April 2008

Document Type


Degree Name



Dept. of Behavioral Neuroscience


Oregon Health & Science University


Few studies have examined the neural areas mediating ethanol-conditioned reinforcement, which may be critically involved in ethanol- seeking behaviors and relapse. Environmental or internal cues closely paired in space and time with a drug’s effects can gain motivational value through an associative process known as Pavlovian conditioning, and in turn exert control over drug seeking and taking behaviors. Conditioned place preference (CPP) offers a way to investigate the learning mechanisms that underlie the ability of an ethanol-paired cue to elicit behavior in the absence of the drug. In CPP, a subject is passively administered a drug paired with a particular cue in the environment. After repeated pairings, preference for the previous drug-paired cue is assessed in the absence of the drug. If the subject spends more time with the previously drug-paired cue, the basic interpretation is the subject finds the drug be rewarding. Associative learning mechanisms that underlie the acquisition and expression of this behavior may control drug-seeking behaviors involved in drug abuse and dependence. Given the paucity of information on the functional neural mechanisms controlling cue-induced ethanol seeking behavior, the following studies used the CPP procedure to gain a further understanding of the processes involved in acquisition and expression of this behavior. Initial investigations have implicated the ventral tegmental area (VTA) in the expression of ethanol CPP (Bechtholt & Cunningham, 2005). However, the neural areas downstream mediating the acquisition and expression of this effect are unknown. In the first part of this thesis (Gremel & Cunningham, 2008), we examined the roles of the nucleus accumbens and amygdala in the acquisition and expression of ethanol CPP (chapter 2). We demonstrate that acquisition of ethanol CPP depends upon an intact accumbens and amygdala, while expression seems to require an intact amygdala. However, lesions of the accumbens core facilitated a loss of this expression behavior. Contributions of dopamine receptors (implicated in reward signaling), and NMDA receptors (implicated in learning processes) in the amygdala and accumbens to expression behavior were examined in chapter 3. Dopamine receptor activation within the basolateral amygdala, but not central amygdala or accumbens, is necessary for cue induced ethanol-seeking behavior. Further, expression of ethanol CPP was dependent upon NMDA receptor activation in accumbens (Gremel & Cunningham, submitted). For the first time, these studies demonstrate that acquisition and subsequent expression of cue-induced ethanol seeking behavior is modulated via mechanisms within the amygdala and accumbens. These are the first studies to delineate neural areas involved in the acquisition versus expression of a drug-conditioned behavior in mice. Further, they provide the first evidence of amygdala dopamine receptor involvement in any ethanol behavior, the first NMDA receptor involvement in mouse accumbens, and the first to delineate contributions of specific mouse amygdala nuclei. The current results also suggest that conditioned reinforcement processes may be controlling the observed expression behavior, providing a possible neural mechanism underlying ethanol conditioned reinforcement. In summary, the work presented in this thesis suggests expression of ethanol-seeking behaviors involved in relapse, may be dependent upon amygdala dopamine receptor activation and accumbens NMDA receptor activation.




School of Medicine



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