NEUROSCIENCE Cocaine: It's All About the Dopamine

Cocaine has complex effects on neurophysiology and behavior, in part because it has at least three major targets, the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepiniphrine transporter (NET). These transporters remove neurotransmitters that are released by neurons into the extracellular space at synapses. Thus, inhibition of the transporters prolongs neuronal stimulation. There is much evidence that dopaminergic signals are important for the "reward" effect on behavior that contributes to the addictive properties of cocaine. However, DAT-knockout mice still respond to cocaine and will administer it to themselves if the drug is made available. Although this argues against the DAT as a primary target for the addictive properties of cocaine, adaptive changes in knockout animals are known to mask important physiological mechanisms. Chen et al. therefore created mice in which the DAT was replaced with a mutant that had relatively normal dopamine transport function but required nearly 100 times greater concentration of cocaine to be inhibited than did the normal transporter. The reward effect of cocaine was measured in a behavioral test in which mice are placed in a box with three easily recognized, distinct chambers. Animals experiencing a reward effect will spend more time in the chamber that they associate with the effects of a drug, in this case cocaine. (The association is formed earlier by keeping the animal in a particular chamber after the drug is administered.) In the mutant animals, cocaine suppressed locomotion (which it normally stimulates) and did not produce a reward effect in the behavioral test. Thus, the authors conclude that, in the presence of functional DAT, the reward effect of cocaine requires its inhibition of DAT. This confirms the DAT as the primary target of efforts to understand addiction and to develop therapeutic therapies to treat addicted individuals.

R. Chen, M. R. Tilley, H. Wei, F. Zhou, F. M. Zhou, S. Ching, N. Quan, R. L. Stephens, E. R. Hill, T. Nottoli, D. D. Han, H. H. Gu, Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter. Proc. Natl. Acad. Sci. U.S.A. 103, 9333-9338 (2006). [Abstract] [Full Text]