Project Summary Neuropsychiatric disorders are a very serious medical and societal problem with many different origins, however, a common and prevalent deficit found in these disorders is hypofrontality. Emerging theories posit that hypofrontality [alterations in the ratio of excitatory (E) and inhibitory (I) synaptic transmission] underlie schizophrenia, anxiety, addiction, autism spectrum disorders and depression. Methamphetamine (METH) addicts frequently develop hypofrontality and deficits in working memory (WM), attention, and impulsivity. Similarly, in rodents, repeated psychostimulant administration or self- administration elicits hypofrontality, WM deficits, psychosis-like behaviors, decreased interest in external stimuli and surroundings, and decreased social functioning, suggesting that psychostimulant administration in rodents represents a strong, face-valid model for studying the basic brain mechanisms that underlie hypofrontality and cognitive disabilities in METH addiction. The overall objective of the proposed studies is to identify the effects of METH-SA on the activity of cortical parvalbumin positive fast spiking interneurons (PV+FSIs) and the resulting changes in E-I ratio. The central hypothesis- informed by strong preliminary data and literature- is that METH treatment elicits cognitive deficits due to an increase in GABAergic synaptic transmission in the PFC via D1R activation of PV+FSIs. The proposal’s rationale is that the experiments will yield fundamental knowledge pertaining to the understanding of the cellular and synaptic mechanisms underlying hypofrontality induced by METH and will provide new insights into the basic mechanisms governing E-I balance in the prefrontal cortex. We will test the central hypothesis by pursuing the following specific aims: Aim 1 will determine the role of PV+FSIs in METH- induced cognitive deficits. Aim 2 will determine whether D1R signaling in PFC PV+FSIs is required for METH- induced enhancements of GABAergic transmission. Aim 3 will determine whether D1R signaling in PFC PV+FSIs is required for METH SA-induced cognitive deficits and METH reinstatement. The proposed research is significant because it will fill a fundamental gap in knowledge pertaining to the mechanisms underlying hypofrontality in METH-addiction and the effects of the psychostimulant in the activity of cortical PV+FSIs. Furthermore, the knowledge obtained from the proposed experiments will help to develop effective treatments to ameliorate drug-related cognitive deficits and can provide new insights into the basic mechanisms underlying hypofrontality in other neuropsychiatric conditions.