“At a purely chemical level, every experience humans find enjoyable – whether listening to music, embracing a lover, or savoring chocolate – amounts to little more than an explosion of dopamine in the nucleus accumbens as exhilarating and ephemeral as a firecracker.”
- J Madelaine Nash

With this kind of imagery, it is not difficult to comprehend the power that dopamine wields over us when it is released, especially for those addicted to cocaine. Cocaine can actually inhibit dopamine reuptake via blockade of the dopamine transporter (DAT), increasing the synaptic availability of dopamine, prolonging its activity and producing the rewarding and addictive properties of the drug. DAT blockade by cocaine is correlated with the “high” experienced by addicts. The dopamine D2 receptor (D2R) plays some role in cocaine addiction, with lower levels of this receptor found in the nucleus accumbens (NAc) of cocaine addicts.

In a recent paper by Volkow and colleagues, the authors treated cocaine-addicted rats with D2R gene therapy in order to increase the levels of D2R in the nucleus accumbens (NAc). Up-regulation of D2R in the NAc was correlated with a decrease in lever pressing for i.v. infusions of cocaine, suggesting a possible therapeutic strategy in the treatment of addiction.

Methods

Rats were trained for 2 hours daily in operant chambers to press a lever for food pellets. After training, jugular catheters (for i.v. infusions) were implanted, along with guide cannulas leading directly into the NAc. After a recovery period of one week, the animals were re-introduced into the operant chambers. Now, rats received an i.v. infusion of cocaine following a lever press, with a 30 second time-out following each infusion. After 7 days of cocaine self-administration, rats then received a microinjection of an “empty” adenovirus, or a null vector, into the NAc. They were then returned to their chambers for another week of cocaine self-administration. Finally, all animals were given a microinjection of the D2R-expressing vector into the NAc and returned to the chambers for 14 more days.

Results

The number of infusions and lever presses were compared between (a) 1-7 days pre-null vector treatment, (b) 8-15 days post-null vector treatment and©16-22 days post-D2R vector treatment. After the animals were expressing increased levels of D2R in the NAc (because of the experimental vector), the average number of infusions decreased by 75% and the number of lever presses was also reduced.

D2R adenoviral infusion resulted in a decrease in cocaine self-administration and lever pressing for up to 6 days post-treatment, with this result eventually returning to baseline. A similar result was also observed for ethanol administration. However, the attenuated response of ethanol self-administration was of a longer duration than that observed for cocaine self-administration, suggesting that there are alternate pathways for dopamine reward. But at the very least, these results demonstrate the broad potential for such a strategy.

Discussion

In this study, D2R up-regulation disrupted cocaine self-administration, however the exact mechanism has yet to be elucidated. A possible explanation for these results is; cocaine use increases dopamine release, desensitizing or decreasing the levels of D2R in the brain and in effect rewiring the brain so that cocaine produces the feeling of reward. By increasing D2R in the NAc, there is an enhanced dopamine-D2R interaction, thereby increasing the sensitivity of the NAc neurons to the effects of the drug and lowering the dose of the drug that would be required to have a rewarding effect. With the animal receiving an equivalent reward with less cocaine, fewer lever presses (and subsequent infusions) would be necessary.

Questions

1. In the paper it is suggested that the D2R in the NAc is not the only route through which the pharmacological effects of cocaine take place; what are the other possible modes of action?

2. What other possible mechanisms may underlie how D2R up-regulation in the NAc decreases cocaine self-administration?

3. The attenuation of cocaine intake was transient in the virus-treated animals; what factors likely influenced this habituation to D2R up-regulation?

4. Is D2R gene therapy a viable treatment for addiction in humans?