Abstract
Rationale
The Netrin-1/DCC guidance cue pathway is critically involved in the adolescent organization of the mesocorticolimbic dopamine circuitry. Adult mice heterozygous for Dcc show reduced dopamine release in the nucleus accumbens in response to amphetamine and, in turn, blunted sensitivity to the rewarding effects of this drug.
Objective
Here, we tested whether the protective effects of Dcc haploinsufficiency are specific to stimulant drugs of abuse or instead extrapolate to opioids and ethanol.
Methods
We used the place preference paradigm to measure the rewarding effects of cocaine (20 mg/kg), morphine (5 or 10 mg/Kg), or ethanol (20%) in adult (PND 75) male Dcc haploinsufficient mice or their wild-type litter mates. In a second experiment, we compared in these two genotypes, in vivo dopamine release in the nucleus accumbens after a single i.p. injection of morphine (10 mg/kg).
Results
We found reduced morphine-induced dopamine release in the nucleus accumbens of Dcc haploinsufficient male mice, but, contrary to the effects of stimulant drugs, there is no effect of genotype on morphine-induced conditioned preference.
Conclusion
These findings show that reduced drug-induced mesolimbic dopamine in Dcc haploinsufficient male mice protects specifically against the rewarding effects of stimulant drugs, but not against the rewarding properties of morphine and ethanol. These results suggest that these drugs exert their rewarding effect via different brain circuits.
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Data availability
The data that support the findings of this study are available on request from the corresponding author.
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Acknowledgements
The authors dedicate this work to the late Dominique Nouel – an excellent and dedicated scientist, a kind mentor and colleague, and a generous and loyal friend.
Funding
The present research was supported by the National Institute on Drug Abuse (# DA037911 to C.F; # DA005010 and # DA048796 to B.L.K.), the Canadian Institutes of Health Research (# FRN 156272 to C.F.), the Natural Sciences and Engineering Research Council of Canada (# RGPIN-2020–04703 to C.F.), the Canada Fund for Innovation and the Canada Research Chairs to E.D. and B.L.K., and the University of Strasbourg initiative of Excellence (to E.D.). We thank Dr. Radu Avramescu for his helpful comments on the manuscript. We thank the NIDA Drug Supply Program (NIH) for providing the morphine.
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Darcq, E., Nouel, D., Hernandez, G. et al. Reduced dopamine release in Dcc haploinsufficiency male mice abolishes the rewarding effects of cocaine but not those of morphine and ethanol. Psychopharmacology 240, 637–646 (2023). https://doi.org/10.1007/s00213-022-06288-1
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DOI: https://doi.org/10.1007/s00213-022-06288-1