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One of the major challenges in preclinical studies of alcohol abuse and dependence remains the development of paradigms that will elicit high ethanol intake and mimic the progressive transition from low or moderate social drinking to excessive alcohol consumption. Exposure of outbred rats to repeated cycles of free-choice ethanol intake and withdrawal with the use of intermittent access to 20% ethanol in a 2-bottle choice procedure (IA2BC) has been shown to induce a gradual escalation of voluntary ethanol intake and preference, eventually reaching ethanol consumption levels of 5–6 g/kg/24 h, and inducing pharmacologically relevant blood ethanol concentrations (BECs). This procedure has recently been gaining popularity due to its simplicity, high validity, and reliable outcomes. Here we review experimental and methodological data related to IA2BC, and discuss the usefulness and advantages of this procedure as a valuable pre-training method for initiating operant ethanol self-administration of high ethanol intake, as well as conditioned place preference (CPP). Despite some limitations, we provide evidence that IA2BC and related operant procedures provide the possibility to operationalize multiple aspects of alcohol abuse and addiction in a rat model, including transition from social-like drinking to excessive alcohol consumption, binge drinking, alcohol seeking, relapse, and neuroadaptations related to excessive alcohol intake. Hence, IA2BC appears to be a useful and relevant procedure for preclinical evaluation of potential therapeutic approaches against alcohol abuse disorders.

Rationale Contemporary animal models of cocaine addiction focus on increasing the amount of drug consumption to produce addiction-like behavior. However, another critical factor is the temporal pattern of consumption, which in humans is characterized by intermittency, both within and between bouts of use. Objective To model this, we combined prolonged access to cocaine (∼70 days in total) with an intermittent access (IntA) self-administration procedure and used behavioral economic indicators to quantify changes in motivation for cocaine. Results IntA produced escalation of intake, a progressive increase in cocaine demand (incentive-sensitization), and robust drug- and cue-induced reinstatement of drug-seeking behavior. We also asked whether rats that vary in their propensity to attribute incentive salience to reward cues (sign-trackers [STs] vs. goal-trackers [GTs]) vary in the development of addiction-like behavior. Although STs were more motivated to take cocaine after limited drug experience, after IntA, STs and GTs no longer differed on any measure of addiction-like behavior. Conclusions Exposure to large quantities of cocaine is not necessary for escalation of intake, incentive-sensitization, or other addiction-like behaviors (IntA results in far less total cocaine consumption than ‘long access’ procedures). Also, the ST phenotype may increase susceptibility to addiction, not because STs are inherently susceptible to incentive-sensitization (perhaps all individuals are at risk), but because this phenotype promotes continued drug use, subjecting them to incentive-sensitization. Thus, the pharmacokinetics associated with the IntA procedure are especially effective in producing a number of addiction-like behaviors and may be valuable for studying associated neuroadaptations and for assessing individual variation in vulnerability.

RationaleOpioid use disorder (OUD) is a major epidemic in the USA. Despite evidence indicating that OUD may be particularly severe for women, preclinical models have yet to establish sex as a major factor in OUD.ObjectivesHere, we examined sex differences in vulnerability to relapse following intermittent access fentanyl self-administration and protracted abstinence and used buprenorphine, the FDA-approved treatment for OUD, to test the validity of our model.MethodsFollowing acquisition of fentanyl self-administration under one of two training conditions, male and female rats were given extended, 24-h/day access to fentanyl (0.25 μg/kg/infusion, 10 days) using an intermittent access procedure. Vulnerability to relapse was assessed using an extinction/cue-induced reinstatement procedure following 14 days of abstinence; buprenorphine (0 or 3 mg/kg/day) was administered throughout abstinence.ResultsLevels of drug-seeking were high following extended-access fentanyl self-administration and abstinence; buprenorphine markedly decreased drug-seeking supporting the validity of our relapse model. Females self-administered more fentanyl and responded at higher levels during subsequent extinction testing. Buprenorphine was effective in both sexes and eliminated sex and estrous phase differences in drug-seeking. Interestingly, the inclusion of a time-out during training had a major impact on later fentanyl self-administration in females, but not males, indicating that the initial exposure conditions can persistently impact vulnerability in females.ConclusionsThese findings demonstrate the utility of this rat model for determining sex and hormonal influences on the development and treatment of OUD.

