Reduced dopamine release in Dcc haploinsufficiency male mice abolishes the rewarding effects of cocaine but not those of morphine and ethanol

Psychopharmacology (Berl). 2023 Mar;240(3):637-646. doi: 10.1007/s00213-022-06288-1. Epub 2022 Dec 6.


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.

Keywords: DCC receptors; Guidance cues; In vivo microdialysis cocaine; Netrin-1; Place preference.

MeSH terms

  • Animals
  • Cocaine* / metabolism
  • Cocaine* / pharmacology
  • DCC Receptor / genetics
  • DCC Receptor / metabolism
  • Dopamine / metabolism
  • Ethanol / pharmacology
  • Haploinsufficiency
  • Male
  • Mice
  • Morphine / metabolism
  • Morphine / pharmacology
  • Nucleus Accumbens
  • Receptors, Cell Surface / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / pharmacology


  • Cocaine
  • Dopamine
  • DCC Receptor
  • Morphine
  • Tumor Suppressor Proteins
  • Ethanol
  • Receptors, Cell Surface
  • Dcc protein, mouse