Aggressive temperament predicts ethanol self-administration in late adolescent male and female rhesus macaques

Abstract

Rationale Anxiety and aggression are associated with ethanol self-administration, but these behaviors can serve as either risk factors for or consequences of heavy drinking in rodents and humans. Baseline levels of aggressive-like and anxious-like behavior in non-human primates have not yet been characterized in relation to future or prior ethanol intake. Objective To test the association between temperament at baseline with future ethanol self-administration in late adolescent male (n=21) and female (n=11) rhesus monkeys. Methods Shortly after entering the laboratory and before exposure to ethanol, the Human Intruder Test (HIT) and the Novel Object Test (NOT) were used to determine baseline anxious-like and aggressive-like behavior in age-matched male and female rhesus monkeys (Macaca mulatta). The monkeys were induced to drink ethanol 4% (w/v) using a schedule-induced polydipsia procedure, followed by “open-access” ethanol self-administration in which the monkeys were allowed a choice of water or 4% ethanol (w/v) for 22 hours/day (h/d) for 52 weeks. Results Aggressive monkeys self-administered more ethanol and attained higher Blood Ethanol Concentrations (BECs). No significant differences in ethanol intakes or BECs were found between anxious and non-anxious monkeys or between behaviorally inhibited and non-inhibited monkeys. Baseline aggressive behavior positively correlated with ethanol intake and intoxication. Conclusions Baseline reactive aggression was associated with higher future ethanol intake and intoxication. While significant sex differences in HIT reactivity were observed, the relationship between aggression and ethanol drinking was observed across sex and is not sex-specific.

Studies using macaque monkeys to address excessive alcohol drinking and stress interactions

“…These temperaments can be viewed as endophenotypes with genetic basis towards development of alcohol use disorders (McClintick and Grant, 2016) and temperament can predict adolescent alcohol use in humans (Dick et al, 2013). Monkeys also exhibit stable temperaments that can be quantified when confronted with strangers or novel objects, by the degree of behavioral inhibition (anxious animals) or aggressive responses (aggressive animals) (Kalin and Shelton, 1989).…”

“…Monkeys also exhibit stable temperaments that can be quantified when confronted with strangers or novel objects, by the degree of behavioral inhibition (anxious animals) or aggressive responses (aggressive animals) (Kalin and Shelton, 1989). In a recent study, a group of 21 male and 11 female rhesus monkeys in the late adolescent/early adult stage of life were typed for temperament prior to being induced to drink alcohol (McClintick and Grant, 2016). The monkeys with aggressive temperaments self-administered more alcohol and attained higher BECs than non-aggressive monkeys.…”

“…No differences were found between anxious and non-anxious monkeys. The relationship between aggression and alcohol drinking was observed across sex and is not sex-specific (McClintick and Grant, 2016). The lack of influence of an anxious temperament is in contrast to previous studies of peer-reared monkeys where stress and anxiety predicted increased alcohol intake (Higley et al, 1991; Schwandt et al, 2010), however both the early rearing environments and the alcohol access conditions were very different between these sets of studies.…”

A Multilevel Computational Characterization of Endophenotypes in Addiction

“…Individual differences in stress and anxiety responses (Dilleen et al, 2012; Jimenez and Grant, 2017), social dominance (Morgan et al, 2002; Covington and Miczek, 2005), aggressive temperament (McClintick and Grant, 2016), preference for saccharine (Carroll et al, 2002), sensation or novelty seeking (Suto et al, 2001; Nadal et al, 2002; Belin et al, 2011; Flagel et al, 2014), impulsivity (Perry and Carroll, 2008; Verdejo-Garcia et al, 2008; Dalley et al, 2011), and sensitivity to rewards (Belcher et al, 2014) have all been found in both animal models and clinical studies in humans to be associated with addiction vulnerabilities, and in particular with the likelihood to develop and maintain addiction, or to resist to treatment (Piazza et al, 1989; Belin et al, 2016; Everitt and Robbins, 2016). However, investigations into the mechanisms underlying this phenotypic differentiation in addiction has so far revealed few neural or computational candidates, which are found associated with diverse and dissociable behavioral traits.…”

CRF1receptor-dependent increases in irritability-like behavior during abstinence from chronic intermittent ethanol vapor exposure

“…In humans, the emotional and physical signs of ethanol withdrawal include anxiety, irritability, mood swings, insomnia, tremors, convulsions, higher blood pressure, accelerated pulse, accelerated breathing, accelerated heart rate, dehydration, and delirium tremens (Schuckit et al, 1995, Finn and Crabbe, 1997). The emotional symptoms of ethanol dependence, including anxiety-like behavior and depression-like behavior, can be modeled in animals during ethanol dependence (Pleil et al, 2015, Marcinkiewcz et al, 2015, Thorsell et al, 2007, Varlinskaya et al, 2017, Kallupi et al, 2014, Gilpin et al, 2012, Gilpin et al, 2015, Heilig et al, 2010, Kliethermes et al, 2004, Pandey et al, 2015, Pandey et al, 2003, Valdez et al, 2004, Valdez et al, 2002a, Ehlers et al, 2013, Vetreno et al, 2016, Rylkova et al, 2009, McClintick and Grant, 2016, Egli et al, 2012, Buck et al, 2014). An important challenge for preclinical researchers is the fact that these tests are usually not repeatable within subjects over time, which prevents conducting reliable longitudinal studies.…”