Novelty-induced locomotor behavior predicts heroin addiction vulnerability in male, but not female, rats.

RATIONALE: The ongoing rise in opioid use disorder (OUD) has made it imperative to better model the individual variation within the human population that contributes to OUD vulnerability. Using animal models that capture such variation can be a useful tool. Individual variation in novelty-induced locomotion is predictive of substance use disorder (SUD) propensity. In this model, rats are characterized as high-responders (HR) or low-responders (LR) using a median split based on distance travelled during a locomotor test, and HR rats are generally found to exhibit a more SUD vulnerable behavioral phenotype. OBJECTIVES: The HR/LR model has commonly been used to assess behaviors in male rats using psychostimulants, with limited knowledge of the predictive efficacy of this model in females or the use of an opioid as the reward. In the current study, we assessed several behaviors across the different phases of drug addiction (heroin taking, refraining, and seeking) in over 500 male and female heterogeneous stock rats run at two geographically separate locations. Rats were characterized as HRs or LRs within each sex for analysis. RESULTS: Overall, females exhibit a more OUD vulnerable phenotype relative to males. Additionally, the HR/LR model was predictive of OUD-like behaviors in male, but not female rats. Furthermore, phenotypes did not differ in anxiety-related behaviors, reacquisition of heroin-taking, or punished heroin-taking behavior in either sex. CONCLUSIONS: These results emphasize the importance of assessing females in models of individual variation in SUD and highlight limitations in using the HR/LR model to assess OUD propensity.

Assessing combined effects of varenicline and N-acetylcysteine on reducing nicotine seeking in rats.

Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most effective pharmacotherapy for smoking cessation is Varenicline (VRN), which reduces both positive and negative reinforcement by nicotine. Clinically, VRN attenuates withdrawal symptoms and promotes abstinence, but >50% of smokers relapse within 3 months following a quit attempt. This may indicate that VRN fails to ameliorate components of nicotine-induced neuroplasticity that promote relapse vulnerability. Animal models reveal that glutamate dysregulation in the nucleus accumbens is associated with nicotine relapse. N-acetylcysteine (NAC) normalizes glutamate transmission and prolongs cocaine abstinence. Thus, combining VRN and NAC may promote and maintain, respectively, nicotine abstinence. In rats, we found that VRN effectively reduced nicotine self-administration and seeking in early abstinence, but not seeking later in abstinence. In contrast, NAC reduced seeking only later in abstinence. Because VRN and NAC are sometimes associated with mild adverse effects, we also evaluated a sequential approach combining subthreshold doses of VRN during self-administration and early abstinence with subthreshold doses of NAC during late abstinence. As expected, subthreshold VRN did not reduce nicotine intake. However, subthreshold VRN and NAC reduced seeking in late abstinence, suggesting a combined effect. Overall, our results suggest that combining subthreshold VRN and NAC is a viable and drug-specific approach to promote abstinence and reduce relapse while minimizing adverse effects. Our data also suggest that different components and time points in addiction engage the different neurocircuits targeted by VRN and NAC.

Drug versus non-drug behaviors: A dual-reward model of sex differences and neurobiological mechanisms in rats.

Substance Use Disorders (SUDs) are an impactful problem characterized by chronic relapse and engagement in drug-related behaviors at the expense of non-drug behaviors. Brain regions implicated in drug and non-drug-related behaviors often overlap, complicating investigations of neurobiological mechanisms underlying SUDs. Here we presented a within-subject model for studying self-administration, reinforcer competition, extinction, and cued reinstatement of cocaine- and food-seeking in rats. Due to differences in cocaine- and food-reinforced behavior, we transformed data to proportions of baseline, revealing increased resistance to extinction and disproportionately greater cued reinstatement of cocaine seeking relative to food seeking. Consistent with previous reports, females showed greater preference for cocaine reinforcement than males, though these findings failed to reach statistical significance. To demonstrate the model's utility for investigating neurobiological mechanisms, we included proof-of-concept calcium imaging data demonstrating the utility of the behavioral model for detecting cellular activity patterns associated with cocaine- and food-seeking behaviors. Future studies utilizing this model should improve understanding of the development and expression of pathological behaviors characteristic of SUDs in humans, sex differences in these behaviors, and their neurobiological correlates. Thus, the model has utility for improving understanding of SUDs, leading to novel treatments to reduce the pathological behaviors associated with SUDs.

