An investigation of the neural substrates underlying the anxiogenic effects of cocaine.

摘要

Cocaine self-administration is known to produce both positive/euphoric and negative/anxiogenic effects. While the rewarding effects of cocaine have been well documented, the neurobiology underlying its anxiogenic effects remains unclear. Our laboratory has employed two behavioral assays to study these opposing actions of cocaine: a runway self-administration test, and a modified place conditioning test. In the runway, the positive and negative effects of cocaine are reflected in the frequency of approach-avoidance conflict behavior that animals develop about entering a goal box associated with cocaine delivery. In the place conditioning test, animals develop preferences for environments paired with the immediate/rewarding effects of cocaine but avoid environments paired with the drug's delayed/anxiogenic actions. The investigations detailed in this dissertation utilize both of these behavioral models in an attempt to understand the neurobiology underlying the negative/anxiogenic effects of cocaine. Four studies were designed and executed to address three broad aims: (1) to determine if the reward-related neurotransmitter dopamine plays a role in cocaine's negative effects, (2) to identify specific brain regions critical to the experience of cocaine's anxiogenic properties, and (3) to examine the role of neurotransmitter systems within identified structures in these properties. Altogether, the experiments detailed in this thesis do not support a role for dopamine in cocaine's anxiogenic effects, but, rather, outline a role for norepinephrine neurotransmission within the extended amygdala in the delayed/negative effects of cocaine administration.