Steady-state methadone blocks cocaine seeking and cocaine-induced gene expression alterations in the rat brain

• Published in: European neuropsychopharmacology Vol. 19; no. 4; pp. 238 - 249
• Main Authors: Leri, Francesco, Zhou, Yan, Goddard, Benjamin, Levy, AnneMarie, Jacklin, Derek, Kreek, Mary Jeanne
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2009
• Subjects: Acoustic Stimulation - methods; Adaptations; Amygdala; Analgesics, Opioid - administration & dosage; Analysis of Variance; Animals; Behavior, Animal - drug effects; Brain; Brain - drug effects; Caudate-putamen; Cocaine; Cocaine - pharmacology; Cocaine-Related Disorders - drug therapy; Cocaine-Related Disorders - metabolism; Conditioning, Classical - drug effects; Conditioning, Operant - drug effects; Dopamine D2 receptors; Dopamine receptor; Dopamine Uptake Inhibitors - pharmacology; Drug Administration Schedule; Drug Delivery Systems - methods; Dynorphins - genetics; Dynorphins - metabolism; Gene expression; Gene Expression Regulation - drug effects; Hypocretin/orexin; Hypothalamus (lateral); Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Intravenous administration; Locomotion - drug effects; Male; Methadone; Methadone - administration & dosage; Mu-opioid receptor; Neuropeptides - genetics; Neuropeptides - metabolism; Nucleus accumbens; Opioid receptors; Opioid receptors (type mu); Orexins; Photic Stimulation - methods; Psychiatry; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - metabolism; RNA, Messenger - metabolism; Sensory integration; Cocaine; Methadone; Mu-opioid receptor; Dopamine receptor; Hypocretin/orexin
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2008.09.004

Abstract 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.