Resurgence of alcohol seeking following abstinence induced by punishment in male and female rats.

To better approximate the human condition, animal models of relapse to drug and alcohol seeking have increasingly employed negative consequences to generate abstinence. Here we report the first demonstration of relapse to punishment-suppressed alcohol seeking induced by loss of non-drug reward (i.e., resurgence). We also report the first examination of potential sex differences in any form of relapse to alcohol seeking following suppression by punishment. Male and female rats first pressed a lever for 20 % oral alcohol. Next, lever pressing for one group continued to produce alcohol, but also produced occasional footshock. For another group, lever pressing similarly produced alcohol and occasional footshock, and a nose-poke response produced alternative non-drug reward (i.e., food). Males showed similar suppression of alcohol seeking by punishment alone and punishment + alternative non-drug reward, whereas females showed less suppression by punishment alone. Finally, when alternative reinforcement and punishment were suspended, resurgence occurred for both sexes in the group that previously had access to non-drug reward. Exposure to and then removal of punishment alone did not produce relapse for males, but it did for females. These results suggest that loss of alternative non-drug reward can generate relapse to alcohol seeking following abstinence induced by negative consequences. Future research should further examine the role of potential sex differences in sensitivity to punishment and how such differences may contribute to relapse more broadly.

Circuit selectivity in drug versus natural reward seeking behaviors.

Substance use disorder (SUD) is characterized, in part by behavior biased toward drug use and away from natural sources of reward (e.g., social interaction, food, sex). The neurobiological underpinnings of SUDs reveal distinct brain regions where neuronal activity is necessary for the manifestation of SUD-characteristic behaviors. Studies that specifically examine how these regions are involved in behaviors motivated by drug versus natural reward allow determinations of which regions are necessary for regulating seeking of both reward types, and appraisals of novel SUD therapies for off-target effects on behaviors motivated by natural reward. Here, we evaluate studies directly comparing regulatory roles for specific brain regions in drug versus natural reward. While it is clear that many regions drive behaviors motivated by all reward types, based on the literature reviewed we propose a set of interconnected regions that become necessary for behaviors motivated by drug, but not natural rewards. The circuitry is selectively necessary for drug seeking includes an Action/Reward subcircuit, comprising nucleus accumbens, ventral pallidum, and ventral tegmental area, a Prefrontal subcircuit comprising prelimbic, infralimbic, and insular cortices, a Stress subcircuit comprising the central nucleus of the amygdala and the bed nucleus of the stria terminalis, and a Diencephalon circuit including lateral hypothalamus. Evidence was mixed for nucleus accumbens shell, insular cortex, and ventral pallidum. Studies for all other brain nuclei reviewed supported a necessary role in regulating both drug and natural reward seeking. Finally, we discuss emerging strategies to further disambiguate the necessity of brain regions in drug- versus natural reward-associated behaviors.

Resurgence of punishment-suppressed cocaine seeking in rats.

Alternative reinforcement-based treatments are among the most effective for reducing substance abuse. However, relapse often occurs when alternative reinforcement ends. Relapse following the loss of alternative reinforcement is called resurgence. An animal model has been used to study basic factors that may ultimately reduce resurgence but uses drug unavailability (i.e., extinction) to reduce drug seeking. In humans, drug abstinence is thought to be a product of aversive consequences associated with drug use rather than extinction. This discrepancy is important because the environmental and neurobiological factors involved in relapse may differ between punished and extinguished behavior. Experiment 1 evaluated resurgence of previously punished cocaine seeking. In Phase 1, rats earned cocaine for pressing levers. In Phase 2, cocaine remained available, but lever pressing also produced mild foot shocks while an alternative response produced food pellets for 1 group but not for another group. In Phase 3, alternative reinforcement and punishment were removed and resurgence of cocaine seeking occurred only in rats previously exposed to alternative reinforcement. In Experiment 2, resurgence was evaluated similarly, except that consequences of cocaine seeking (i.e., punishment and cocaine) remained available during Phase 3. Resurgence did not occur in either group during Experiment 2. The animal models of resurgence developed herein could increase translational utility and improve examination of the environmental and neurobiological factors underlying resurgence of drug seeking. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Resurgence as Choice in Context: Treatment duration and on/off alternative reinforcement.

