A new paper (Renthal et al., Neuron 2009) that was examining the genome-wide chromatin regulation that occurs in the nucleus accumbens (an important area in the brain for reward) during cocaine addiction turned up some interesting results. The researchers took a closer look at some of the specific changes including sirtuin 1 and 2 (Sirtuins are believed to be involved in the positive effects of the potential longevity treatment resveratrol.)
To manipulate sirtuin 1 and 3 they turned to the widely studied sirtuin activator - resveratrol. Now most of you are probably quite familiar with resveratrol because it is investigated as a potential dietary restriction mimicker to potentially increase life span (see: Resveratrol for better brain health, Resveratrol improves heart health but not lifespan of mice (on normal diet), The testing of a new sirt activator: SRT1720, Sirt1 and aging: fighting wars on two fronts, 60 minutes coverage of potential longevity treatments). Now if increasing sirtuin proteins with resveratrol (or similar derivatives) is a dietary restriction mimicker we might expect some of the same overall positive and negative effects.
A bit of background:
Dietary restriction (DR), in the form of straight calorie restriction (CR), or every-other-day fasting (EODF)(which can also lead to calorie restriction depending on the species), with adequate nutrients, has been reported to increase life span in a wide range of organisms (they have been studying this for 80 years).
Interestingly, a number of studies have demonstrated an increase propensity for addiction in dietary restricted animals (both straight CR, or EODF). When I tell people about dietary restriction I always caution them about the one of the downsides of DR, which is a potential for increased addiction (for review see: Carr 2007). DR appears to notch up the reward system in an attempt to give the organism more incentive, more reward, for going to seek food (and maybe many other rewards). However, with this increase of gain in the reward system, it appears the organism is more easily develops addiction to rewarding drugs. But I also give the flip side that a notched up reward system with CR or EODF may make the average sunset more rewarding.
the question then is resveratrol invokes some of the same positive molecular changes as DR does - since it is hoped to be a DR mimicker - then maybe it makes sense it might also play a role in addiction.
New paper results: Resveratrol and cocaine addiction
Renthal et al., Neuron 2009 among a host of other genes changes with the intake of cocaine found an increased expression of sirt 1 and 2, as mentioned earlier.
We identified Sirt1 and Sirt2 from our ChIP-chip analyses of delta FosB target genes that also were regulated by histone acetylation. We then identified significant increases in both Sirt1 and Sirt2 mRNA and protein activity in the NAc after chronic cocaine administration.
Now having found an interesting target they manipulated it using resveratrol (a sirtuin activator) and an inhibitor of the pathway, sirtinol. Resveratrol increased the rewarding effects of cocaine, and sirtinol (sirtuin inhibitor) decreased the rewarding effect (in the conditioned place preference paradigm). Inhibiting sirtuins with sirtinol also decreased the amount of self administered cocaine by the animals (less addictive). Activating sirtuins with resveratrol increased the electrical excitability of nucleus accumbens neurons and potentiated the rewarding effects of cocaine.
The authors concluded in their discussion:
Thus, sirtuins appear to act downstream of delta FosB and may contribute
to a positive-feedback loop in which repeated drug exposure
increases levels of delta FosB and sirtuins, which in turn enhances
the motivation to take additional drug. These findings raise the
possibility of using SIRT1/2 inhibitors as potential treatment
agents for cocaine addiction.
So they are talking about inhibiting sirtuins as a treatment for cocaine addiction. Combined with their presented data that resveratrol accentuates cocaine’s reward would suggest that this dietary restriction mimicker may increase the potential for drug addiction (or lower the threshold). This would be consistent with the other similarities that resveratrol and dietary restriction have in common - both good and bad.
Take home message:
Activating the sirtuin pathway either via the intake of the potential pharmaceutical treatment to increase life span resveratrol appears to increase the rewarding effects of addictive drugs, and therefore may increase the potential for addiction (which is similar to the effects of dietary restriction). I guess a word of caution should be noted for anyone contemplating either resveratrol or dietary restriction (know thyself).