Restriction of food intake increases the acquisition of drug abuse behavior and enhances there in forcing efficacy of those drugs. However, the neurophysiological mechanisms responsible for the interactions between feeding state and drug use are largely unknown. Here we show that chronic mild food restriction increases the burst firing of dopamine neurons in the substantia nigra. Dopamine neurons from food-restricted mice exhibited increased burst firing in vivo, an effect that was enhanced by an injection of the psychomotor stimulant cocaine (10 mg/kg, i.p.). Food restriction also enhanced aspartic acid-induced burst firing of dopamine neurons in an ex vivo brain slice preparation, consistent with an adaptation occurring in the somatodendritic compartment and independent of a circuit mechanism. Enhanced burst firing persisted after 10 d of free feeding following chronic food restriction but was not observed following a single overnight fast. Whole-cell patch-clamp recordings indicated that food restriction also increased electrically evoked AMPAR/NMDAR ratios and increased D2 autoreceptor-mediated desensitization in dopamine neurons. These results identify dopamine neurons in the substantia nigraas a convergence point for the interactions between feeding state and drugs ofabuse. Furthermore, increased glutamate transmission combined with decreased autoreceptor inhibition could work in concert to enhance drug efficacy in response to food restriction.
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