Resurgence as Choice (RaC) is a quantitative theory suggesting that an increase in an extinguished target behavior with subsequent extinction of an alternative behavior (i.e., resurgence) is governed by the same processes as choice more generally. We present data from an experiment with rats examining a range of treatment durations with alternative reinforcement plus extinction and demonstrate that increases in treatment duration produce small but reliable decreases in resurgence. Although RaC predicted the relation between target responding and treatment duration, the model failed in other respects. First, contrary to predictions, the present experiment also replicated previous findings that exposure to cycling on/off alternative reinforcement reduces resurgence. Second, RaC did a poor job simultaneously accounting for target and alternative behaviors across conditions. We present a revised model incorporating a role for more local signaling effects of reinforcer deliveries or their absence on response allocation. Such signaling effects are suggested to impact response allocation above and beyond the values of the target and alternative behaviors as longer-term repositories of experience. The new model provides an excellent account of the data and can be viewed as an integration of RaC and a quantitative approximation of some aspects of Context Theory.

Resurgence of a target behavior suppressed by a combination of punishment and alternative reinforcement.

Differential-reinforcement-based treatments involving extinction of target problem behavior and reinforcement of an alternative behavior are highly effective. However, extinction of problem behavior is sometimes difficult or contraindicated in clinical settings. In such cases, punishment instead of extinction may be used in combination with alternative reinforcement. Although it is well documented that omitting alternative reinforcement can produce recurrence (i.e., resurgence) of behavior previously suppressed by extinction plus alternative reinforcement, it remains unclear if resurgence similarly occurs for behavior previously suppressed by punishment plus alternative reinforcement. The present experiment examined this question with rats. In Phase 1, a target behavior (lever pressing) was reinforced with food pellets. In Phase 2, the target behavior continued to be reinforced, but it also produced mild foot shock and an alternative behavior (nose poking) also produced food. Finally, all consequences were removed and resurgence of target behavior occurred. Resurgence did not occur for another group that similarly received punishment of target behavior in Phase 2 but not alternative reinforcement. These results indicate that resurgence was a product of the history of exposure to and then removal of alternative reinforcement and that the removal of punishment alone did not produce resurgence of target behavior.

Continuous nicotine exposure does not affect resurgence of alcohol seeking in rats.

Alcohol is the most commonly used drug in the United States and alcohol abuse can lead to alcohol use disorder. Alcohol use disorder is a persistent condition and relapse rates following successful remission are high. Many factors have been associated with relapse for alcohol use disorder, but identification of these factors has not been well translated into preventative utility. One potentially important factor, concurrent nicotine use, has not been well investigated as a causal factor in relapse for alcohol use disorder. Nicotine increases the value of other stimuli in the environment and may increase the value of alcohol. If nicotine increases the value of alcohol, then nicotine use during and after treatment may make relapse more probable. In the current study, we investigated the effect of continuous nicotine exposure (using osmotic minipumps to deliver nicotine or saline, depending on group, at a constant rate for 28 days) on resurgence of alcohol seeking in rats. Resurgence is a type of relapse preparation that consists of three phases: Baseline, Alternative Reinforcement, and Resurgence Testing. During Baseline, target responses produced a dipper of alcohol. During Alternative Reinforcement, target responses were extinguished and responses on a chain produced a chocolate pellet. During Resurgence Testing, responses on the chain were also extinguished and a return to responding on the target lever was indicative of resurgence. Multilevel modeling was used to analyze the effect of nicotine on resurgence. Both the nicotine and saline group showed resurgence of alcohol seeking, but there was no difference in the degree of resurgence across groups. Future directions could involve testing alternative drug delivery techniques.

