Norepinephrine and Dopamine: Mediating Drug vs. Natural Rewards

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DESCRIPTION (provided by applicant): Addiction is a disease primarily characterized by compulsive drug seeking and taking; however, equally devastating is the loss of interest in one's normal activities (e.g., interpersonal relationships, work and recreational activities). Typically, this reduction is viewed as a secondary consequence of the heightened reinforcing value of drugs (i.e., drugs become so important/salient that everything else necessarily pales in comparison). We propose that drugs exert at least two distinct influences on motivation circuits: 1) the enhanced motivation for drugs, mediated primarily by enhanced dopamine (DA) signaling in the nucleus accumbens (NAc), and 2) the loss of interest in natural rewards, which we hypothesize is mediated by enhanced norepinephrine (NE) signaling in the NAc. Individual differences in DA and NE levels are expected to render some more (or less) vulnerable to the development of addiction. NE levels in the striatum are greater in females and vary over the reproductive cycle. Therefore, we propose that one mechanism predisposing women to addiction is their heightened NE levels, which become further exacerbated with drug use. This results in the loss of interest in natural rewards and renders women more susceptible to the reinforcing effects of drugs. Males are less likely to experience these effects to the same degree (due to their relatively lower NE levels); however, with chronic use, drug-induced neuroadaptations in NE signaling may contribute to more severe signs of dependence in both sexes. To test this hypothesis we will examine the effects of adrenergic antagonists in the NAc on the self-administration of cocaine and natural rewards (e.g., food) in male and female rats. We predict that NE antagonists will reduce drug intake by reinvigorating interest in natural rewards, which is suppressed over the course of self-administration, and that this effect will be most pronounced in females. We will also examine sex differences in the NE system, including 21 adrenergic receptors, NE biosynethetic enzymes and innervation in the NAc via immunohistochemistry, and basal and cocaine-induced NE levels in the NAc via microdialysis. The sum of these experiments will lay the groundwork for understanding sex differences in the function of the noradrenergic system in the NAc under basal conditions and following drug exposure and provide a rationale for different pharmacotherapies for men and women in the treatment of addiction.