Behavioral Sensitization to the Disinhibition Effect of Ethanol Requires the Dopamine/Ecdysone Receptor in Drosophila

Abstract

Male flies under the influence of ethanol display disinhibited courtship, which is augmented with repeated ethanol exposures. We have previously shown that dopamine is important for this type of ethanol-induced behavioral sensitization but the underlying mechanism is unknown. Here we report that DopEcR, an insect G-protein coupled receptor that binds to dopamine and steroid hormone ecdysone, is a major receptor mediating courtship sensitization. Upon daily ethanol administration, dumb and damb mutant males defective in D1 (dDA1/DopR1) and D5 (DAMB/DopR2) dopamine receptors, respectively, showed normal courtship sensitization; however, the DopEcR-deficient der males exhibited greatly diminished sensitization. der mutant males nevertheless developed normal tolerance to the sedative effect of ethanol, indicating a selective function of DopEcR in chronic ethanol-associated behavioral plasticity. DopEcR plays a physiological role in behavioral sensitization since courtship sensitization in der males was reinstated when DopEcR expression was induced during adulthood but not during development. When examined for the DopEcR’s functional site, the der mutant’s sensitization phenotype was fully rescued by restored DopEcR expression in the mushroom body (MB) αβ and γ neurons. Consistently, we observed DopEcR immunoreactivity in the MB calyx and lobes in the wild-type Canton-S brain, which was barely detectable in the der brain. Behavioral sensitization to the locomotor-stimulant effect has been serving as a model for ethanol abuse and addiction. This is the first report elucidating the mechanism underlying behavioral sensitization to another stimulant effect of ethanol.

Cellular diversity in the Drosophila midbrain revealed by single-cell transcriptomics

“…Finally, the Dopamine/Ecdysteroid receptor ( DopEcR ) was found in several cell types, including KCs, PNs, the ocelli, and many other non-attributed clusters ( Figure 8B ), suggesting a broad role for this receptor. Expression of this DopEcR in PNs corroborates previous data showing its involvement in pheromone sensitization in these neurons, both in flies and moths ( Abrieux et al, 2014 ; Aranda et al, 2017 ).…”

Voluntary intake of psychoactive substances is regulated by the dopamine receptor Dop1R1 in Drosophila

“…4a,d). The DopEcR mutant flies are less sensitive to ethanol sedation 66,67 , and show defects in dealing with various stressors such as starvation, heat and sexual rejection [68][69][70] . Therefore, DopEcR might mediate aversive effects of drugs, which include ethanol sedation, thereby function as a 'brake' for the further drug intake.…”

Naltrexone Reverses Ethanol Preference and Protein Kinase C Activation in Drosophila melanogaster

“…It thus appears that naltrexone affects preferentially the behavioral seeking of ethanol in ethanol-exposed flies. The dopaminergic system is known to be implicated in addictive mechanisms in Drosophila (Azanchi et al, 2013 ; Aranda et al, 2017 ) and in the mammalian nervous system this is influenced by the opiate system (Koob and Volkow, 2016 ), further work is required to investigate this relationship in Drosophila .…”