Repeated methamphetamine administration produces cognitive deficits through augmentation of GABAergic synaptic...

Methamphetamine (METH) abuse is associated with the emergence of cognitive deficits and hypofrontality, a pathophysiological marker of many neuropsychiatric disorders that is produced by altered balance of local excitatory and inhibitory synaptic transmission. However, there is a dearth of information regarding the cellular and synaptic mechanisms underlying METH-induced cognitive deficits and associated hypofrontal states. Using PV-Cre transgenic rats that went through a METH sensitization regime or saline (SAL) followed by 7-10 days of home cage abstinence combined with cognitive tests, chemogenetic experiments, and whole-cell patch recordings on the prelimbic prefrontal cortex (PFC), we investigated the cellular and synaptic mechanisms underlying METH-induce hypofrontality. We report here that repeated METH administration in rats produces deficits in working memory and increases in inhibitory synaptic transmission onto pyramidal neurons in the PFC. The increased PFC inhibition is detected by an increase in spontaneous and evoked inhibitory postsynaptic synaptic currents (IPSCs), an increase in GABAergic presynaptic function, and a shift in the excitatory-inhibitory balance onto PFC deep-layer pyramidal neurons. We find that pharmacological blockade of D1 dopamine receptor function reduces the METH-induced augmentation of IPSCs, suggesting a critical role for D1 dopamine signaling in METH-induced hypofrontality. In addition, repeated METH administration increases the intrinsic excitability of parvalbumin-positive fast spiking interneurons (PV + FSIs), a key local interneuron population in PFC that contributes to the control of inhibitory tone. Using a cell type-specific chemogenetic approach, we show that increasing PV + FSIs activity in the PFC is necessary and sufficient to cause deficits in temporal order memory similar to those induced by METH. Conversely, reducing PV + FSIs activity in the PFC of METH-exposed rats rescues METH-induced temporal order memory deficits. Together, our findings reveal that repeated METH exposure increases PFC inhibitory tone through a D1 dopamine signaling-dependent potentiation of inhibitory synaptic transmission, and that reduction of PV + FSIs activity can rescue METH-induced cognitive deficits, suggesting a potential therapeutic approach to treating cognitive symptoms in patients suffering from METH use disorder.