This paper was published two months ago, but I forgot to blog about it, probably because I had three grants and several meeting abstracts due within a two week period in early December. At any rate, this paper focused on brain areas, particularly those that independently (and now, arguably co-dependently) regulate circadian timing and reward-seeking, that were sensitive to acamprosate.
Acamprosate is an anti-(alcohol) relapse medication that has been approved for use by the FDA since 2004. Unlike its competing anti-relapse meds, such as naltrexone, that pharmacologically act in the brain and are used to treat or mitigate a variety of drug addictions (heroin, nicotine), acamprosate is specific for the treatment of alcohol use disorders. However, there are very few studies that have assessed acamprosate’s neurobiological effects since its early days of study in the pharmaceutical and clinical labs and since its near-decade long prescription use.
In this study, I used a very simple and extremely cheap method (relative to other biomedical supplies in basic research) to have acamprosate be constantly-release over a 4 week period from specific brain areas: I mixed a sub-optimal dose of acamprosate in beeswax and bilaterally popped these beeswax pellets (height of 1.25 mm and width of 0.75 mm) into the lateral edges of specific circadian (SCN, intergeniculate leaflet) and reward (ventral and pedunculopontine tegmental areas, nucleus accumbens) brain areas.
I used wild-type mice which have moderate levels of ethanol intake (drink the equivalent of 4-6 beers a night) and Per2-mutant mice which have very high levels of ethanol intake (drink 12 beers a night). Both of these strains are responsive to acamprosate, nevertheless.
In terms of the experimental protocol: 1) the mice had a choice between a 15% alcohol solution (boxed wine) or water for one month; 2) were withdrawn from alcohol for another 3 weeks; 3) underwent brief anesthesia and three days of post-surgical recovery for the implantation of constant-release acamprosate micropellets; and 4) were re-introduced to free-choice between alcohol and water for another month.
Across many brain areas, acamprosate suppressed levels of alcohol intake and craving over a longer period of time in wild-type compared with PER2-mutant mice. Lower brainstem reward areas (ventral and pedunculopontine tegmental areas) were also more sensitive to acamprosate compared with hypothalamic and thalamic circadian areas and compared with forebrain, cortical reward areas (nucleus accumbens, hippocampus). These results were in agreement with our general hypothesis of what should occur within the reward-processing brain areas; the ventral tegmental area is the primary neural site for the integration, local and global processing, and transmission of reward-related information to the pedunculopontine tegmentum and nucleus accumbens. We were very surprised by the large, suppressive effect of acamprosate released from circadian areas on drinking, however (only because we didn’t know what the hell would happen).
I am compelled to boast about my presentations of acamprosate’s long-term suppressive effects because each graph (there are 12 in the paper) took an average of 4 hrs to make.
I try to repress how long Figure 2 took to collate, including, of course, all the rounds of successful and unsuccessful immunohistochemistry, hours of killing my right retina manifest from microphoto-snapping, and determining the exact three-dimensional placement of each micropellet. But here it is, at last, in its final form!
Brager A, Prosser RA, & Glass JD (2011). Acamprosate-responsive brain sites for suppression of ethanol intake and preference. American journal of physiology. Regulatory, integrative and comparative physiology, 301 (4) PMID: 21697518