Analysis of modulation of the metabotropic glutamate receptor type 5 in a novel heritable model of drug abuse vulnerability

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Project Summary Schizophrenia is a debilitating mental illness affecting an estimated 1% of the global population. Substance abuse comorbidity is common in a number of mental illnesses, including post-traumatic stress disorder, bipolar disorder, and schizophrenia, with nicotine being the most commonly abused substance. This comorbidity has several detrimental effects, including reduced quality of life and reduced efficacy of treatment. My lab is therefore interested in developing pharmacological interventions to reduce the rewarding effects of nicotine and alleviate deficits in endophenotypic markers of psychosis. Previously published work in our laboratory has established that rats neonatally treated with the dopamine D2-like receptor (DAD2) agonist quinpirole for the first 21 days of life show lifelong increases in DAD2 receptor sensitivity, displaying a number of behavioral phenotypes of relevance to substance abuse comorbidity in psychosis, including enhanced nicotine conditioned place preference and deficits in sensorimotor gating. Our lab has more recently developed a heritable model of drug abuse vulnerability in psychosis by breeding rats neonatally treated with quinpirole (NQ) to either another NQ or a saline (NS) treated animal to produce a subsequent F1 generation. This F1 generation displays increased dopamine signaling comparable to NQ animals in the F0 generation. DAD2 receptors have been found to form a functionally distinct heteroreceptor complex with the metabotropic glutamate type 5 (mGlu5) receptor, such that stimulation of mGlu5 results in reduced DAD2 affinity. In specific aim 1, I will outline predoctoral work that has been completed which has shown that treatment with the positive allosteric modulator of the mGlu5 receptor 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) reduces the associative rewarding properties of nicotine and alleviates deficits in sensorimotor gating in F1 generation animals, suggesting this therapeutic agent may be a promising target for the dual treatment of tobacco use disorder and psychosis. In the F99-phase of this proposal, I will establish the therapeutic efficacy of CDPPB in preventing relapse-like behavior in a system sensitized to dopamine using optogenetic tools to manipulate dopaminergic signaling in the brain reward pathway. Changes in subcellular localization of dopamine signaling markers following administration of CDPPB will be analyzed using subcellular fractionation to determine mechanism of action of CDPPB. Further, mechanisms of heritability conferring enhanced DAD2 sensitivity in the F1 generation will be assessed using next generation RNA sequencing techniques. In specific aim 2, I will seek a postdoctoral position with a strong mentoring team that will allow me to expand my training to include use of neural recording and imaging techniques to analyze how changes on a cellular level translate to observable changes in behavior that may contribute to the development of neuropsychiatric conditions during the K00 phase of this proposal.