Evidence of long-term expression of behavioral sensitization to both cocaine and ethanol in dopamine transporter knockout mice.
BACKGROUND
Locomotor sensitization, defined as the progressive and enduring enhancement of the motor stimulant effects elicited by repeated exposure to drugs of abuse, is the consequence of drug-induced cellular neuroadaptations that likely contribute to addictive behavior. Neuroadaptations within the dopaminergic system have been shown to be involved both in the induction phase and in the long-term expression phase of sensitization upon drug readministration after withdrawal.


METHODS
Mice lacking the dopamine transporter (DAT-KO) were used to test the effect of constitutive hyperdopaminergia on the durability of behavioral sensitization to both cocaine and ethanol. The effect of the DAT mutation was simultaneously tested on two inbred genetic backgrounds, C57Bl/6 and DBA/2, chosen for their contrasting addiction-related phenotypes, as well as on the hybrid F(1) offspring of a cross between C57Bl/6 and DBA/2 congenic strains.


CONCLUSIONS
In spite of the absence of the DAT, mutant mice were able to develop long-term expression of sensitization to cocaine. Compared to their wild-type littermates, DAT-KO mice exhibited a markedly increased acute ethanol-evoked locomotor activity and developed stronger behavioral sensitization to ethanol during both induction and long-term expression phases. Interestingly, this increased ethanol-induced sensitization was potentiated by the DBA/2 genetic background.


CONCLUSIONS
These findings, showing that DAT deletion facilitates sensitization, suggest a cross-sensitization-like effect between genetic- and pharmacological-induced hyperdopaminergia.
Morice
Elise
E
Institut National de la Santé et de la Recherche Médicale (INSERM), U952, 9 quai Saint Bernard, 75005, Paris, France.
Denis
Cécile
C
Giros
Bruno
B
Nosten-Bertrand
Marika
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D004334:Drug Administration Schedule; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010641:Phenotype
D050483:Dopamine Plasma Membrane Transport Proteins; D000431:Ethanol; D003042:Cocaine