Mu-opioid receptor and CREB activation are required for nicotine reward.
Environmental cues associated with nicotine delivery are an important part of the stimulus that sustains smoking behavior and is often coupled with craving and relapse; however, the neuronal circuitry and molecular substrates underlying this process are still poorly understood. Exposure to an environment previously associated with rewarding properties of nicotine results in an increase of CREB phosphorylation similar to that seen following nicotine administration, and this response is absent in MOR(-/-) mice. Moreover, a single administration of an opioid receptor antagonist, naloxone, blocks both the conditioned molecular response (CREB phosphorylation) and the conditioned behavioral response (nicotine reward) in a place preference paradigm. Lastly, repeated nicotine administration results in increased expression of MORs. However, this effect, along with rewarding properties of nicotine, is blocked in mice with a targeted disruption in the CREB gene. Together, pharmacologic and genetic manipulations indicate that phosphorylation of CREB and upregulation of functional MORs are required for nicotine-conditioned reward.
Walters
Carrie L
CL
Department of Pharmacology, University of Pennsylvania, Philadelphia 19104, USA.
Cleck
Jessica N
JN
Kuo
Yuo-chen
YC
Blendy
Julie A
JA
D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009538:Nicotine / Q000009:adverse effects*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012201:Reward; D013997:Time Factors; D014029:Tobacco Use Disorder / Q000209:etiology / Q000378:metabolism
D000779:Anesthetics, Local; D017362:Cyclic AMP Response Element-Binding Protein; D009292:Narcotic Antagonists; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009538:Nicotine; D003042:Cocaine