Decreased brain reward function during nicotine withdrawal in C57BL6 mice: evidence from intracranial self-stimulation (ICSS) studies.
Deficits in brain reward function during nicotine withdrawal may serve as an important substrate for negative reinforcement that contributes to the persistence of the tobacco habit in human smokers. The ability to assess withdrawal-associated reward deficits in genetically modified mice may facilitate understanding of the neurobiological mechanisms of nicotine dependence. Here, we assessed the effects of nicotine withdrawal on brain reward function in mice, as measured by intracranial self-stimulation (ICSS) thresholds. Male C57BL6 mice were trained in a discrete-trial current-threshold ICSS procedure until stable reward thresholds were obtained. Mice then received experimenter-administered saline or nicotine (2 mg/kg/injection salt; x4 daily) injections for 7 consecutive days, and ICSS thresholds assessed for 3 days after cessation of injections. Thresholds were unaltered in nicotine- and saline-treated mice after cessation of injections, indicating that this treatment regimen was not sufficient to induce withdrawal-associated reward deficits. Next, mice were implanted subcutaneously with osmotic minipumps delivering a constant daily amount of saline or nicotine (24 mg/kg/day; free-base), with pumps surgically removed 13 days later. The nicotinic receptor antagonist mecamylamine (2 mg/kg) elevated ICSS thresholds in nicotine- but not saline-treated mice when administered 8-10 days after pump implantation. Similarly, reward thresholds were elevated in nicotine-treated mice 12-72 h after minipump removal. These data demonstrate that antagonist-precipitated or spontaneous withdrawal from nicotine delivered via osmotic minipumps induced reward deficits in mice. Further, these findings highlight the potential utility of the ICSS procedure for assessing this important affective component of nicotine withdrawal in genetically modified mice.
Johnson
Paul M
PM
Department of Molecular Therapeutics, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, FL 33458, USA.
Hollander
Jonathan A
JA
Kenny
Paul J
PJ
D000818:Animals; D001921:Brain / Q000502:physiology*; D004343:Drug Implants; D004567:Electrodes, Implanted; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000009:adverse effects*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D012201:Reward; D012653:Self Stimulation; D013375:Substance Withdrawal Syndrome / Q000523:psychology*; D014029:Tobacco Use Disorder / Q000523:psychology*
D004343:Drug Implants; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D008464:Mecamylamine; D009538:Nicotine