Abstract
Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; however, their effects on striatal pathway function in vivo remain unclear. One model that has been proposed to account for these motor effects suggests that stimulants drive hyperactivity via activation and inhibition of direct and indirect pathway striatal neurons, respectively. Although this hypothesis is consistent with the cellular actions of dopamine receptors and received support from optogenetic and chemogenetic studies, it has been rarely tested with in vivo recordings. Here, we test this model and observe that cocaine increases the activity of both pathways in the striatum of awake mice. These changes are linked to a dopamine-dependent cocaine-induced strengthening of upstream orbitofrontal cortex (OFC) inputs to the dorsomedial striatum (DMS) in vivo. Finally, depressing OFC-DMS pathway with a high frequency stimulation protocol in awake mice over-powers the cocaine-induced potentiation of OFC-DMS pathway and attenuates the expression of locomotor sensitization, directly linking OFC-DMS potentiation to cocaine-induced hyperactivity.
Highlights
Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; their effects on striatal pathway function in vivo remain unclear
Recent work indicates that lateral inhibition between dMSNs and iMSNs plays a pivotal role in determining the locomotor effects of cocaine[16,17], which is consistent with the idea that opposing activation in each pathway underlies cocaine-induced hyperactivity
To monitor circuit plasticity as it occurs in vivo, we investigated the consequences of low-frequency (LFS: 5 Hz for 15 min; n = 7 mice for noLFS and n = 7 mice for low-frequency stimulation (LFS)) and theta-burst (TBS: 10 repetitions of 40 stimulations organized in trains of 50 Hz every 10.5 Hz; n = 8 mice for noTBS and n = 13 mice for theta-burst stimulation (TBS)) stimulation of orbitofrontal cortex (OFC) on the amplitude of OFCe local field potentials (LFPs) responses in dorsomedial striatum (DMS)
Summary
Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; their effects on striatal pathway function in vivo remain unclear. One model that has been proposed to account for these motor effects suggests that stimulants drive hyperactivity via activation and inhibition of direct and indirect pathway striatal neurons, respectively We identified a high-frequency stimulation protocol that robustly depressed the OFC-DMS evoked responses, and found that this same protocol attenuated the cocaine-induced OFC-DMS potentiation and the hyperlocomotor actions of cocaine in vivo These data suggest that cocaine facilitates OFC-DMS synapses, increasing both direct and indirect pathway activity in the striatum of awake mice, and thereby driving cocaine-induced hyperactivity
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