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A Molecular Mechanism for Choosing Alcohol Over an Alternative Reward Eric Augier, Estelle Barbier, Russell S

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A Molecular Mechanism for Choosing Alcohol Over an Alternative Reward Eric Augier, Estelle Barbier, Russell S Corrected 9 July 2018. See full text. RESEARCH ALCOHOL DEPENDENCY ward 26.2% of the time (Fig. 1C). However, al- though the vast majority of rats strongly preferred saccharin,aminority,4ratsoutof32inthefirst A molecular mechanism for choosing experiment (12.5% of the population, Fig. 1D, left) continued to choose alcohol despite having access to a high-value alternative (alcohol-preferring, alcohol over an alternative reward AP). Although this was a small number, it aligns well with human addiction rates (7, 8) and promp- Eric Augier1*, Estelle Barbier1, Russell S. Dulman2, Valentina Licheri3, Gaëlle Augier1, ted us to expand the study of individual differences Esi Domi1, Riccardo Barchiesi1, Sean Farris4, Daniel Nätt1, R. Dayne Mayfield4, in choice behavior. Ultimately, this percentage Louise Adermark3, Markus Heilig1 was stable across a large number of rats from successive batches (see below; Fig. 1D, right). Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established Alcohol preference was not influenced by hold- an exclusive choice procedure in which ~15% of outbred rats chose alcohol over a ing prior history of alcohol and saccharin self- high-value reward. These animals displayed addiction-like traits, including high motivation administration identical (fig. S3). to obtain alcohol and pursuit of this drug despite adverse consequences. Expression of the g-aminobutyric acid (GABA) transporter GAT-3 was selectively decreased within the Extensive pre-exposure to saccharin amygdala of alcohol-choosing rats, whereas a knockdown of this transcript reversed choice does not affect subsequent preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression alcohol choice was selectively decreased in the central amygdala of alcohol-dependent people compared People who go on to develop addictive disorders to those who died of unrelated causes. Impaired GABA clearance within the amygdala have typically had extensive exposure to sweet Downloaded from contributes to alcohol addiction, appears to translate between species, and may offer reward prior to initiating alcohol use. We there- targets for new pharmacotherapies for treating this disorder. fore tested whether this kind of preexposure would affect subsequent alcohol choice. A sep- lcohol use accounts for almost 5% of global the presence of an alternative (13, 14). Indeed, arate group of rats was offered the opportunity disease burden (1), and the harm from al- in epidemiological studies, only a minority of ex- to drink a 0.2% saccharin solution or water (ex- cohol use has been estimated to exceed that posed people develop addiction (5, 10). periment 2, n = 32 per group) in their home A due to heroin or cocaine (2). Basic neuro- Here, we set out to identify molecular mecha- cage for 4 weeks, before operant training was http://science.sciencemag.org/ science has identified brain circuits and nisms underlying the choice of alcohol over a nat- initiated. Rats that had access to the sweet so- molecular mechanisms that contribute to drug ural reward. Conceptually and methodologically, lution consumed extensive amounts of saccha- and alcohol reward, craving, and relapse (3, 4). we built on the exclusive choice model pioneered rin during the first week of exposure (101.6 ± These advances have, however, had limited im- with cocaine and heroin by Ahmed and colleagues 6.8 ml/day) and maintained this consumption pact on the treatment of addictive disorders, sug- (5, 13, 14). We first established an exclusive choice- throughout their 4 weeks of exposure (week 4: gesting that research in model organisms needs based method to identify rats that continue to 89.8 ± 5.4 ml/day; fig. S4A). There was no to incorporate additional processes (3, 5). self-administer alcohol at the expense of a high- significant difference in acquisition of alcohol Once established, alcohol addiction—hereafter value alternative, a sweet solution, and assessed self-administration between saccharin- and water- equated with alcoholism—is a chronic relapsing whether these animals show other characteristics preexposed animals (fig. S4B, no main effect of disorder in which alcohol use becomes compul- of clinical alcoholism (15). We then used gene group: saccharin versus water, F1,61 =0.13,p = on August 23, 2018 sive, i.e., continues despite negative consequences expression profiling to identify a molecular mech- 0.72; main effect of sessions, F29,1769 = 5.28, p < (6). Understanding the transition from controlled anism that mediates compulsive alcohol drinking 0.001; h2 = 0.08 but no interaction between to compulsive alcohol use is a critical challenge for at the expense of other high-value options. group and sessions: F29,1769 =0.98,p = 0.48). addiction research. In humans, only a subset of Extensive preexposure to saccharin also left users transition to compulsive drug use (7, 8). Intense sweetness outcompetes alcohol acquisition of the choice procedure unaffected In contrast, in commonly used animal models, reward in most but not all rats (fig. S4C, no main effect of group: saccharin ver- nearly all rats learn to self-administer addict- Sweetness is a fundamental reward that is highly sus water, F1,57 = 0.40, p = 0.53; main effect of 2 ive drugs, including alcohol (9). This points to conserved between humans and other animals sessions, F18,1026 = 7.82, p <0.001; h = 0.12 but the possibility that focusing on self-administration (16). To tap into its value without the confound of no interaction between group and sessions: may be insufficient to identify key mechanisms caloric content, we used as alternative reward a F18,1026 = 1.00, p =0.45). of addiction (5, 10). solution of the noncaloric sweetener saccharin. Once responding had stabilized, both groups This realization has prompted important con- In a first experiment (see fig. S1 for experimental strongly favored the sweet solution (22.3 ± 3.8% ceptual advances. When rats are allowed to self- timelines), rats (n = 32) were trained to self- alcohol choice for the saccharin-exposed group administer cocaine over a prolonged period of administer 20% alcohol for about 10 weeks until versus 20.6 ± 4.0% for the water-exposed group; time, only a minority of them develop compul- reaching stable response rates on a fixed-ratio 3 fig. S4D, no main effect of group: saccharin ver- sive drug taking (11, 12). Furthermore, most rats (FR-3) reinforcement schedule (fig. S2, A and B). sus water, F1,61 =0.32,p =0.57).Again,asub- will cease to self-administer cocaine when a high- They were then offered daily sessions of mu- population of animals chose alcohol over saccharin value alternative becomes available, but a subset tually exclusive choice between alcohol and 0.04% (fig. S4E, n = 3 in each group). Extensive pre- of animals continue self-administration despite saccharin (Fig. 1A). Overall, despite not having exposure to the sweet solution did not affect previously been trained to respond to saccharin, sampling (fig. S4F) or completed trials (F1,61 =0.56, rats quickly started to choose more saccharin p = 0.46). Thus, the alcohol choice observed in 1Center for Social and Affective Neuroscience, IKE, than alcohol (Fig. 1B). The percentage of choice experiment 1 was not sensitive to the individual’s 2 Linköping University, Linköping, 581 83, Sweden. Center for saccharin over alcohol became even higher prior history of sweet-reward exposure. for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois, Chicago, IL 60612, USA. when a more rewarding concentration of sac- Finally, we investigated whether AP rats would 3Department of Psychiatry and Neurochemistry, charin, 0.2%, was introduced (Fig. 1C, significant persist in working for alcohol if the alternative Sahlgrenska Academy, University of Göteborg, 413 90 effect of the saccharin concentration: F = reward was readily available. We used a modified 4 1,31 Göteborg, Sweden. The Waggoner Center for Alcohol 21.56, p < 0.0001, h2 =0.41). choice paradigm in which rats had continuous and Addiction Research, University of Texas, Austin, TX 78712, USA. Once operant responding had stabilized, the access to both sources of reinforcement and found *Corresponding author. Email: [email protected] rats only chose alcohol over the alternative re- that AP rats maintained a strong preference for Augier et al., Science 360, 1321–1326 (2018) 22 June 2018 1of6 Corrected 9 July 2018. See full text. RESEARCH | RESEARCH ARTICLE alcohol despite the concurrent availability of sac- available (saccharin-preferring, SP). Only 95 rats We then investigated whether AP rats would charin throughout five consecutive sessions (fig. S5). out of 620 tested on the choice procedure con- maintain their alcohol drinking despite negative tinued to choose alcohol despite having access to consequences: quinine adulteration or footshock Alcohol-choosing rats show a high-value alternative (15.3% of the population). punishment. AP rats showed a robust resistance addiction-like behaviors We first assessed the motivation of AP and to quinine adulteration (Fig. 1F, main effect of 2 Owing the low frequency of the AP phenotype, SP rats to obtain and consume alcohol or sac- group, F1,40 = 4.48, p < 0.05; h = 0.10). Their we repeated the first experiment on several charin using a progressive ratio reinforcement choice behavior remained unaffected even when batches of rats and screened them for preference schedule (17). AP rats showed a higher motiva- alcohol was adulterated with a highly aversive during the choice procedure before carrying out tion to obtain alcohol than SP rats (Fig. 1E, left concentration of quinine, 200 mg/liter. There further behavioral testing (Fig. 1D, right). We bars), whereas the motivation to obtain sac- was no statistical difference in the preference then characterized the subpopulation of animals charin did not statistically differ between the score for quinine alone when separately tested that chose alcohol over saccharin with regard to two groups (Fig.
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