title: Treatment-like steady-state methadone in rats interferes with incubation of cocaine sensitization and associated alterations in gene expression.
abstract: In a previous study, steady-state methadone treatment was found to prevent associative cocaine learning, as well as related decreases in mRNA expression of preprohypocretin/preproorexin (ppHcrt) in the lateral hypothalamus (LH) and dopamine D2 receptor (DR2) in the caudate-putamen (CP), and increases in mu-opioid receptor in the ventral striatum of rats. To investigate whether the same regimen of methadone exposure could prevent the incubation of cocaine sensitization and related alterations in gene expression, male Sprague-Dawley rats received 45 mg/kg/day steady-dose "binge" cocaine administration (IP) for 14 days followed by mini-pumps releasing 30 mg/kg/day methadone (SC). After 14 days of methadone, and a subsequent 10-day drug-free period, all rats were tested for sensitization (cocaine test dose: 15 mg/kg) and brain tissue was collected to quantify mRNA expression. Rats exposed to cocaine displayed cocaine-induced stereotypy at test, as well as enhanced ppHcrt mRNA in the LH and reduced DR2 mRNA in the CP. Importantly, these alterations were significantly reduced in rats treated with methadone following cocaine. These results suggest that steady-state methadone can interfere with the incubation of neuroadaptations underlying changes in behavioral responses to cocaine and cocaine-associated stimuli, and that these effects can be observed even after withdrawal from methadone.
authors: Department of Psychology, University of Guelph, Canada. fleri@uoguelph.ca
authors: Francesco
authors: F
authors: Leri
authors: Yan
authors: Y
authors: Zhou
authors: Brendan
authors: B
authors: Carmichael
authors: Erin
authors: E
authors: Cummins
authors: Mary Jeanne
authors: MJ
authors: Kreek
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008691:Methadone / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017450:Receptors, Opioid, mu; D004399:Dynorphins; D003042:Cocaine; D008691:Methadone