Steady-state methadone blocks cocaine seeking and cocaine-induced gene expression alterations in the rat brain.
To elucidate the effects of steady-state methadone exposure on responding to cocaine conditioned stimuli and on cocaine-induced alterations in central opioid, hypocretin/orexin, and D2 receptor systems, male Sprague-Dawley rats received intravenous infusions of 1 mg/kg/inf cocaine paired with an audiovisual stimulus over three days of conditioning. Then, mini pumps releasing vehicle or 30 mg/kg/day methadone were implanted (SC), and lever pressing for the stimulus was assessed in the absence of cocaine and after a cocaine prime (20 mg/kg, IP). It was found that rats treated with vehicle, but not methadone, responded for the cocaine conditioned stimulus and displayed elevated mu-opioid receptor mRNA expression in the nucleus accumbens core and basolateral amygdala, reduced hypocretin/orexin mRNA in the lateral hypothalamus, and reduced D2 receptor mRNA in the caudate-putamen. This is the first demonstration that steady-state methadone administered after cocaine exposure blocks cocaine-induced behavioral and neural adaptations.
Leri
Francesco
F
Department of Psychology, University of Guelph, Guelph, Canada. fleri@uoguelph.ca
Zhou
Yan
Y
Goddard
Benjamin
B
Levy
AnneMarie
A
Jacklin
Derek
D
Kreek
Mary Jeanne
MJ
D000161:Acoustic Stimulation / Q000379:methods; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D003214:Conditioning, Classical / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems / Q000379:methods; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008691:Methadone / Q000008:administration & dosage*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D000068797:Orexins; D010775:Photic Stimulation / Q000379:methods; 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
D000701:Analgesics, Opioid; D018765:Dopamine Uptake Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D017450:Receptors, Opioid, mu; D004399:Dynorphins; D003042:Cocaine; D008691:Methadone