Drinking Typography Established by Scheduled Induction Predicts Chronic Heavy Drinking in a Monkey Model of Ethanol Self-Administration

Alcohol abuse and alcoholism represent significant public health concerns recognized throughout the world. In the United States, the Centers for Disease Control and Prevention has ranked alcohol abuse the number 3 preventable cause of death in the country (Mokdad et al., 2004). The current estimate of the number of Americans who meet the diagnostic criteria of alcohol abuse or dependence is 18 million or 8.5% of the population 18 years and older (Grant et al., 2004). Heavy alcohol consumption (greater than 6 drinks per day, >1.5 g/kg, and 20% of daily calories in the form of alcohol) is comorbid with brain, heart, lung, liver, pancreatic and kidney disease states, and is a cofactor in cancer, reproductive and immune system dysfunction (Gunzerath et al., 2004). Although nearly all individuals in the United States are exposed to alcohol, consumption of alcohol is unevenly distributed, with 64% of the adult U.S. population actively drinking alcohol and 20%of this population consuming approximately 80% of all the alcohol sold (Dawson, 2000). Thus, individuals are not at equal risk for drinking alcohol excessively. Research directed at predicting which individuals are at high risk for alcoholism is a matter of urgent public health concern for the development of prevention and harm-reduction programs. At present, the relative contributions of risk factors that prompt some individuals to drink alcohol excessively are not known, although sex, age of onset of drinking, social networks, genetics, availability, and stressful events have all been implicated. Animal models of human disease are commonly used to identify and assess etiological factors, including diseases that involve a large behavioral component such as alcohol abuse and alcoholism. Among the different animals used in alcohol research, nonhuman primates are important subjects because of their genetic homology with humans, their propensity to self-administer large quantities of alcohol (ethanol) orally, and their absorption and metabolism of ethanol that are similar to humans (Grant and Bennett, 2003). Despite the rigorous control that nonhuman primates offer in studies assessing risk for alcohol abuse and alcoholism, the characterization of voluntary and excessive ethanol drinking in monkeys has been very limited. Particularly sparse are data that capture accurate consumption patterns of chronic intake in the range of 12 to 24 drinks per day (>3.0 to 6.0 g/kg) for periods of time encompassing months or years. In humans, periods of heavy alcoholic drinking are often described as “benders” or “sprees” and the resultant intoxication is associated with many adverse outcomes such as traffic fatalities, violent behavior, and biomedical complications. Binges are currently defined as drinking 5 or more alcoholic drinks on an occasion and are the target for harm-reduction policies (Dawson, 2000). However, studies on the patterns of drinking in alcoholics given unlimited access to alcohol have reported sprees (or benders) of much more excessive intake consisting of approximately 1 quart of distilled alcohol, such as bourbon, a day (roughly 22 to 24 drinks) for several consecutive days (Majchrowicz, 1977; Majchrowicz and Mendelson, 1970; Mello and Mendelson, 1970; Nathan et al., 1971). A perhaps crucial factor in alcoholic binging is the desire to increase alcohol consumption far above an already substantial baseline of intake. For many reasons, direct laboratory studies of human alcoholic drinking have been curtailed since the 1970s and today most studies rely on self-report of drinks per drinking days (Stahre et al., 2006). Without direct studies of chronic, alcoholic drinking under unlimited access, many fundamental questions concerning individual risk for, and the biological basis of, excessive ethanol consumption remain unanswered. We have utilized a model of oral ethanol self-administration in monkeys that results in a high proportion (approximately 35%) of heavy drinking individuals that averaged daily ethanol intakes of 3.0 g/kg per day (>12-drink equivalent) for 12 months with frequent episodes of spree drinking that fit the characteristics of human alcoholic spree drinking. The monkeys attain blood ethanol concentrations (BEC) between 100 and 400 mg/dl when measured 7 to 8 hours after the onset of drinking (Vivian et al., 2001) and metabolize ethanol at rates similar to human beings (Green et al., 1999). These daily intakes and BECs are similar to those reported for alcoholic men who were given 20 to 60 consecutive days of free access to ethanol 24 h/d (Majchrowicz and Mendelson, 1970; Mello and Mendelson, 1970, 1971; Nathan et al., 1971). In this procedure, we utilize a schedule-induction procedure to initiate