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Single dose of amphetamine induces delayed subregional attenuation of striatal cholinergic interneuron activity

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-rpS6). We found that amphetamine did not induce neurotoxic effects on ChIs, as their distribution and morphology were not affected. While low- or high-dose amphetamine did not affect ChI activity after 2.5 hours, ChI activity was significantly reduced in all striatal subregions after 24 hours, with a dose-dependent effect in the nucleus accumbens. Thus, our findings suggest that a single dose of amphetamine has delayed regionally heterogeneous effects on ChI activity. Significance statement Using the activity dependent marker phosphorylated ribosomal protein S6 (p-rpS6), we mapped amphetamine effects on the activity of cholinergic interneurons (ChIs) across the striatum. Amphetamine caused a delayed attenuation of ChI activity in all striatal subregions, and a dose-dependent effect in the ventral striatum/nucleus accumbens, a critical site of psychostimulant action.