects of antidepressant treatments on the regulation of the brain-pituitary-adrenal axis may assist in elucidating the therapeutic basis of antidepressant actions. In the present investigation, both swim stress and acute fluoxetine challenge increased release of corticosterone and progesterone to reflect an activation of the brain pituitary-adrenal axis. The effects of chronic antidepressant treatment (21 days) on corticosterone and progesterone secretion induced by these challenges were investigated. Chronic fluoxetine treatment (5 mg/kg/day) completely blocked the increased secretion of corticosterone and progesterone in response to the acute fluoxetine challenge. Chronic treatment with desipramine, imipramine or amytriptyline (15 mg/kg/day) also markedly attenuated fluoxetine-induced corticosterone and progesterone secretion. However, chronic treatment with the monoamine oxidase inhibitors, phenelzine (5 mg/kg) and tranylcypromine (5 mg/kg), did not affect this hormonal response to acute fluoxetine challenge. Plasma levels of fluoxetine after acute challenge were not significantly different for the various chronic antidepressant treatment conditions from the chronic saline controls; therefore, an increase in the metabolism of fluoxetine can not explain the antagonism of the fluoxetine-induced hormonal response after chronic antidepressant treatment. In contrast to the effects of selected antidepressants on acute fluoxetine-induced steroid release, chronic treatment with imipramine (20 mg/kg/day), fluoxetine (5 mg/kg/day) or phenelzine (5 mg/kg) did not significantly alter this swim stress-induced corticosterone or progesterone secretion. Because chronic fluoxetine and tricyclic antidepressant drugs blocked the acute action of fluoxetine to increase adrenal cortical secretion, but did not alter swim stress-induced secretion of these steroids, we propose that distinct neurochemical mechanisms control fluoxetine and swim stress-induced steroid release. We speculate that the substantial adaptive response to those chronic antidepressant treatments, which minimize the effect of acute fluoxetine challenge to increase in corticosterone and progesterone secretion, may be relevant to the therapeutic actions of these drugs.     

Altered responsivity to central administrations of corticotropin-releasing factor in rats with a history of opiate exposures.

The authors studied the effects of a history of opiate exposures on behavioral responses to intracerebroventricular (ICV) microinjections of the stress-related peptide corticotropin-releasing factor (CRF). Rats were injected for 10 days with morphine (10 mg/kg) or saline, and 1 or 7 days later they received an ICV microinjection of CRF (0.5 μg or 2.5 μg) or artificial cerebrospinal fluid. Microinjections of CRF produced anxiety-like behavior, locomotor activity, and self-grooming. The anxiogenic response was altered so that morphine-treated rats showed reduced responses to 0.5-μg CRF but showed exaggerated responses to 2.5-μg CRF 1 or 7 days after last opiate exposure. These findings suggest that alterations in central CRF circuits may underpin the increased vulnerability to anxiety observed following opiate exposures. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of diet on sensitization to cocaine-induced stereotypy in female rats

The progressive increase in cocaine-induced stereotyped behavior that accompanies repeated cocaine injections (sensitization) was examined in rats consuming different diets. Adult female Sprague-Dawley rats were fed one of three diets: low protein (6% casein), adequate protein (25% casein), or a standard chow diet. Following 1 week of adaptation to the diets, the rats were injected every 3-4 days with either cocaine (30 mg/kg, IP) or saline, and the total amount of stereotypy was measured over a 90-min interval following each of four injections. Cocaine-induced stereotypy peaked at 40-50 min following each injection, after which it declined for all diet groups. With repeated injections, the total amount of stereotypy increased in all diet groups. By the fourth injection, the low protein diet group (6% casein) exhibited a slower onset and a possibly prolonged duration of cocaine-induced stereotypy when compared with the two adequate protein diet groups (25% casein and chow). Interestingly, the rats in the two purified diet groups (6% casein and 25% casein) exhibited significantly more stereotypy across injections than those in the chow diet group. Weight differences did not explain the differences in stereotypy present among the diet groups. This study concludes that diet significantly alters the pattern of cocaine-induced stereotypy in female rats, especially after repeated exposure.     

Relationship of cocaine-induced c-Fos expression to behaviors and the role of serotonin 5-HT2A receptors in cocaine-induced c-Fos expression.

