Effects of the CRH Receptor Antagonist CP-154,526 on Intravenous Cocaine Self-administration in Rats

125

106

The acute effects of smoking a low-or high-nicotine cigarette on hypothalamic-pituitary-adrenal (HPA) hormones, subjective responses, and cardiovascular measures were studied in 20 healthy men who met American Psychiatric Association Diagnostic and Statistical Manual IV criteria for nicotine dependence. Within four puffs (or 2 min) after cigarette smoking began, plasma nicotine levels and heart rate increased significantly (Po0.01), and peak ratings of 'high' and 'rush' on a Visual Analogue Scale were reported. Reports of 'high,' 'rush,' and 'liking' and reduction of 'craving' were significantly greater after smoking a high-nicotine cigarette than a low-nicotine cigarette (Po0.05). Peak plasma nicotine levels after high-nicotine cigarette smoking (23.972.6 ng/ml) were significantly greater than after lownicotine cigarette smoking (3.6370.59 ng/ml) (Po0.001). After smoking a low-nicotine cigarette, adrenocorticotropin hormone (ACTH), cortisol, dehydroepiandrosterone (DHEA), and epinephrine did not change significantly from baseline. After high-nicotine cigarette smoking began, plasma ACTH levels increased significantly above baseline within 12 min and reached peak levels of 21.8875.34 pmol/l within 20 min. ACTH increases were significantly correlated with increases in plasma nicotine (r ¼ 0.85; Po0.0001), DHEA (r ¼ 0.66; P ¼ 0.002), and epinephrine (r ¼ 0.86; Po0.0001). Cortisol and DHEA increased significantly within 20 min (Po0.05) and reached peak levels of 424748 and 21.1372.55 ng/ml within 60 and 30 min, respectively. Thus cigarette smoking produced nicotine dose-related effects on HPA hormones and subjective and cardiovascular measures. These data suggest that activation of the HPA axis may contribute to the abuse-related effects of cigarette smoking.

Section: Subjective Responses To Smoking High-and Low-nicotine Cigarementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Low- and High-Nicotine Cigarette Smoking on Mood States and the HPA Axis in Men

Mendelson

Sholar

Goletiani

et al. 2005

125

106

“…The HPA axis has also been suggested as a target for the treatment of substance abuse, as drug-related behaviors can be disrupted by treatment with corticotropin-releasing hormone (CRH) antagonists (Goeders, 1997;McCarthy et al, 1999). Treatment with the CRH antagonist CP-154,526 has been reported to reduce the amount of cocaine self-administered by rats (Goeders and Guerin, 2000), and attenuate the reinstatement of drug-related behaviors for cocaine (Shaham et al, 1998) and opioids (Lu et al, 2000). These findings have helped fuel the recent investigation of CRH antagonists for use in the treatment of these disorders.…”

Section: Introductionmentioning

confidence: 99%

Corticotropin-Releasing Hormone Antagonists, Astressin B and Antalarmin: Differing Profiles of Activity in Rhesus Monkeys

Broadbear

Winger

Rivier

et al. 2004

The present study compares the activity of two chemically distinct corticotropin-releasing hormone (CRH) antagonists at the level of the pituitary gland in rhesus monkeys, using exogenous CRH-stimulated increases in adrenocorticotropin (ACTH) and cortisol. Of chief interest was whether the CRH-R1-selective pyrrolopyrimidine, antalarmin, shown previously to have activity in the central nervous system (CNS), would differ in its antagonist profile from the CRH-R1-& 2-selective peptide, astressin B, which is unlikely to have access to the CNS following systemic administration. Nine rhesus monkeys (eight male), each with an indwelling venous catheter, were subjects in this study. Astressin B (0.001, 0.003, 0.03, 0.1, and 0.3 mg/kg) or antalarmin (1.0, 3.2, and 10 mg/kg) was administered as an intravenous (i.v.) pretreatment 15 min prior to administration of 1 or 10 mg/kg i.v. CRH. Antalarmin (10 mg/kg) was also administered alone on six occasions and its effects on behavior as well as on ACTH and cortisol levels were measured. Astressin B was assessed following i.v. and intracisternal (i.c.) administration. Astressin B dose-dependently abolished the CRH-stimulated ACTH and cortisol responses, with an antagonist effect lasting in excess of 24 h. Astressin B was approximately 300-times more potent when given i.c. than when it was administered via the i.v. route. By contrast, antalarmin antagonized the effects of CRH on ACTH but not cortisol at 1.0 and 3.2 mg/kg. At a larger dose, antalarmin stimulated ACTH and cortisol release and produced behavioral sedation. These latter effects diminished with repeated administration of antalarmin. The differences between astressin B and antalarmin may be due either to non-CRH receptormediated effects of antalarmin or to a complex interaction of antalarmin's effects at both central and peripheral CRH receptors.

“…In preclinical studies, stimulation of the HPA axis appears to be essential for acquisition and maintenance of cocaine self-administration in rats (Goeders, 1997(Goeders, , 2002a. Moreover, administration of a corticotropin-releasing hormone (CRH) antagonist produced a dose-dependent decrease in cocaine self-administration in rats (Goeders and Guerin, 2000).…”

Section: Introductionmentioning

confidence: 99%

The Effects of Cocaine on Gonadal Steroid Hormones and LH in Male and Female Rhesus Monkeys

Mello

Mendelson

Negus

et al. 2004

Cocaine stimulates significant increases in estradiol, testosterone (T), and luteinizing hormone (LH) in rhesus monkeys, but the temporal interactions between the gonadal steroid hormones and LH have not been determined. The effects of i.v. cocaine (0.8 mg/kg) or saline placebo administration on estradiol, T, and LH were compared in follicular phase female and male rhesus monkeys. Samples for hormone analysis were collected at 2-min intervals for 20 min, then at 10-min intervals for 50 min. Peak plasma cocaine levels were detected at 4 min and pharmacokinetic analyses showed no significant gender differences. Baseline hormone levels were equivalent before saline and cocaine administration, and saline did not alter LH or estradiol levels. In females, when baseline estradiol levels were low (o100 pg/ml), LH increased significantly within 8 min after cocaine administration (Po0.05), but when baseline estradiol levels were high (4100 pg/ml), LH levels did not change significantly after cocaine administration. Estradiol and T increased significantly after LH, within 16 min after cocaine administration (Po0.01-0.001). In males, significant LH increases were detected at 16 min after cocaine administration (Po0.05-0.001), but estradiol and T did not change significantly. Thus, cocaine may stimulate significant increases in estradiol and T in females but not in males. These rapid hormonal changes may contribute to cocaine's abuse-related effects, as well as to disruptions of the menstrual cycle during chronic cocaine administration.