This manuscript was a red-headed stepchild in that it took two journal rejections and seven manuscript revisions to finally have this data published (with honors!) in Chronobiology International. The first submission was to Psychopharmacology where it was accepted by all reviewers after three rounds of review, but then had to be withdrawn because the editor decided to wait until that moment to request a replication of all experiments (which took about two years of my time) with a higher or lower dose of the drug of study; acamprosate. Let this be noted by all you future reviewers. The second submission was to American Journal of Physiology: Integrative, Regulatory, Comparative, but it was rejected due to a lack of “salience and merit.” Oddly enough, the paper was then accepted by a journal with a substantially higher impact factor than AJP– Chronobiology International– after three minor rounds of revisions. Below is a summary of the experiments which combined actography, microdialysis, and pharmacology to characterize circadian drinking and concomitant locomotor behaviors in mice lacking the PER2 clock gene, which would provide additional, mechanistic evidence of their alcoholic phenotype, and in order to determine if functional loss of the PER2 clock gene would affect the suppression of ethanol intake and craving by acamprosate, which has been prescribed to alcoholics since the early millennium.
As shown in this series of actograms of locomotor activity and drinking (achieved by placing an infrared sensor at the tip of a recessed water bottle), the PER2-mutant mice wake up about 2 hrs earlier than wild-types, immediately begin drinking [ethanol], and continue to drink ethanol across the nighttime, which over time, results in higher levels of ethanol intake [and craving], more ethanol drinking episodes at a particular circadian phase, and greater circulating levels of ethanol in systemic tissue. Yep, they are members of Sigma Chi.
Acamprosate , when given daily in all mice at the beginning of the PER2-mutant’s predictive rise time, reduced overall ethanol intake [and craving] without affecting the circadian pattern of drinking. Acamprosate simply reduced the number of drinks and subsequent levels of circulating ethanol at a particular circadian phase, but was less efficacious in PER2-mutants, such that higher levels of ethanol intake and craving were maintained in these Sigma Chis vs. your typical, moderate-drinking (wild-type) engineers.
What is the big picture? A few years ago, a colleague of ours, Dr. Rainer Spanagel at the University of Heidelberg in Germany of whom gratefully supplied the acamprosate for this study published a paper in Nature Medicine that revealed the neurobiological manifestations of elevated ethanol intake [and craving] in the PER2-mutant mice; basically, functional loss of PER2 reduces the reuptake of glutamate at the synapse, which causes an increase in extracellular glutamate, and as shown in several other alcohol studies, can led to a long-term, downward spiral of ethanol intake and craving. This study paralleled Dr. Spanagel’s study by providing a behavioral (and circadian) cause for their elevated ethanol intake. Phew!
Brager AJ, Prosser RA, & Glass JD (2011). Circadian and Acamprosate Modulation of Elevated Ethanol Drinking in mPer2 Clock Gene Mutant Mice. Chronobiology international, 28 (8), 664-672 PMID: 21929298