ethanol self-administration. Induction procedures are necessary in animal models of ethanol self-administration because in a vast majority of the studies simply allowing access to ethanol is not sufficient to result in repeated consumption of intoxicating quantities. The low levels of ethanol intake of uninitiated animals have been attributed to the taste of alcohol, the delay between the consumption of alcohol and its pharmacological effects, the volume of alcohol needed for a pharmacological effect, and the particular pharmacological effects of alcohol (including positively reinforcing as well as aversive effects). To circumvent these difficulties, it is now standard to use an induction procedure to establish ethanol drinking in animals that have not been specifically bred to drink large amounts of an alcohol solution. Induction procedures include food deprivation, adulterating the taste of ethanol, associating the consumption of ethanol with the presentation or removal of other reinforcers, acclimating the animal to gradually increasing concentrations of ethanol, and restricting access to the alcohol solution (see Meisch, 1984; Rhodes et al., 2005; Samson, 1987). We previously published data on the following cohort of monkeys showing baseline deoxycorticosterone and pregnenolone response to a dexamethasone challenge correlated with average ethanol intakes over the next 12 months of ethanol self-administration (Pearson R = −0.78, p < 0.006; Porcu et al., 2005, 2006). These results were from assays taken prior to induction. The objective of the following experiment was to characterize a large number of behavioral and organismal variables related to drinking during the initial exposure to alcohol and determine which, if any, variables could predict which monkeys would become chronic and heavy drinkers. For the initial exposure to drinking ethanol, the monkeys were placed under a schedule-induction procedure. Schedule-induced drinking occurs when a fluid is available and access to food is restricted, with small quantities of food delivered intermittently at fixed intervals of time (Falk, 1993; Sanger, 1986). Schedule-induced drinking was first reported in 1961 when it was observed that food-deprived rats allowed access to small quantities of food under an intermittent schedule drank water in amounts equivalent to nearly half of their body weight in a 3-hour period (Falk, 1961). Under schedule-induction conditions, drinking is neither required nor explicitly reinforced. Nevertheless, animals persistently drank large volumes of fluid when the interval between pellet delivery lies somewhere between freely available and very long, usually 3 to 20 minutes (Allen and Kenshalo, 1978; Byrd, 1980; Grant and Johanson, 1988; Porter and Kenshalo, 1974; Schuster and Woods, 1966). Peak adjunctive drinking of water ranged from 463 to 840 ml/h in rhesus monkeys (Allen and Kenshalo, 1976; Schuster and Woods, 1966) to 281 to 365 ml/h in cynomolgus monkeys (Allen and Kenshalo, 1978). Indeed, nonhuman primates appear to be easily susceptible to schedule-induced polydipsia (SIP), and can be induced by the intermittent delivery of food pellets without food deprivation (Grant and Johanson, 1988). Schedule-induced procedures have been used to induce large volumes of ethanol consumption in rats, monkeys, and humans (see Doyle and Samson, 1985; Meisch, 1984; Samson, 1987). Indeed, there is a wealth of data that suggest specific parameters for obtaining physical dependence and high blood alcohol levels using SIP in rodents (for reviews see, Falk, 1971, 1993). It appears that the optimal concentration of ethanol that rodents can be induced to drink is 5% v/v ethanol (Falk et al., 1972) and the optimal schedule is a 2-minute fixed-time (FT) interval of pellet presentation (Falk, 1966; Falk et al., 1972; Samson and Falk, 1975). In cynomolgus monkeys, we determined that 4% (w/v) ethanol and 5 minutes is an optimal FT interval schedule of food pellet delivery to induce consumption of 1.0 g/kg ethanol (Shelton et al., 2001). That is, all monkeys exposed to the 5 minute interval schedule using 4% (w/v) ethanol were induced to drink the 1.0 g/kg dose. Furthermore, we used these schedule parameters to establish ethanol self-administration for over a year in monkeys kept at their free-feeding weight (Vivian et al., 2001). In the following procedure, after the induction of ethanol self-administration, monkeys were immediately placed under “open access” conditions and given a choice of ethanol (4% w/v) or water to drink for 22 h/d, 7 d/wk for 12 months. The daily average ethanol intake (gram ethanol per kg body weight per day) over the 12 months of open access served as the major correlate and outcome measure in searching for predictions of future heavy drinking (operationally defined as an average of >3.0 g/kg/d, Vivian et al., 2001).