Single Dose of Amphetamine Induces Delayed Subregional Attenuation of Cholinergic Interneuron Activity in the Striatum

Psychostimulants such as amphetamine target dopamine neuron synapses to engender drug-induced plasticity. While dopamine neurons modulate the activity of striatal cholinergic interneurons (ChIs) with regional heterogeneity, how amphetamine affects ChI activity has not been elucidated. Here, we applied quantitative fluorescence imaging approaches to map the dose-dependent effects of a single dose of amphetamine on ChI activity at 2.5 and 24 hours after injection across the mouse striatum using the activity-dependent marker phosphorylated ribosomal protein S6 (p-rpS6240/244). Amphetamine did not affect the distribution or morphology of ChIs in any striatal subregion. While amphetamine at either dose had no effect on ChI activity after 2.5 hours, ChI activity was dose-dependently reduced after 24 hours specifically in the ventral striatum/nucleus accumbens, a critical site of psychostimulant action. Amphetamine at either dose did not affect the spontaneous firing of ChIs. Altogether this work demonstrates that a single dose of amphetamine has delayed regionally heterogeneous effects on ChI activity, which most likely involves extra-striatal synaptic input. Significance statement Using the activity dependent marker phosphorylated ribosomal protein S6 (p-rpS6240/244), we mapped amphetamine effects on the activity of cholinergic interneurons (ChIs) across the striatum. Amphetamine reduced ChI activity in dose-dependent manner in the ventral striatum/nucleus accumbens, a critical site of psychostimulant action.