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Acomplia (Rimonabant) reduces the reinforcing properties of heroin
by Pop E. Caille S, Parsons LH.Department of Neuropharmacology, CVN-7, The cripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Eur J Neurosci. 2003 Dec;18(11):3145-9
The present experiments tested the hypothesis that the selective CB1 receptor antagonist SR141716A alters heroin self-administration by attenuating heroin-induced increases in nucleus accumbens dopamine levels. SR141716A pretreatment dose-dependently (0.3-3 mg/kg, i.p.) reduced operant heroin self-administration by male Wistar rats under a fixed ratio schedule of reinforcement, and significantly lowered the breaking point of responding for heroin under a progressive ratio schedule of reinforcement. These observations are consistent with recent reports that CB1 receptor inactivation reduces the rewarding properties of opiates. Operant responding for water reinforcement by water-restricted rats was unaltered by these SR141716A doses. Microdialysis tests revealed that heroin self-administration significantly increases interstitial dopamine levels in the nucleus accumbens shell of vehicle-pretreated control rats. However, whereas SR141716A pretreatment dose-dependently reduced heroin self-administration, it did not alter the heroin-associated increase in nucleus accumbens dopamine. These findings suggest that the CB1 antagonist-induced attenuation of heroin reward does not involve dopaminergic mechanisms in the nucleus accumbens shell. RATIONALE AND OBJECTIVES: Previous work indicated that tolerance to the anorectic effect of the cannabinoid CB(1) receptor antagonist/inverse agonist, rimonabant, developed rather rapidly in rats and mice given access to a standard rodent chow. The present study was designed to investigate whether the reducing effect of rimonabant on intake of a highly palatable food such as a chocolate-flavoured beverage underwent a development of tolerance as rapid as that manifested on intake of a standard rodent chow. MATERIALS AND METHODS: To this aim, Wistar rats were concurrently exposed, with unlimited access for 24 h/day, to the chocolate-flavoured beverage, regular food pellets and water. Rimonabant (0, 1.25, 2.5 and 5 mg/kg; i.p.) was administered once a day for 21 consecutive days. RESULTS: Rimonabant administration resulted in a dose-dependent suppression of the high, daily intake of the chocolate-flavoured beverage; this effect lasted for the entire 21-day treatment period, without any apparent development of tolerance. Conversely, rimonabant-induced reduction in daily intake of regular food pellets was of a smaller magnitude and was limited to the first 3-4 days of treatment. CONCLUSIONS: Together, these results indicate that chronically administered rimonabant was more effective and longer-lasting in reducing the intake of a highly palatable food than that of regular food pellets in rats. These results also suggest that rimonabant may be more active on the hedonic rather than nutritive properties of diets. Approximately two-thirds of U.S. adults are overweight or obese, which greatly increases the risk of developing diabetes mellitus and cardiovascular disease and death from related causes. Researchers believe that besides weight loss, obesity management should target improvement in certain cardiometabolic risk factors, which include abnormal cholesterol and glucose (blood sugar) levels and excess weight around the waist, according to background information in the article. Long-term weight management remains a challenge for patients and clinicians.
F. Xavier Pi-Sunyer, M.D., of St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, and colleagues evaluated the efficacy and safety of the weight-loss medication rimonabant in conjunction with diet and exercise in promoting reductions in body weight and waist circumference, long-term weight maintenance, and reduction of cardiometabolic risk factors in obese and higher risk overweight patients. The randomized, double-blind, placebo-controlled study, conducted from August 2001 to April 2004, included 3,045 adults who were obese (body mass index 30 or greater) or overweight (body mass index greater than 27 and treated or untreated hypertension [high blood pressure] or dyslipidemia [abnormal levels of certain lipids and lipoproteins in the blood]). Patients were randomized to receive placebo, 5 mg/d of rimonabant, or 20 mg/d of rimonabant for 1 year. Rimonabant-treated patients were re-randomized to receive placebo or continued to receive the same rimonabant dose while the placebo group continued to receive placebo during year 2.
Year 1 of the study was completed by 51 percent of patients in the placebo group, 51 percent in the 5 mg of rimonabant group, and 55 percent in the 20 mg of rimonabant group. After randomization, weight loss from baseline to 1-year was significantly greater in patients receiving 20 mg or 5 mg of rimonabant than in patients receiving placebo. The percentage of patients achieving a 5 percent or greater weight loss at 1-year was 26.1 percent for patients receiving 5 mg of rimonabant, 48.6 percent for patients receiving 20 mg of rimonabant, and 20.0 percent for patients receiving placebo. Compared with the placebo group, the 20 mg of rimonabant group produced greater average reductions in weight, waist circumference, and level of triglycerides and a greater increase in level of high-density lipoprotein (HDL) cholesterol.
Patients who were switched from the 20 mg of rimonabant group to the placebo group during year 2 experienced weight regain while those who continued to receive 20 mg of rimonabant maintained their weight loss and favorable changes in cardiometabolic risk factors. Rimonabant was generally well tolerated; the most common drug-related adverse event was nausea (11.2 percent for the 20 mg of rimonabant group vs. 5.8 percent for the placebo group).
"It must be acknowledged that the trial was limited by a high dropout rate and that long-term effects of the drug require further study. Still, our observations collectively suggest that rimonabant may well represent an innovative approach to the management of multiple cardiometabolic risk factors, facilitating and maintaining improvements through weight loss-dependent and -independent pathways," the authors conclude.
