Lack of cocaine self-administration in mice expressing a cocaine-insensitive dopamine transporter.
Cocaine addiction is a worldwide public health problem for which there are no established treatments. The dopamine transporter (DAT) is suspected as the primary target mediating cocaine's abuse-related effects based on numerous pharmacological studies. However, in a previous study, DAT knockout mice were reported to self-administer cocaine, generating much debate regarding the importance of the DAT in cocaine's abuse-related effects. Here, we show that mice expressing a "knockin" of a cocaine-insensitive but functional DAT did not self-administer cocaine intravenously despite normal food-maintained responding and normal intravenous self-administration of amphetamine and a direct dopamine agonist. Our results have three implications. First, they imply a crucial role for high-affinity DAT binding of cocaine in mediating its reinforcing effects, reconciling mouse genetic engineering approaches with data from classic pharmacological studies. Second, they demonstrate the usefulness of knockin strategies that modify specific amino acid sequences within a protein. Third, they show that it is possible to alter the DAT protein sequence in such a way as to selectively target its interaction with cocaine, while sparing other behaviors dependent on DAT function. Thus, molecular engineering technology could advance the development of highly specialized compounds such as a dopamine-sparing "cocaine antagonist."
Thomsen
Morgane
M
Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA. mthomsen@mclean.harvard.edu
Han
Dawn D
DD
Gu
Howard H
HH
Caine
S Barak
SB
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D050483:Dopamine Plasma Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011897:Random Allocation; D012055:Reinforcement Schedule; D012646:Self Administration
D050483:Dopamine Plasma Membrane Transport Proteins; D003042:Cocaine