Effects of naltrexone, duloxetine, and a corticotropin-releasing factor type 1 receptor antagonist on binge-like alcohol drinking in rats

Abstract

A 'binge' is defined by National Institute on Alcohol Abuse and Alcoholism as an excessive pattern of alcohol drinking that produces blood-alcohol levels (BALs) greater than 0.08 g% within a 2-h period and may or may not be associated with dependence. The purpose of this investigation was to explore the effects of several neuropharmacological agents in an animal model in which outbred rats voluntarily and orally self-administer pharmacologically meaningful alcohol doses that produce BALs ≥ 0.08 g% in daily limited access two-bottle choice and operant drinking sessions. Rats were trained to self-administer either 10% (w/v) alcohol solution sweetened with 'supersac' (3% glucose + 0.125% saccharin) or supersac alone versus water in a two-bottle choice or operant situation during 30-min daily sessions. Rats were then injected systemically with multiple doses of duloxetine, naltrexone, and the corticotropin-releasing factor antagonist, MPZP, in Latin-square designs. Alcohol binge drinkers reliably consumed amounts of alcohol sufficient to produce BALs ≥ 0.08 g%. Duloxetine dose-dependently suppressed two-bottle choice alcohol binge drinking and operant alcohol responding as well as operant supersac responding, but did not affect two-bottle choice supersac drinking. Naltrexone-suppressed alcohol binge drinking at very low doses and suppressed supersac drinking at moderate-to-high doses. MPZP did not affect alcohol or supersac consumption. Different profiles for drugs that suppress binge-like alcohol drinking compared with dependenceinduced drinking provide a heuristic foundation for future medications development.

In vitroandin vivomodels of acute alcohol exposure

“…Among non-human vertebrates commonly involved in alcohol research are primates [90,91,148] , pigs [104,120] , dogs [114,121] , mice [70,72,74,86,89,96,109,118,119,141] , rats [88,94,108,149,150] and rabbits [132] . The rodent AAA models (mice and rats) are used most frequently due to their relatively well-defined genetic background and the availability of diverse genetic traits, including those coding for high or low alcohol consumption [88,89,96,109] .…”

“…The rodent AAA models (mice and rats) are used most frequently due to their relatively well-defined genetic background and the availability of diverse genetic traits, including those coding for high or low alcohol consumption [88,89,96,109] . Most non-human AAA models currently in use [93,95] examine relative oral self-administration from a bottle containing alcohol versus one [86,94,108] or multiple bottles [119] containing water (preference drinking) or administration of alcohol against the will, either by physiological (by mouth using gavage)…”

“…In vivo the consumption of alcohol in one setting implies that the entire dose of alcohol is consumed at once, while a 'binge' is defined by NIAAA as an excessive pattern of alcohol drinking that produces BAL greater than 0.08% within a 2-h period and may, or may not, be associated with dependence [11,12,17,18] . Thus any model using consumption of biologically active amounts of alcohol within 2 h is considered an acceptable model of AAA [81,[107][108][109][110][111][112][113][114][115][116][117][118][119][120][121] . (2) Establish an exposure to an accurate concentration of ethanol.…”

“…For in vitro studies the 10-100 mmol/L ethanol range is considered physiological, with 25 mmol/L ethanol being close to 0.08% BAL achieved in vivo after 4-5 drink equivalents [7,11,12,[98][99][100][101][102][103][104][105][106] . For the in vivo studies an 0.08% BAL or above this level yields signs of intoxication and it is employed in the majority of biomedical studies [107][108][109][110][111][112][113][114][115][116][117][118][119][120][121] . (3) Recruit individuals who are currently not and never have been alcohol abusers for in vivo studies and employ alcohol-naïve primary cells or cell lines for in vitro studies.…”

Potent Inhibition of Alcohol Self-Administration in Alcohol-Preferring Rats by aκ-Opioid Receptor Antagonist

“…The alcohol-preferring rat (P-rat) has been effectively used as a small animal model to study binge drinking (Li et al, 1987). In the P-rat, naltrexone (Biggs and Myers, 1998;Gilpin et al, 2008;Ji et al, 2008) and other opioids (Weiss et al, 1990) have been shown to be effective in decreasing alcohol self-administration. Nalmefene (Scheme 1), the 6-methylene analog of naltrexone, is a more potent k-opioid antagonist than naltrexone and is an effective antagonist of alcohol self-administration in outbred and P-rats (June et al, 1998(June et al, , 2004.…”