Alcohol use disorder (AUD) is a complex and widespread disease with limited pharmacotherapies. Preclinical animal models of AUD use a variety of voluntary alcohol consumption procedures to recapitulate different phases of AUD, including binge alcohol consumption and dependence. However, voluntary alcohol consumption in mice is widely variable, making it difficult to reproduce results across labs. Accumulating evidence indicates that different brands of commercially available rodent chow can profoundly influence alcohol intake. In this study, we investigated the effects of three commercially available and widely used rodent diet formulations on alcohol consumption and preference in C57BL/6 J mice using the 24 h intermittent access procedure. The three brands of chow tested were LabDiet 5,001 (LD5001), LabDiet 5,053 (LD5053), and Teklad 2019S (TL2019S) from two companies (Research Diets and Envigo, respectively). Mice fed LD5001 and LD5053 displayed higher levels of alcohol consumption and preference compared to mice fed TL2019S. We also found that alcohol consumption and preference could be rapidly switched by changing the diet 48 h prior to alcohol administration. Sucrose, saccharin, and quinine preferences were not altered, suggesting that the diets did not alter sweet and bitter taste perception. We also found that mice fed LD5001 displayed increased quinine-resistant alcohol intake compared to mice fed TL2019S, suggesting that diets could influence the development of compulsive behaviors such as alcohol consumption. We profiled the gut microbiome of water- and alcohol-drinking mice that were maintained on different diets and found significant differences in bacterial alpha- and beta-diversities, which could impact the gut–brain axis signaling and alcohol consumption.

Alcohol use disorder is highly comorbid with other neuropsychiatric disorders such as depression and anxiety. Importantly, women and men are affected differentially by heavy drinking, with women experiencing longer negative affective states after intoxication and increased likelihood to present with comorbid mood or anxiety disorders. In rodents, several studies using different alcohol administration models have shown the development of depressive-like or anxiety-like phenotypes that emerge during abstinence. In this study, we compared the emergence of negative affective behaviors during abstinence from 7 weeks of two-bottle choice intermittent access to 20% alcohol in male and female C57BL/6J mice, a drinking paradigm little studied in this context. Half of the mice were tested 24 hours into abstinence on the elevated zero maze and 19–20 days into abstinence in a novel object in the home cage encounter test. The other half of the mice were tested 27–28 days into abstinence with the novelty-suppressed feeding test. As expected, females drank more than males across the 7 weeks of access to alcohol. Drinking history did not affect performance on these tasks, with the exception of increasing the number of open arm entries on the elevated zero maze. Interestingly, in alcohol-naïve mice, females showed fewer anxiety-like behaviors than males in the elevated zero maze and the novelty-suppressed feeding test. Our results suggest that the intermittent access model does not reliably induce negative affective behaviors on these tasks, and that behavior in female and male mice differs across these tests. Rather, intermittent alcohol drinking may induce a mild form of behavioral disinhibition. Thus, the model of alcohol access is a critical factor in determining the appearance of behavioral disturbances that emerge during abstinence. •Female C57s drink more ethanol and have higher preference than males in the 24 h intermittent access to alcohol model.•Alcohol drinking history did not affect performance on tasks measuring negative affective, with some minor exceptions.•In alcohol-naïve mice, females showed less of an anxiety-like phenotype than males on two behavioral tasks.

RationaleIntermittent Access (IntA) cocaine self-administration, which models intermittent patterns of cocaine use in humans during the transition to addiction, is especially effective in producing incentive-sensitization and other addiction-like behavior in male rats. However, female rats show more robust psychomotor sensitization than males, and following initial use, women develop problematic patterns of drug use more readily than men. We hypothesized, therefore, that female rats might be more susceptible to the incentive-sensitization produced by IntA experience.ObjectiveTo assess changes in motivation for cocaine, using a behavioral economic indicator of cocaine demand (“elasticity” of demand curves), and other addiction-like behavior, as a function of IntA cocaine self-administration experience in male and female rats.ResultsIntA experience produced a progressive increase in motivation for cocaine in both males and females, as indicated by a decrease in the elasticity of cocaine demand curves, and this persisted undiminished following 14 days of abstinence. However, IntA produced a more rapid and greater increase in motivation for cocaine (incentive-sensitization) in females than males. Females also consumed more cocaine than males, although this did not predict changes in motivation. On the other hand, there were no sex differences in the preferred level of cocaine consumption when cost was low (Q0), nor in cocaine- or cue-induced reinstatement of drug-seeking behavior.ConclusionsThe observation that females are more susceptible to incentive-sensitization when intermittently exposed to cocaine may provide a mechanism for the more rapid development of problematic drug use in females (“telescoping effect”) reported in clinical studies.

Opioid use disorder (OUD) is a major epidemic in the United States, and fentanyl is a major culprit. The National Institute on Drug Abuse has highlighted an urgent need for research on the risks and outcomes of OUD with fentanyl; a better understanding of sex/gender differences is also critically needed given that the opioid epidemic has been particularly impactful on women. In response to this need, we developed a rat model of OUD with fentanyl and showed that sex impacts relapse vulnerability following extended-access self-administration under a low fentanyl dose. Here, our goal was to determine sex differences across a broad dose range, including high doses expected to maximize the expression of addiction-like features (e.g., vulnerability to relapse and physical dependence). Male and female rats were assigned to self-administer one of four fentanyl doses (0.25, 0.75, 1.5, and 3.0 µg/kg/infusion), and once they acquired, they were given extended (24-h/day), intermittent access (2, 5 min trials/h, fixed-ratio 1) to fentanyl for 10 days. Physical dependence (spontaneous weight loss) was assessed during early withdrawal, and relapse vulnerability was assessed on withdrawal day 15 using an extinction/cue-induced reinstatement procedure. Despite markedly higher intake in the high- versus low-dose groups, each group responded similarly during relapse testing (extinction and cue-induced reinstatement). However, number of infusions, or frequency of use, during extended access was predictive of later vulnerability to relapse, whereas total intake impacted physical dependence given that weight loss only occurred following the discontinuation of fentanyl self-administration at the three highest doses. Females self-administered more fentanyl each day and within each binge (active trial), and had longer lasting weight loss during withdrawal than males. Relapse vulnerability was also higher in females than males and highest in females tested during estrus. These findings indicate that sex is an important risk factor for patterns and levels of fentanyl intake, relapse, and physical dependence, and while fentanyl intake predicts physical dependence, frequency of use predicts relapse.

