title: Dopaminergic signaling mediates the motivational response underlying the opponent process to chronic but not acute nicotine.
abstract: The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist alpha-flupenthixol (alpha-flu) and in DA D(2) receptor knockout mice. Conversely, alpha-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D(2) receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON, Canada. taryn.grieder@utoronto.ca
authors.forename: Taryn E
authors.initials: TE
authors.lastname: Grieder
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Sellings
authors.forename: Hector
authors.initials: H
authors.lastname: Vargas-Perez
authors.forename: Ryan
authors.initials: R
authors.lastname: Ting-A-Kee
authors.forename: Eric C
authors.initials: EC
authors.lastname: Siu
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.forename: Derek
authors.initials: D
authors.lastname: van der Kooy
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004334:Drug Administration Schedule; D005475:Flupenthixol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009042:Motivation / Q000187:drug effects* / Q000235:genetics; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000172:deficiency; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D014029:Tobacco Use Disorder / Q000503:physiopathology* / Q000523:psychology
chemical_list: D018492:Dopamine Antagonists; D018722:Nicotinic Agonists; D017448:Receptors, Dopamine D2; D009538:Nicotine; D005475:Flupenthixol; D004298:Dopamine