Probing the Mesolimbic Dopamine Reward System: A Common Neurocircuitry in Substance Abuse and Schizophrenia
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Substance abuse is more prevalent among patients with schizophrenia than in the general population. Interestingly, the pathophysiology of schizophrenia is thought to share many overlapping features with drug addiction, including disruption of the mesolimbic dopaminergic pathway. My thesis work was aimed at investigating drug-induced alterations in dopamine function that leads to addiction-related behavior using animal models of substance abuse. In the first part of my studies, I combined small animal imaging with behavioral tests to probe the effects of abused inhalants on overall brain activity and the dopaminergic system in rats. These studies lead me to the second part of my thesis, where I characterized a dopamine-based phenotype in mice that have targeted deletion of a schizophrenia susceptibility gene, NRG1, to investigate the contribution of NRG1 signaling on dopamine dysfunction in schizophrenia. First, a radiolabeled analog of glucose [(18)FDG] monitored regional changes in glucose uptake during a drug-preference behavioral task. Next, striatal D2 dopamine receptor density was measured by [(11)C]raclopride, a D2 receptor antagonist. In another set of studies, [(11)C]raclopride was used as an assay for synaptic dopamine release upon drug challenge. In parallel, baseline and drug effects on synaptic dopamine release and metabolism was measured in vivo using microdialysis. The results of the first part of my thesis indicated that the rewarding effects of toluene are mediated, at least in part, by the DA system. Further, in the second part of my thesis, I investigated whether genetic disruption of a candidate schizophrenia susceptibility gene, NRG1, altered drug seeking behavior and / or the DA system. My results suggest that mice heterozygous for a disruption of the Type III isoforms of the Nrg1 gene are more responsive to the behavioral and neurochemical effects of cocaine. Additional results demonstrate that Nrg1 heterozygous mice have alterations in striatal dopamine receptor levels and altered baseline DA metabolism. These results mirror clinical reports demonstrating DA sensitization in neuroleptic treated schizophrenic patients. My results validate the use of behavior and small animal imaging to study drug abuse, and therefore, this paves the way for future studies on other drugs of abuse or in other genetic animal models.