Open source devices are becoming widely used in behavioral neuroscience. Despite their advantages in cost effectiveness, modularity, and customization, measurements obtained using newly developed devices may not always recapitulate measurements from existing and validated equipment, potentially due to the materials used in manufacture. In this study, we evaluated a commonly used open-source optical lickometer that delivers fluid via a Hydropac® plastic valve in a multi-site intermittent access two-bottle choice (IA2BC) paradigm for alcohol consumption. Mice were tested with both traditional metal sippers and plastic sippers equipped with Hydropac® valves to assess differences in alcohol intake, preference, and total fluid consumption. Our findings revealed that mice displayed reduced intake and preference for alcohol (10–20% v/v) delivered via the Hydropac® containing plastic sippers. Notably, the effect was observed at both testing sites, suggesting a generalizable phenomenon. The decreased intake was also specific to alcohol, as water, quinine, and sucrose consumption were unaffected by sipper type. To investigate the underlying cause of the reduced alcohol consumption, we pre-incubated Hydropac® valves in 20% alcohol and found that the pre-treated alcohol reduced intake even when delivered via metal sippers. This suggests that prolonged interaction between alcohol and the components of the Hydropac® valves alter the fluid, likely by generating unpalatable contaminants. These results highlight a limitation of using plastic sippers in long-term alcohol self-administration studies. While these devices may remain suitable for limited access paradigms their use in extended access protocols may compromise data integrity. Our study underscores the need for rigorous validation of open-source hardware in each research project. •Synthetic components of plastic sippers can reduce alcohol intake in rodents.•Plastic sippers did not affect intake of water, quinine, or sucrose.•Validation of open-source hardware is crucial for accurate long-term alcohol studies.

A key question in addiction research concerns how, in some individuals, initial recreational or casual patterns of drug use may change brain and psychological function in ways that promote a transition to the problematic patterns of use that define substance use disorders (addiction). In preclinical studies, this is modeled using self-administration procedures. However, most cocaine self-administration procedures produce continuously high brain concentrations of drug, whereas in people, bouts of use are thought to be more intermittent. Here, we ask whether such temporal pharmacokinetic factors matter, by comparing and contrasting the neuropsychological consequences of intermittent vs. long access cocaine self-administration experience. It turns out, the temporal pattern of cocaine use has profound effects on a number of outcomes. First, despite much less total drug consumption, intermittent access to cocaine is more effective in producing addiction-like behavior. Second, intermittent and long access cocaine self-administration change the brain in very different ways to influence motivated behavior. We argue that intermittent access self-administration procedures might be better suited than traditional self-administration procedures for isolating drug-induced changes in neuropsychological function that contribute to the transition to cocaine addiction.

RationaleWhen people with drug addiction encounter cues associated with drug use, this can trigger cravings and relapse. These cues can include conditioned stimuli (CSs) signaling drug delivery and discriminative stimuli (DSs) signaling drug availability. Compared to CS effects, DS effects are less explored in preclinical studies on cue-induced relapse.ObjectiveWe compared CS and DS effects on reward seeking following abstinence from intermittent-access cocaine (or sucrose) self-administration.MethodsDuring 15–20 intermittent-access sessions, rats self-administered i.v. cocaine or sucrose pellets paired with a light-tone CS. Cocaine/sucrose was available for 5-min (signalled by a light; DS+) and unavailable for 25 min (signalled by different lighting conditions; DS-), and this cycled for 4 h/session. Following abstinence, we measured cocaine/sucrose seeking under extinction triggered by CS and DS presentation, and instrumental responding reinforced by these cues.ResultsAcross intermittent-access sessions, rats increased lever pressing for cocaine or sucrose during DS+ periods and decreased responding during DS- periods. On days 2 and 21 of abstinence, only presentation of the DS+ or DS+ and CS combined elicited increased cocaine/sucrose-seeking behaviour (i.e., increased active lever presses). Presenting the DS- alongside the DS+ suppressed the increased cocaine-seeking behaviour otherwise produced by the DS+ . Finally, on day 21 of abstinence, rats showed equivalent levels of lever pressing reinforced by the DS+ , CS and by the DS+ and CS combined, suggesting comparable conditioned reinforcing value.ConclusionsAfter intermittent self-administration, cocaine-associated DSs and CSs acquire similar conditioned reinforcing properties, but DSs more effectively trigger increases in drug seeking.