August 2008

Document Type


Degree Name



Dept. of Behavioral Neuroscience


Oregon Health & Science University


Drug abuse is harmful to individuals, their families and a costly drain on scarce societal resources. Treatment for drug dependence can be difficult and produces mixed results. Therefore, it is incumbent upon researchers in the field of drug abuse to evaluate models and methods of testing procedures intended for therapeutic intervention. Animal models of drug dependence have become more sophisticated in representing the human condition of drug dependence. One such model is the long-access protocol of drug self-administration. Rats allowed an extended period of time to self-administer cocaine significantly escalate their drug consumption as compared to animals with only limited drug access. This is a robust phenomenon that is hypothesized to model the loss-of control aspect in human drug dependent individuals. More than likely several neurotransmitter systems are involved in the shift from drug use to drug dependence. Nicotine and cocaine are drugs commonly co-abused in human drug users. Experimental evidence suggests that the co-occurrence of these two drugs in drug users is more than a coincidence. Cocaine exerts its primary rewarding effects by acting within the mesoaccumbens reward pathway in the brain. Nicotine, the prototypical agonist of the nicotinic acetylcholine receptor (nAChR) has been reported to enhance the rewarding experience of cocaine and possibly inducing an increase cocaine intake. Therefore, I have hypothesized that nicotinic receptors are critically involved in the experience of cocaine reward. This includes the escalated intake of cocaine that is observed in animals with long-access to self-administer the drug. Furthermore, this thesis will detail a possible mechanism and site specific location within the mesoaccumbens pathway that the nAChRs may be exerting their effects. Experimental data indicated that systemic blockade of nicotinic receptors blunted the effect of long-access on the rat’s daily cocaine consumption. The data was such that animals would not escalate their cocaine intake during periods of nAChR antagonism. Further research revealed that once animals had significantly increased their cocaine intake, as a function of long-access, antagonism of nAChRs in the ventral tegmental area (VTA) significantly decreased, but did not completely eliminate, cocaine self-administration. Given that nicotinic receptors in the VTA disrupted cocaine intake, a final experiment was conducted to elucidate a possible mechanism by which nAChRs exert influence over VTA dopamine projection neurons. The findings in this thesis implicate the neuronal nicotinic receptors—particularly nAChRs in the VTA— as being functionally involved in cocaine self-administration. These findings may be of importance for clinicians and therapists when treating patients for cocaine dependence.




School of Medicine



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