Defense Date

2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

M. Imad Damaj

Abstract

Neuronal nicotinic acetylcholine receptors modulate both cholinergic and non-cholinergic synaptic transmission. Our research concerns α6 and α4 neuronal nicotinic subunits because they often co-assemble with the β2 subunit, which has abundant expression in the CNS and previous work has demonstrated that β2* nAChRs are involved in nicotine and cocaine reward. α6β2* and α4β2* nAChRs are highly expressed in midbrain, which is known to be critical for the incentive salience associated with natural and artificial (drug) reward. Our goal was to assess the role of α6β2* and α4β2* nAChRs in nicotine and cocaine reward using an unbiased conditioned place preference (CPP) test in mice. Adult male C57BL/6J mice or male mice null for the α6 or α4 nicotinic receptor subunit were used. For CPP: On day 1, pre-conditioning scores were recorded; Days 2-4 mice underwent conditioning, where they were randomly assigned to either the black or the white compartment paired with drug, and the opposite chamber paired with saline; Day 5 was a drug-free test day where post conditioning scores were recorded. α-Conotoxin MII[H9A;L15A], a selective antagonist of α6β2* nAChRs, was given centrally either into the lateral ventricle or the nucleus accumbens on conditioning days, which tested for acquisition of CPP, or it was given only once into the lateral ventricle on test day which tested for expression of CPP. Antagonizing α6*nAChRs resulted in a significant attenuation of both nicotine and cocaine place preference. This was complemented with diminished nicotine and cocaine place preference in α6 KO mice compared to WT littermates. Studies with α4 KO mice showed significantly reduced nicotine place preference scores compared to WT littermates. In contrast, α4 KO and WT mice showed significant place preference for 20mg /kg cocaine, suggesting that the α4 subunit is not required for the reward-like effects of cocaine in our behavioral test. Our results implicate α6β2* and α4β2* nAChR involvement in nicotine and cocaine CPP, but only α6β2* nAChR involvement in cocaine CPP. Lithium conditioned place avoidance and food reward were not altered in α6 KO mice or by α-Conotoxin MII[H9A;L15A], thereby validating the specificity of hedonics of targeting α6* nAChRs in CPP. Our studies suggest that α6β2* and α4β2*nAChR should be further characterized for future nicotine cessation therapies, and α6β2* could provide a new target for treating cocaine addiction.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-11-2012

Share

COinS