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Date of Award

6-2016

Document Type

Restricted Thesis: Campus only access

Degree Name

Master of Arts in General Experimental Psychology

Department

Psychology

First Reader/Committee Chair

Iñiguez, Sergio

Abstract

Major depressive disorder (MDD) is commonly diagnosed prior to adulthood, and when left untreated, may result in negative consequences that extend into adulthood. It is estimated that children and adolescents who suffer from MDD are more likely to develop conduct and anxiety disorders, and that up to 25% eventually develop substance abuse disorder. Consequently, this has resulted in a disproportionate increase in the prevalence of antidepressants prescribed to populations below 20 years of age, many of whom remain treatment-resistant. Recently, the non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist, ketamine, has been shown to alleviate symptoms of MDD in individuals that suffer from treatment-resistant depression. However, little is known about the potential long-term consequences of ketamine exposure during early development. This is important to examine at the preclinical level, given ketamine’s abuse potential, and the diffuseness of glutamatergic innervation within the reward circuit. We first demonstrate that juvenile ketamine treatment enhances preference for natural reward (i.e., 1% sucrose) three weeks post ketamine administration. In order to determine whether these long lasting increases in reward sensitivity extend to drugs of abuse, we examined whether adolescent ketamine treatment leads to an increased preference for cocaine later in life. Specifically, male c57BL/6 mice were exposed to ketamine (0 or 20 mg/kg) either during adolescence (postnatal days [PD] 35-49) or adulthood (PD70-84), and later assessed for sensitivity to cocaine (0.0, 2.5, 5.0, 7.5, or 10.0 mg/kg) place conditioning (CPP). We show that, when compared to saline pretreated controls, adult mice treated with ketamine during adolescence display an enhanced preference for environments previously paired with moderate doses of cocaine (5.0, 7.5, and 10.0 mg/kg). In contrast, mice that are pretreated with ketamine during adulthood do not show an enhanced preference for cocaine later in life. This study is the first to show that ketamine exposure during adolescence, but not adulthood, leads to a heightened preference for cocaine in adulthood. Future research is needed in order to determine to what extent ketamine exerts age-dependent functional modification of the reward circuit, and the mechanisms by which these responses are mediated.

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