Serotonin 5-HT2A receptor antagonists have been shown to attenuate the locomotor stimulant effects of cocaine in rats. The present study used the expression of c-Fos protein as a marker to identify brain areas through which 5-HT2A receptors may modulate cocaine-induced behaviors. Significant correlations were observed between cocaine-induced hyperactivity and c-Fos expression in the nucleus accumbens core (NAcC), caudate-putamen (CPu), and subthalamic nucleus. In a separate experiment, a low, behaviorally relevant dose of cocaine was found to increase c-Fos immunoreactivity in the medial CPu, NAcC, and nucleus accumbens shell (NAcSh). The selective 5-HT2A receptor antagonist M100907 significantly attenuated cocaine-induced c-Fos expression in the medial CPu and in the NAcSh. These data suggest that 5-HT2A receptors in the NAcSh and CPu or in afferents to these regions may contribute to genomic responses to cocaine in the brain as well as to cocaine-induced locomotor activity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The development of the serum corticosterone rhythm in rats

The purpose of this study was to determine whether the sequence of changes that occur in the adrenal rhythm in maturing female rats (development of a peak, shift in acrophase and amplitude) requires experience with a photoperiodic stimulus or a change in ovarian status. The emergence of the serum corticosterone (CS) rhythm occured more quickly in adult rats placed in a 14 h light, 10 h dark (14:10) cycle at 50 days of age after rearing in constant light (LL) than in weanling rats placed in 14:10. Ovariectomy at weaning age did not alter the pattern of CS development in 14:10 although the amplitude of the peak was reduced even in 25-day-old rats. Adult rats reared in 14:10 held a population rhythm of CS longer after they were placed in LL than did weanling rats placed in LL. This difference was not dependent upon the presence of the ovaries since acutely and chronically ovariectomized (OVX) adult rats responded in a similar manner to adult controls. It can be concluded that the adrenal rhythm emerges as a function of age rather than as a result of a change in ovarian status. The capacity to synchronize serum CS to light-dark cycles develops in the absence of photoperiodic cues.     

Serotonin stimulates corticotropin-releasing factor gene expression in the hypothalamic paraventricular nucleus of conscious rats

To examine the direct effects of serotonin (5-HT) on the release and synthesis of corticotropin-releasing factor (CRF) in the hypothalamic paraventricular nucleus (PVN), 5-HT was microinjected just onto the bilateral PVN of conscious rats. Plasma adrenocorticotropic hormone (ACTH) levels peaked at 30 min and returned to the basal levels in 90 min. Northern blot analysis revealed that the CRF messenger RNA (mRNA) level in the PVN as well as the proopiomelanocortin mRNA level in the anterior pituitary significantly increased 120 min after the 5-HT injections (50-250 nmol/side). Pretreatment with intracerebroventricular (i.c.v.) injection of pindobind 5-HT1A (5 nmol) or LY-278584 (500 nmol) completely abolished the 5-HT-induced ACTH response, whereas LY-53857 (100 nmol) was without effect. These results suggest that 5-HT stimulates CRF release, which has interactions with 5-HT1A and 5-HT3 receptors on CRF neurons in the PVN, and activates CRF synthesis in conscious rats.     

The role of glucocorticoids at the corticosterone level after stress in the early ontogeny of gray rats]

Norway rats were subjected to stress procedure of saline or hydrocortisone injections. The saline-treated rats revealed an increased level of the plasma corticosterone as opposed to hydrocortisone-treated ones. The modification of adrenocortical function with the stress in early postnatal life seems to be connected with changes in hypothalamic catecholamine synthesis and can be prevented with exogenous glycocorticoids.     

Male role and gender role conflict: Relations to help seeking in men.

Tested theory that adherence to the traditional male gender role and help-seeking attitudes and behaviors are related. Ss were 401 undergraduate men who completed measures of help-seeking attitudes and behaviors, attitudes toward the stereotypic male role, and gender role conflict factors (i.e., success/power/competition, restrictive emotionality, and restrictive affectionate behavior between men). Canonical analysis and regression indicated that traditional attitudes about the male role, concern about expressing emotions, and concern about expressing affection toward other men were each significantly related to negative attitudes toward seeking professional psychological assistance. Restrictive emotionality also significantly predicted decreased past help-seeking behavior and decreased likelihood of future help seeking. The implications of these results for theory, research, and counseling practice are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of proposed treatments for cocaine addiction on hemodynamic responsiveness to cocaine in conscious rats

Several agents may treat cocaine addiction and toxicity including bromocriptine, desipramine, GBR 12909 [1-(2-(bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl) piperazine], diazepam, buprenorphine and dizocilpine. In this study, we sought to determine whether these specific therapeutic agents alter cardiovascular responses to cocaine in conscious rats. Arterial pressure responses to cocaine (5 mg/kg, i.v.) were similar in all rats whereas cardiac output responses varied widely. In 26 of 33 rats (named vascular responders), cocaine induced a decrease in cardiac output of 8% or more. The remaining rats with little change or an increase in cardiac output were classified as mixed responders. Pretreatment with bromocriptine (0.1 mg/kg) or desipramine (1 mg/kg) increased cardiac output in mixed responders and increased systemic vascular resistance in vascular responders similar to the differential effects noted with cocaine. GBR 12909 (0.5-10 mg/kg) elicited a decrease in cardiac output at higher doses. Diazepam (0.1 and 0.5 mg/kg) had small, short-lasting effects on cardiovascular parameters. Buprenorphine (0.3 mg/kg) or the NMDA (N-methyl-D-aspartic acid) receptor antagonist, dizocilpine (0.05 mg/kg), increased arterial pressure, heart rate and cardiac output in vascular responders. Bromocriptine and desipramine prevented the difference in cardiac output responses in vascular and mixed responders by reducing the cocaine-induced decrease in cardiac output in vascular responders. Pretreatment with GBR 12909 (1 mg/kg) had little effect on cardiovascular responses to cocaine except to depress the increase in cardiac output noted in mixed responders. Buprenorphine selectively enhanced the increase in systemic vascular resistance whereas dizocilpine enhanced the pressor response. These data suggest that several treatment regimens for cocaine addiction alter the cardiovascular responses to cocaine and that dopamine D2 receptor activation may be necessary for the decrease in cardiac output noted in vascular responders.     

