| Summary: | Summary: The ventral pallidum (VP) is part of the basal ganglia circuitry and a target of both direct and indirect pathway projections from the nucleus accumbens. VP is important in cocaine reinforcement, and the firing of VP neurons is modulated in vivo during cocaine self-administration. This modulation of firing is thought to be indirect via cocaine actions on dopamine in the accumbens. Here, we show that cocaine directly inhibits synaptic transmission evoked by selective stimulation of indirect pathway projections to VP neurons. The inhibition is independent of dopamine receptor activation, absent in 5-HT1B knockout mice, and mimicked by a serotonin transporter (SERT) blocker. SERT-expressing neurons in dorsal raphe project to the VP. Optogenetic stimulation of these projections evokes serotonin transients and effectively inhibits GABAergic transmission to VP neurons. This study shows that cocaine increases endogenous serotonin in the VP to suppress synaptic transmission selectively from indirect pathway projections to VP neurons. : Matsui and Alvarez show that acute effects of cocaine on accumbal to VP projections in brain slices are mainly mediated by serotonin, not dopamine, and involve serotonergic projections from the dorsal raphe. Cocaine inhibition selectively targets indirect pathway projections from accumbens and is expected to shift the balance of direct pathway projections toward VP. Keywords: cocaine, ventral pallidum, serotonin, 5-HT1B receptors, dorsal raphe, serotonin transporter, SERT
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