CYP2B6 and Bupropion’s Smoking-Cessation Pharmacology: The Role of Hydroxybupropion.
CYP2B6 and Bupropion’s Smoking-Cessation Pharmacology: The Role of Hydroxybupropion.
Filed under: Addiction Rehab
Clin Pharmacol Ther. 2012 Nov 14;
Zhu AZ, Cox LS, Nollen N, Faseru B, Okuyemi KS, Ahluwalia JS, Benowitz NL, Tyndale RF
Bupropion is indicated to promote smoking cessation. Animal studies suggest that the pharmacologic activity of bupropion can be mediated by its major metabolite, hydroxybupropion. We measured plasma bupropion and its metabolite levels in a double-blind, placebo controlled, randomized smoking-cessation trial. Among the treatment-adherent individuals, higher hydroxybupropion concentrations (per ?g/ml) resulted in better smoking-cessation outcomes (week 3, 7, and 26 odds ratio (OR) = 2.82, 2.96, and 2.37, respectively, P = 0.005-0.040); this was not observed with bupropion levels (OR = 1.00-1.03, P = 0.59-0.90). Genetic variation in CYP2B6, the enzyme that metabolizes bupropion to hydroxybupropion, was identified as a significant source of variability in hydroxybupropion formation. Our data indicate that hydroxybupropion contributes to the pharmacologic effects of bupropion for smoking cessation, and that variability in response to bupropion treatment is related to variability in CYP2B6-mediated hydroxybupropion formation. These findings suggest that dosing of bupropion to achieve a hydroxybupropion level of 0.7 ?g/ml or increasing bupropion dose for CYP2B6 slow metabolizers could improve bupropion’s cessation outcomes.Clinical Pharmacology & Therapeutics (2012); advance online publication 14 November 2012. doi:10.1038/clpt.2012.186.
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Hypothalamic Neuropeptide S receptor blockade decreases discriminative cue-induced reinstatement of cocaine seeking in the rat.
Filed under: Addiction Rehab
Psychopharmacology (Berl). 2012 Nov 13;
Kallupi M, de Guglielmo G, Cannella N, Li HW, Caló G, Guerrini R, Ubaldi M, Renger JJ, Uebele VN, Ciccocioppo R
RATIONALE: Previous studies have shown that activation of brain neuropeptide S receptor (NPSR) facilitates reinstatement of cocaine seeking elicited by environmental cues predictive of drug availability. This finding suggests the possibility that blockade of NPSR receptors may be of therapeutic benefit in cocaine addiction. To evaluate this hypothesis, we investigated the effect of two newly synthetized NPSR antagonists, namely the quinolinone-amide derivative NPSR-QA1 and the NPS peptidic analogue [D-Cys(tBu)(5)]NPS on cocaine self-administration and on discriminative cue-induced relapse to cocaine seeking in the rat. METHODS: Separate groups of rats self-administered food and cocaine 0.25 mg/kg/inf in FR1 and FR5 (fixed ratio reinforcement schedules) for 30-min and 2-h sessions per day. After food and cocaine intake reached baseline levels, the effect of NPSR-QA1 was tested on cocaine and food self-administration. The NPSR-QA1 was injected intraperitoneally and its effect on discriminative cue-induced reinstatement was evaluated, while [D-Cys(tBut)(5)]NPS was injected intracranially, intra-lateral hypothalamus, intra-perifornical area of the hypothalamus, and intra-central amygdala. The effect of the NPSR-QA1 on extinction of cocaine seeking was also assessed. RESULTS: Intraperitoneal administration of NPSR-QA1 (15-30 mg/kg) did not affect cocaine self-administration. Conversely, NPSR-QA1 (15-30 mg/kg) decreased discriminative cue-induced cocaine relapse. At the lowest dose, this effect was specific, while at the highest dose, NPSR-QA1 also reduced food self-administration. The efficacy of NPSR antagonism on cocaine seeking was confirmed with [D-Cys(tBu)(5)]NPS (10-30 nmol/rat) as it markedly inhibited relapse behavior following site-specific injection into the lateral hypothalamus and the perifornical area of the hypothalamus but not into the central amygdala. CONCLUSIONS: The identification of the NPS/NPSR system as an important new element involved in the physiopathology of cocaine addiction and the discovery of the anti-addictive properties of NPSR antagonists opens the possibility of exploring a new mechanism for cocaine addiction treatment.
HubMed – addiction
Impaired Metacognitive Capacities in Individuals with Problem Gambling.
Filed under: Addiction Rehab
J Gambl Stud. 2012 Nov 13;
Brevers D, Cleeremans A, Bechara A, Greisen M, Kornreich C, Verbanck P, Noël X
Impaired insight into behavior may be one of the clinical characteristics of pathological gambling. In the present study, we tested whether the capacity to evaluate accurately the quality of one’s own decisions during a non-gambling task was impaired in problem gamblers. Twenty-five problem gamblers and 25 matched healthy participants performed an artificial grammar-learning paradigm, in which the quality of choice remains uncertain throughout the task. After each trial of this task, participants had to indicate how confident they were in the grammaticality judgements using a scale ranging from 1 (low confidence) to 7 (high confidence). Results showed that (i), problem gamblers’ performance on the grammaticality test was lower than controls’; (ii) there was a significant correlation between grammaticality judgments and confidence for control participants, which indicates metacognitive insight and the presence of conscious knowledge; (iii) this correlation was not significant in problem gamblers, which suggests a disconnection between performance and confidence in this group. These findings suggest that problem gamblers are impaired in their metacognitive abilities on a non-gambling task, which suggests that compulsive gambling is associated with poor insight as a general factor. Clinical interventions tailored to improve metacognition in gambling could be a fruitful avenue of research in order to prevent pathological gambling.
HubMed – addiction
Correlates of Depressive Symptom Severity in Problem and Pathological Gamblers in Couple Relationships.
Filed under: Addiction Rehab
J Gambl Stud. 2012 Nov 13;
Poirier-Arbour A, Trudel G, Boyer R, Harvey P, Goldfarb MR
Problem and pathological gamblers (PPG) often suffer from depressive symptoms. Gambling problems have negative consequences on multiple aspects of gamblers’ lives, including family and marital relationships. The objectives of the current study were to (1) replicate the results of studies that have suggested a stronger and more significant relationship between gambling and depression in PPG than in non-problem gamblers (NPG) and (2) explore specific correlates of depressive symptom severity in PPG in couple relationships. Variables demonstrated to be significantly correlated with depressive symptoms in the general population were selected. It was hypothesized that gender, age, gambler’s mean annual income, perceived poverty, employment status, clinical status (i.e., problem or pathological gambler versus non-problem gambler), trait anxiety, alcoholism, problem-solving skills, and dyadic adjustment would be significant predictors of depressive symptoms. Sixty-seven PPG were recruited, primarily from an addiction treatment center; 40 NPG were recruited, primarily through the media. Results revealed that PPG reported significantly greater depressive symptoms than did NPG. Further, elevated trait anxiety and poor dyadic adjustment were demonstrated to be significant and specific correlates of depressive symptom severity in PPG. These findings contribute to the literature on depressive symptomatology in PPG in relationships, and highlight the importance of the influence of the couple relationship on PPG.
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