Effect of repeated abstinence on chronic ethanol self-administration in the rhesus monkey

Abstract

RATIONALE Abstinence-based approaches to treating alcohol use disorder (AUD) are highly prevalent, but abstinence from chronic drinking may exacerbate subsequent levels of alcohol intake in relapse. OBJECTIVE Use a non-human primate model that encompasses a range of chronic voluntary ethanol drinking to isolate biological responses to repeated cycles of imposed abstinence as a function of baseline voluntary alcohol drinking levels. METHODS Over a 26-month protocol, young adult male rhesus macaques were first induced to drink alcohol and then given continuous access to 4% (w/v) ethanol (n=8) or water (n=4) for approximately 14 months, followed by three 28–35 day abstinence phases, with 3 months of ethanol access in between. Ethanol intake and BEC were the primary dependent variables. Observational signs of physical dependence and circulating ACTH and cortisol were monitored. RESULTS Prior to abstinence, stable, categorical, individual differences in voluntary ethanol intake under chronic access conditions were found. Following abstinence, categorical “non-heavy” drinking subjects increased drinking transiently (increased between 0.7–1.4 g/kg/day in first month after abstinence), but returned to baseline after three months. Categorical “heavy” drinkers, however maintained drinking 1.0–2.6 g/kg above baseline for over 3 months following abstinence. Signs of physical dependence were rare, although huddling and social withdrawal increased in ethanol and control subjects. The most prominent effect on hormonal measures was heightened cortisol during abstinence that increased to a greater extent in ethanol subjects. CONCLUSION Involuntary abstinence increases drinking in the absence of overt physical withdrawal symptoms, and heavy drinkers are more robustly affected compared to non-heavy drinkers.

Modulation of Gpr39, a G-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice

“…in mice [26]. Taken in conjunction with the ability of TC-G 1008 to prevent an escalating frequency of drinking bouts that typically accompanies consecutive alcoholaccess sessions in mice [35], TC-G 1008 may show pharmacotherapeutic promise when administered during active drinking or abstinence when a relapse-associated escalation in drinking is possible [39].…”

Dose-dependent effects of chronic alcohol drinking on peripheral immune responses

“…1a,b). These cohorts of animals were previously described in detail 38,69 and leveraged in several immunological studies 42,44,45 . Differentials from whole blood were obtained using a complete blood count machine calibrated for rhesus blood.…”

Chronic heavy drinking drives distinct transcriptional and epigenetic changes in splenic macrophages

“…These animals came from three separate cohorts (6a, 7a, and 10) that followed two variations of the voluntary consumption protocol (detailed at MATRR.com). Briefly, spleen samples were collected at necropsy either at the end of the approximately 12 months voluntary consumption or a continuation of “open access drinking” with intermittent 1-month periods of forced abstinence over an additional year (details in [37]). The age of the subjects ranged from 5.5–8.4 years of age at the time of sample collection.…”