Courtesy of the Kobal Collection.

Understanding the molecular basis of the rewarding and reinforcing effects of addictive drugs such as cocaine is important for developing therapies to combat addiction. Cocaine blocks the reuptake of dopamine, serotonin and noradrenaline from the synaptic cleft by inhibiting the corresponding neuronal transporters, DAT, SERT and NET. As with other drugs of abuse, the consequent increase in synaptic dopamine levels in the nucleus accumbens — a major brain reward centre — is thought to be a key factor behind cocaine reward/reinforcement. Surprisingly, however, cocaine reward was found to be intact in mice lacking DAT, indicating that blockade of this transporter is not the sole mechanism that mediates reward. Other experiments have implicated SERT blockade in cocaine reward, but reward is also intact in mice lacking this transporter. One possible explanation for these observations is that cocaine normally produces reward through simultaneous actions at both DAT and SERT, with sufficient redundancy in the mechanism to maintain reward in the absence of one or other transporter. By generating double-knockout mice with deletions of one or both copies of the DAT and SERT genes, Sora et al. have now provided strong evidence to support this idea, and also insights into the relative contributions of dopamine- and serotonin-mediated mechanisms to cocaine reward.

The authors used cocaine-conditioned place preference as a measure of cocaine reward/reinforcement. Mice with only a single copy of DAT and no copies of SERT showed near-wild-type levels of preference for places where they had received cocaine. However, mice lacking DAT and having either one or no copies of SERT no longer showed any such preference. Densities of DAT and SERT expression were reduced in a gene-dose-dependent manner, suggesting that DAT has a greater role than SERT in cocaine reward/reinforcement in wild-type mice.

We lack a truly effective agent to block the rewarding and reinforcing effects of cocaine. These results indicate that therapeutic strategies targeting both dopamine- and serotonin-mediated pathways might be effective in combating cocaine addiction. Indeed, if the relationship in mice between transporter expression and reward is paralleled in humans, a drug causing strong inhibition of cocaine binding to DAT and moderate inhibition of binding to SERT while sparing transmitter reuptake might be highly efficacious. Alternatively, drugs targeting specific dopamine and serotonin receptors could prove to be a rewarding avenue of research.