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G protein-coupled receptor signaling in VTA dopaminergic neurons bidirectionally regulates the acute locomotor response to amphetamine but does not affect behavioral sensitization

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Amphetamine (AMPH) acts as a substrate of the dopamine transporter (DAT) and causes a dramatic increase in extracellular dopamine (DA). Upon entering DA neurons, AMPH promotes DA efflux via DAT through a mechanism implicating depletion of DA from vesicular stores, activation of kinase pathways and transporter phosphorylation. Despite the role of intracellular signaling for AMPH action, it remains elusive how the response to AMPH is affected in vivo by metabotropic regulation via G protein coupled receptor signaling pathways. Here, we show by employment of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) that the acute hyperlocomotor response to AMPH is bidirectionally regulated by metabotropic input to VTA DA neurons with a markedly enhanced response upon activation of a Gs-coupled pathway and a markedly decreased locomotor response upon activation of a Gi-coupled pathway. The unique mechanism of action for AMPH was underlined by the absence of an effect of Gs activation on the locomotor response to the DAT inhibitor cocaine. Regardless of the profound effect on the acute AMPH response, repeated Gs activation or Gi activation did not affect development of AMPH sensitization. Furthermore, activation of a Gs-pathway or activation of a Gi-pathway in DA neurons did not have any effect on the AMPH-induced locomotor response in the AMPH sensitized mice. This suggests induction of alterations in DA neuronal functions that overrule the stimulatory or inhibitory effect of metabotropic input seen in drug-naïve mice. The data thereby underline the remarkable strength of maladaptive changes that occur upon intake of strong psychostimulants. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.

OriginalsprogEngelsk
TidsskriftNeuropharmacology
Vol/bind161
Sider (fra-til)107663
ISSN0028-3908
DOI
StatusUdgivet - 15 dec. 2019

Bibliografisk note

Copyright © 2019 Elsevier Ltd. All rights reserved.

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