M T Bardo1, E D Denehy2, L R Hammerslag2, L P Dwoskin3, B E Blough4, A Landavazo4, J Bergman5, S J Kohut5. 1. Department of Psychology, University of Kentucky, Lexington, KY, 40536, USA. mbardo@uky.edu. 2. Department of Psychology, University of Kentucky, Lexington, KY, 40536, USA. 3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536, USA. 4. Research Triangle Institute, Center for Drug Discovery, Research Triangle Park, NC, USA. 5. McLean Hospital - Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA.
Abstract
RATIONALE: Methamphetamine (METH) abuse is generally attributed to the d-isomer. Self-administration of l-METH has been examined only in rhesus monkeys with a history of cocaine self-administration or drug-naïve rats using high toxic doses. OBJECTIVES: In this study, the ability of l-METH and, for comparison, d-METH to engender self-administration in experimentally naïve rats, as well as to decrease d-METH self-administration and food-maintained responding, was examined. METHODS: Male Sprague-Dawley rats were used in 3 separate experiments. In experiment 1, the acquisition of l- or d-METH self-administration followed by dose-response determinations was studied. In experiment 2, rats were trained to self-administer d-METH (0.05 mg/kg/infusion) and, then, various doses of l- or d-METH were given acutely prior to the session; the effect of repeated l-METH (30 mg/kg) also was examined. In experiment 3, rats were trained to respond for food reinforcement and, then, various doses of l- or d-METH were given acutely prior to the session; the effect of repeated l-METH (3 mg/kg) also was examined. RESULTS: Reliable acquisition of l- and d-METH self-administration was obtained at unit doses of 0.5 and 0.05 mg/kg/infusion respectively. The dose-response function for l-METH self-administration was flattened and shifted rightward compared with d-METH self-administration, with peak responding for l- and d-METH occurring at unit doses of 0.17 and 0.025 respectively. l-METH also was approximately 10-fold less potent than d-METH in decreasing d-METH self-administration and 2-fold lower in decreasing food-maintained responding. Tolerance did not occur to repeated l-METH pretreatments on either measure. CONCLUSIONS: As a potential pharmacotherapeutic, l-METH has less abuse liability than d-METH and its efficacy in decreasing d-METH self-administration and food-maintained responding is sustained with repeated treatment.
RATIONALE: Methamphetamine (METH) abuse is generally attributed to the d-isomer. Self-administration of l-METH has been examined only in rhesus monkeys with a history of cocaine self-administration or drug-naïve rats using high toxic doses. OBJECTIVES: In this study, the ability of l-METH and, for comparison, d-METH to engender self-administration in experimentally naïve rats, as well as to decrease d-METH self-administration and food-maintained responding, was examined. METHODS: Male Sprague-Dawley rats were used in 3 separate experiments. In experiment 1, the acquisition of l- or d-METH self-administration followed by dose-response determinations was studied. In experiment 2, rats were trained to self-administer d-METH (0.05 mg/kg/infusion) and, then, various doses of l- or d-METH were given acutely prior to the session; the effect of repeated l-METH (30 mg/kg) also was examined. In experiment 3, rats were trained to respond for food reinforcement and, then, various doses of l- or d-METH were given acutely prior to the session; the effect of repeated l-METH (3 mg/kg) also was examined. RESULTS: Reliable acquisition of l- and d-METH self-administration was obtained at unit doses of 0.5 and 0.05 mg/kg/infusion respectively. The dose-response function for l-METH self-administration was flattened and shifted rightward compared with d-METH self-administration, with peak responding for l- and d-METH occurring at unit doses of 0.17 and 0.025 respectively. l-METH also was approximately 10-fold less potent than d-METH in decreasing d-METH self-administration and 2-fold lower in decreasing food-maintained responding. Tolerance did not occur to repeated l-METH pretreatments on either measure. CONCLUSIONS: As a potential pharmacotherapeutic, l-METH has less abuse liability than d-METH and its efficacy in decreasing d-METH self-administration and food-maintained responding is sustained with repeated treatment.
Authors: John Mendelson; Naoto Uemura; Debra Harris; Rajneesh P Nath; Emilio Fernandez; Peyton Jacob; E Thomas Everhart; Reese T Jones Journal: Clin Pharmacol Ther Date: 2006-10 Impact factor: 6.875
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