Alterations in the reinforcing efficacy of cocaine in adult rats following prenatal exposure to cocaine.

Adult male rats gestationally exposed to cocaine and nonexposed control offspring were examined for differences in operant responding for cocaine and sucrose reinforcement. Offspring were derived from dams that had received subcutaneous injections of 40 mg/kg/3cc cocaine hydrochloride daily on gestational Days 8–20 and nontreated control dams. Although no prenatal treatment differences were seen when the animals lever pressed for sucrose pellets on a progressive-ratio (PR) schedule, adult offspring prenatally exposed to cocaine were observed to exhibit an enhanced rate of cocaine intravenous self-administration on a fixed-ratio 5 (FR-5) schedule along with a marked decrease in break point on the PR reinforcement schedule. These results suggest that the reinforcing efficacy of cocaine may be reduced in animals with a prenatal history of cocaine exposure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of endogenous nitric oxide and platelet-activating factor in hypoxia-induced intestinal injury in rats

BACKGROUND/AIMS: Nitric oxide is an endothelium-derived relaxing factor that promotes capillary integrity, inhibits leukocyte adherence and activation, and scavenges oxygen radicals. Because these effects are important in experimental intestinal injury, we studied the role of NO inhibition on hypoxia-induced bowel necrosis in the rat and investigated the interaction between platelet-activating factor (PAF) and NO in this model. METHODS: Sprague-Dawley rats were treated with either hypoxia, NO synthase inhibition (NG-methyl-L-arginine [LNMA] or NG-nitro-L-arginine methyl ester [L-NAME]), hypoxia+LNMA, hypoxia+LNMA+NO donors, or hypoxia+LNMA+PAF receptor inhibition. Evaluations included blood pressure, superior mesenteric artery blood flow, arterial blood gases, histological intestinal injury, intestinal myeloperoxidase activity, and intestinal PAF activity. RESULTS: We found that hypoxia alone for 90 minutes (10% O2, partial O2 pressure = 45 mm Hg) or LNMA alone had no detrimental effects. However, hypoxia+LNMA together caused hypotension, metabolic acidosis, intestinal injury, increased intestinal myeloperoxidase activity, and elevated intestinal PAF concentrations that were prevented by exogenous L-arginine. Furthermore, the hypotension and intestinal injury was prevented by PAF receptor blockade. CONCLUSIONS: We conclude that endogenous NO protects the intestine from hypoxia-induced inflammation and injury, and the balance between local PAF and NO modulates the outcome of hypoxia-stressed intestine.     

Altered ACTH and corticosterone responses to interleukin-1 beta in male rats exposed to an alcohol diet: possible role of vasopressin and testosterone

We have previously shown that female rats exposed to an alcohol (ethanol, E) diet exhibited a blunted ACTH response to systemically administered interleukin-1 beta (IL-1 beta). Because of the presence of gender differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and of the possible role played by sex steroids in modulating the inhibitory influence of E in females, we studied the ability of a 10-day E diet to alter ACTH and corticosterone secretion of intact or castrated male rats injected with IL-1 beta or endotoxin, a releaser of endogenous cytokines. Pituitary responsiveness to secretagogues that mediate the endocrine effects of IL-1 beta, namely corticotropin-releasing factor (CRF) and vasopressin (VP), was also investigated. The ACTH responses of animals fed ad libitum (C group) or pair-fed (PF group) to the intravenous administration of IL-1 beta or endotoxin were not statistically different (p > 0.05); therefore, results from these two groups were combined in the initial experiments. Subsequent experiments only used E and C animals. When compared with this latter group, intact E males showed a significant (p < 0.01) decrease in ACTH levels measured 30 and 60 min after the intravenous injection of IL-1 beta or endotoxin. In contrast, E rats released as much corticosterone as C rats in response to IL-1 beta, but significantly (p < 0.05) more following administration of endotoxin (lipopolysaccharide). The stimulatory effect of VP on ACTH release was also measurably blunted by alcohol, whereas that of CRF was not. In none of these experiments were any significant differences observed between C and PF rats.(ABSTRACT TRUNCATED AT 250 WORDS)