Modeling Aversion Resistant Alcohol Intake in Indiana Alcohol-Preferring (P) Rats

Abstract

With the substantial social and medical burden of addiction, there is considerable interest in understanding risk factors that increase the development of addiction. A key feature of alcohol use disorder (AUD) is compulsive alcohol (EtOH) drinking, where EtOH drinking becomes “inflexible” after chronic intake, and animals, such as humans with AUD, continue drinking despite aversive consequences. Further, since there is a heritable component to AUD risk, some work has focused on genetically-selected, EtOH-preferring rodents, which could help uncover critical mechanisms driving pathological intake. In this regard, aversion-resistant drinking (ARD) takes >1 month to develop in outbred Wistar rats (and perhaps Sardinian-P EtOH-preferring rats). However, ARD has received limited study in Indiana P-rats, which were selected for high EtOH preference and exhibit factors that could parallel human AUD (including front-loading and impulsivity). Here, we show that P-rats rapidly developed compulsion-like responses for EtOH; 0.4 g/L quinine in EtOH significantly reduced female and male intake on the first day of exposure but had no effect after one week of EtOH drinking (15% EtOH, 24 hr free-choice paradigm). Further, after 4–5 weeks of EtOH drinking, males but not females showed resistance to even higher quinine (0.5 g/L). Thus, P-rats rapidly developed ARD for EtOH, but only males developed even stronger ARD with further intake. Finally, rats strongly reduced intake of quinine-adulterated water after 1 or 5 weeks of EtOH drinking, suggesting no changes in basic quinine sensitivity. Thus, modeling ARD in P-rats may provide insight into mechanisms underlying genetic predispositions for compulsive drinking and lead to new treatments for AUDs.

Animal models of compulsion alcohol drinking: Why we love quinine-resistant intake and what we learned from it

“…Further, genetically-selected, alcohol-preferring Marchigian Sardinian P-rats develop quinine-resistance faster than Wistars and Listar Hooded rats, developing CLAD after 1-2 months of IAA but not CAA (112). However, a recent study found that male and female Indiana alcohol-preferring P-rats develop CLAD, with quite high levels of quinine, within 1 week of alcohol drinking (104). Interestingly, P-rat alcohol intake is significantly reduced by quinine the 1st day of consumption (104), suggesting that only brief drinking history is needed for this line of alcohol-preferring rat to develop compulsion for alcohol.…”

“…However, a recent study found that male and female Indiana alcohol-preferring P-rats develop CLAD, with quite high levels of quinine, within 1 week of alcohol drinking (104). Interestingly, P-rat alcohol intake is significantly reduced by quinine the 1st day of consumption (104), suggesting that only brief drinking history is needed for this line of alcohol-preferring rat to develop compulsion for alcohol. However, while Indiana Prats tolerate 400 mg/L quinine in alcohol after 1 week of drinking, it takes 3-5 weeks of drinking for males to tolerate even higher quinine (500 mg/L), which females won't tolerate.…”

“…Also, a recent study in the geneticallyselected, alcohol-preferring cHAP mouse line found that, when alcohol was paired with 0.25 mA footshock, both female and male mice continue responding for alcohol; however, when the shock increased to 0.35 mA only females keep responding (95). On the other hand, in the genetically-selected, alcohol-preferring Indiana P-rat, females and males overall tolerate high levels of quinine, with males tolerating the higher doses more than females (104). Furthermore, several factors could contribute to lack of sex differences under "simpler" (bottle drinking) vs. more complex (or perhaps less ethological) behaviors such as lever pressing.…”

Non-Consummatory Behavior Signals Predict Aversion-Resistant Alcohol Drinking in Head-Fixed Mice

“…A standard method for modeling aversion-resistant drinking in rodents is to assess the degree to which an animal is willing to consume alcohol that is adulterated with the bitter tastant quinine [2-6], with the view that animals that are more willing to consume quinine adulterated alcohol are more aversion-resistant. This method of assessing ARD has been used in numerous animal models, including mice [6-17], Wistar rats [18-24], alcohol preferring P rats [18-20, 25, 26], and Sprague-Dawley rats [27].…”