| Abstract No.: | C-G3183 |
| Country: | Canada |
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| Title: | NICOTINE DEPENDENT MICE DEMONSTRATE CONDITIONED PLACE AVERSIONS FOR NICOTINE WITHDRAWAL THAT ARE MEDIATED BY DOPAMINE |
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| Authors/Affiliations: | 1 Taryn Grieder*; 1 Ryan Ting-A-Kee; 1 Laurie Sellings; 1 Derek van der Kooy;
1 University of Toronto, ON, Canada.
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| Content: | Objectives: Although nicotine is one of the most widely used addictive drugs, the motivational properties that make it so addictive are largely unknown. The purpose of our work is to determine what neurobiological substrates are mediating the motivational effects of nicotine withdrawal.
Materials and Methods: We implanted mice with AlzetŪ osmotic minipumps containing a high dose of nicotine (35 mg/kg/day) for 2 weeks. Upon pump removal, mice were observed for withdrawal signs at a variety of time points, and conditioned in a modified conditioned place preference (CPP) paradigm, the BNW procedure, at the time point where the largest nicotine abstinence score was demonstrated. Since the mesolimbic dopamine (DA) system plays an important role in the rewarding and aversive aspects of many drugs of abuse, including nicotine, we investigated the role of DA in dependent and withdrawn nicotine motivation by administering the broad spectrum DA receptor antagonist α-flupenthixol (α-flu, 0.08 mg/kg i.p.) to nicotine dependent and withdrawn mice. Acute nicotine withdrawal and the involvement of the DA system was also investigated by administering large single doses of nicotine (1.75 mg/kg, s.c.) and α-flu (0.08 mg/kg, i.p.) to separate groups of mice.
Results: The mice demonstrated a variety of withdrawal signs that were strongest 8 hours after pump removal. When conditioned in the CPP paradigm at the 8 hour time point, nicotine dependent mice showed an aversion to the withdrawal-paired environment (or a preference for the environment previously paired with nicotine). Interestingly, when our nicotine dependent and withdrawn mice were pre-treated with α-flu prior to CPP training under conditions where α-flu has no motivational effects on its own, then the conditioned place aversions were abolished.
These results indicate that the motivational response to chronic nicotine is due to a withdrawal aversion rather than a nicotine preference. Conversely, when naive mice were administered a large single dose of nicotine and conditioned 8 hours later they demonstrated a significant CPP for the acute withdrawal paired side that was not blocked by α-flu.
Conclusion: These results suggest that dopamine receptor activation mediates the aversive motivational effects of nicotine withdrawal when animals are in a drug dependent and withdrawn state.
Supported by: CIHR, CTCRI
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