Methamphetamine (METH) is among the most addictive of abused substances, by some measures surpassing other drugs of abuse in terms of the degree of persistent drug-seeking behavior and impairments in quality of life. In addition to its highly addictive properties, METH abuse has been shown to deplete monoamine terminals in the prefrontal cortex (PFC), which can lead to psychiatric symptoms such as anxiety, attention-deficit-hyperactivity-disorder (ADHD), mood disturbances, and deficits in working memory function. Although several mechanisms have been proposed, one highly promising target is the serotonin transporter (SERT). Both clinical and animal data have shown that altered serotonin activity in the PFC leads to many of the same deficits and symptoms reported after chronic METH abuse. The goal of the current revised A1 proposal is to examine the effects of chronic METH self-administration on working memory function, reinstatement of drug-seeking, and monoamine transporter function in an animal model. In addition, this proposal will examine a putative mechanism of action for METH-induced working memory dysfunction and investigate a potential preventative treatment for METH-induced changes in transporter function. It is hypothesized that greater METH usage will lead to functional SERT adaptations in PFC, increased working memory deficits, and significantly greater reinstatement of METH-seeking. The studies proposed in this project will study cue- and drug-induced relapse by using the reinstatement model of METH-seeking in rats and employ a task sensitive to working memory for visual objects to study potential cognitive deficits. Multiple regression analysis will probe the factors that may predict the degree of relapse and novel object recognition, such that greater METH exposure should lead to greater cognitive deficits, greater decreases in monoamine transporter function, and altered reinstatement due to putative neurotoxic effects. Further, this proposal will use a novel technique to selectively lesion the SERT within the medial PFC to test its role in working memory. Finally, this proposal will utilize a selective serotonin reuptake inhibitor to determine if METH-induced dysfunction is preventable. In sum, this training proposal hopes to provide valuable insights into the effects of chronic METH usage on both cognitive function and monoamine transporter proteins with the hopes of exploring a potential link between the behavioral and molecular levels. This research is timely given the interest in translational research, especially when examining the effects of such a major public health concern like METH. It is the goal to examine a potential mechanism while offering a putative treatment to combat the detrimental effects of METH usage. ? ? ?
