Chronic alcohol exposure disrupts metabotropic glutamate receptor-mediated modulation of neurotransmission in the striatum

Authors

• KA Johnson
• DM Lovinger

Abstract

The striatum is a part of the brain that plays important roles in movement, action selection, and habit formation. Chronic exposure to drugs of abuse alters striatal function and biases action selection to promote drug-seeking behavior. Understanding how striatal function is regulated will provide critical opportunities to pharmacologically modify drug-induced adaptations in striatal circuits and related behaviors. Previous efforts to evaluate G protein-coupled receptor (GPCR)-mediated modulation of striatal glutamatergic transmission have employed techniques that cannot distinguish the contributions of different inputs to the striatum; particularly, little is known about modulation of thalamostriatal circuitry. Inputs from individual cortical and thalamic regions exert differential control over striatum-dependent behaviors, so it is critical to understand how discrete circuits are modulated to identify novel therapeutic strategies that are targeted to the circuit-level causes of pathological behavior. To study modulation of striatal circuits by metabotropic glutamate receptors (mGlu2 and mGlu3), we expressed Channelrhodopsin-2 (ChR2) in cortical or thalamic projections to the mouse striatum. We performed whole-cell patch clamp recordings of optically-evoked excitatory postsynaptic currents (oEPSCs) in striatal neurons and evaluated effects of drugs targeting mGlu2/3 on corticostriatal and thalamostriatal transmission. Pharmacological interrogation of this effect revealed a critical role for mGlu2. Inhibition of corticostriatal transmission by mGlu2 was less pronounced. Finally, inhibition of EPSCs by LY379268 was disrupted by chronic alcohol exposure. Because drugs that enhance mGlu2 function are currently in clinical development for alcohol and drug use, these timely studies will provide critical information about how mGlu2 activation could correct drug-related behaviors.

Scientific Focus Area: Neuroscience

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