JOURNAL CLUB: Curbing cocaine addiction using gene therapy
Aine Duffy
Wednesday, 30 April 2008 17:47 UTC
“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?
Updated 30 April 2008 18:16 UTC
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Replies
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nice article mate. but will the test on rats have the same effect on humans?
micheal smith
Addiction treatment and recovery resources for the addict and their families. http://www.addictiontreatment.net
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Hey Michael,
Thank you for your question. The dopamine D2 receptor gene therapy reported on in the paper above may treat one aspect of drug addiction, but would probably not be as effective in humans. Dopamine D2 receptor dysfunction in the nucleus accumbens is just one characterisitc of drug addiction. Other areas of the brain in particular the prefrontal cortex and the cortico-striatal circuitry are thought to be central to drug addiction. Here is a review detailing the neural systems involved in addiction.
Aine
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Interesting article. I don’t know that what is the D2R gene therapy. So please give bit information about it. I’m eager to know that.
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SujithAddiction Therapy
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I heard about this before and I would really like it to be true because this would bring salvation for thousands of weak drug addicts. The truth is that I am skeptical about the method and still believe traditional methods like drug rehab are more effective at this moment…
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So it was my understanding that D2 receptors are primarily pre-synaptic on Dopamine neurons and typically inhibitory. Is it possible that this increased D2 population decreases presynaptic Dopamine and reduces the effect of cocaine after DAT block?
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Paul, that is certainly another explanation. The dopamine D2 receptor is often located presynaptically, mostly on GABA interneurons in the nucleus accumbens. Another possible mechanism of action could be through inhibition of GABA release due to dopamine D2 receptor activation. The reduction in inhibitory GABA may allow for increased dopamine release. Therefore post-treatment, a lower dose of cocaine will produce the same effects as a higher dose pre-treatment.
The exact mechanism of action through which the increased levels of dopamine D2 receptors curb cocaine intake in this study hasn’t been fully elucidated, and until it is, this therapy cannot be an option for human subjects. At study of the precise subcellular localization of these “extra” receptors would help explain the effects observed.
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Maybe Volkow et al should concurrently pursue gene therapy with the mutant human cocaine hydrolase described here.
Could this be a wiser approach?
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Same question as Michael. Great stuff, very interesting read, but how does this effect humans??? Is it really synonymous?
If you can curb cocaine therapy through gene therapy, how will this effect rehab facilities like http://www.recoveryconnection.org, Passages, and other well known ones? Do you think they’ll integrate it into their recovery process or do you think it will take away from their business?
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Response to Q4. Insertional mutagenesis which increases cancer risk hinders the use of viral vector-based gene therapy in humans. In particular, drug addition is not life-threatening condition in which the risk of gene therapy outweigh the clinical benefit.
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