Abstract
At cellular and circuit levels, drug addiction is considered a dysregulation of synaptic plasticity. In addition, dysfunction of the glutamate transporter 1 (GLT-1) in the nucleus accumbens (NAc) has also been proposed as a mechanism underlying drug addiction. However, the cellular and synaptic impact of GLT-1 alterations in the NAc remain unclear. Here we show in the NAc that 10 days withdraw after 5 days treatment with cocaine or amphetamine decreases GLT-1 expression in astrocytes, which results in the prolongation of the excitatory postsynaptic potential (EPSP) decay kinetics in D1 receptor-containing medium spiny neurons (D1R-MSNs). Using the spike timing dependent plasticity (STDP) paradigm, we found that enlargement of EPSP duration results in switching the LTP elicited in control animals to LTD in psychostimulant-treated mice. In contrast to D1-MSNs, D2-MSNs did not display changes in EPSP kinetics and synaptic plasticity. Notably, the psychostimulant-induced synaptic transmission and synaptic plasticity effects were absent in IP3R2(-/-) mice, which lack astrocyte calcium signal, but were mimicked by the selective astrocytes stimulation with DREADDs. Finally, ceftriaxone, which upregulates GLT-1, restored normal GLT-1 function, EPSP kinetics, and synaptic plasticity in psychostimulant-treated mice. Therefore, we propose that cocaine and amphetamine increase dopaminergic levels in the NAc, which stimulates astrocytes and downregulates the GLT-1. The decreased GLT-1 function prolonged the EPSP kinetics, leading to the modulation of the STDP, transforming the LTP observed in control animals into LTD in psychostimulant-treated mice. Present work reveals a novel mechanism underlying the synaptic plasticity changes induced by these drugs of abuse.