The emergence of addictive patterns of drug-seeking behavior is thought to arise from persistent neuroadaptations in the natural reward and motivation circuits of the brain, particularly the corticoaccumbens and mesocorticolimbic circuitry during relapse. This proposal addresses whether methamphetamine (meth) abuse alters dorsal medial prefrontal cortex (dmPFC) and nucleus accumbens core (NAc) extracellular glutamate and dopamine expression in a consistent manner as seen with cocaine and amphetamine abuse in the NAc. In addition, whether drug associated cues, drug prime, or their combination induce differential effects on expression of these transmitters will also be measured with in vivo microdialysis. We hypothesize that a history of meth self-administration will decrease both basal glutamate and dopamine levels in the dmPFC and NAc (Specific Aim #1). We also expect that these changes will reverse (i.e., increase) both glutamate and DA in the NAc, while dopamine will increase in the dmPFC only, when rats are given a meth drug-prime, presented with drug-associated cues, or the combination, as compared to yoked-saline or saline primed controls. Identifying the dysregulation of glutamate in both the dmPFC and NAc after meth self-administration would address whether there are differences with meth than cocaine and the dmPFC and NAc expression of glutamate and dopamine. PUBLIC HEALTH RELEVANCE: The investigation of the impact of methamphetamine abuse on the neurochemical balance of dopamine and glutamate in the dorsal medial prefrontal cortex and nucleus accumbens, critical brain areas involved in executive function and addiction, is highly relevant to public health. New knowledge gained from these studies will contribute to a better understanding of the neurochemical changes that underlie methamphetamine addiction and will help identify novel pharmacotherapeutic targets for broadly treating abuse, withdrawal, and relapse in human addicts.