Longer treatment with alternative non-drug reinforcement fails to reduce resurgence of cocaine or alcohol seeking in rats.

Provision of alternative non-drug reinforcement is among the most effective methods for treating substance use disorders. However, when alternative reinforcers become unavailable during treatment interruptions or upon cessation of treatment, relapse often occurs. Relapse following the loss of alternative reinforcement is known as resurgence. One factor that could reduce resurgence is longer duration of treatment with alternative reinforcement, but the available data are mixed. Further, the effects of length of treatment have previously only been examined with food seeking. The present experiments directly examined if duration of treatment impacted the magnitude of resurgence of cocaine or alcohol seeking in rats. First, rats were trained to self-administer cocaine (Experiment 1) or alcohol (Experiment 2) by performing a target behavior. Second, target behavior was extinguished and performing an alternative behavior produced an alternative non-drug (i.e., food) reinforcer. Finally, resurgence was assessed following removal of alternative reinforcement after either 5 or 20 sessions of treatment. Treatment duration did not differentially affect resurgence of cocaine seeking in Experiment 1 or Alcohol seeking in Experiment 2. These results suggest that extended treatment with alternative non-drug reinforcement may not decrease propensity to relapse. Further, these results may have implications for treatment of substance use disorders and for theories of resurgence.

Resurgence and alternative-reinforcer magnitude.

Resurgence is defined as an increase in the frequency of a previously reinforced target response when an alternative source of reinforcement is suspended. Despite an extensive body of research examining factors that affect resurgence, the effects of alternative-reinforcer magnitude have not been examined. Thus, the present experiments aimed to fill this gap in the literature. In Experiment 1, rats pressed levers for single-pellet reinforcers during Phase 1. In Phase 2, target-lever pressing was extinguished, and alternative-lever pressing produced either five-pellet, one-pellet, or no alternative reinforcement. In Phase 3, alternative reinforcement was suspended to test for resurgence. Five-pellet alternative reinforcement produced faster elimination and greater resurgence of target-lever pressing than one-pellet alternative reinforcement. In Experiment 2, effects of decreasing alternative-reinforcer magnitude on resurgence were examined. Rats pressed levers and pulled chains for six-pellet reinforcers during Phases 1 and 2, respectively. In Phase 3, alternative reinforcement was decreased to three pellets for one group, one pellet for a second group, and suspended altogether for a third group. Shifting from six-pellet to one-pellet alternative reinforcement produced as much resurgence as suspending alternative reinforcement altogether, while shifting from six pellets to three pellets did not produce resurgence. These results suggest that alternative-reinforcer magnitude has effects on elimination and resurgence of target behavior that are similar to those of alternative-reinforcer rate. Thus, both suppression of target behavior during alternative reinforcement and resurgence when conditions of alternative reinforcement are altered may be related to variables that affect the value of the alternative-reinforcement source.

Higher rate alternative non-drug reinforcement produces faster suppression of cocaine seeking but more resurgence when removed.

Relapse following removal of an alternative source of reinforcement introduced during extinction of a target behavior is called resurgence. This form of relapse may be related to relapse of drug taking following loss of alternative non-drug reinforcement in human populations. Laboratory investigations of factors mediating resurgence with food-maintained behavior suggest higher rates of alternative reinforcement produce faster suppression of target behavior but paradoxically generate more relapse when alternative reinforcement is discontinued. At present, it is unknown if a similar effect occurs when target behavior is maintained by drug reinforcement and the alternative is a non-drug reinforcer. In the present experiment three groups of rats were trained to lever press for infusions of cocaine during baseline. Next, during treatment, cocaine reinforcement was suspended and an alternative response was reinforced with either high-rate, low-rate, or no alternative food reinforcement. Finally, all reinforcement was suspended to test for relapse of cocaine seeking. Higher rate alternative reinforcement produced faster elimination of cocaine seeking than lower rates or extinction alone, but when treatment was suspended resurgence of cocaine seeking occurred following only high-rate alternative reinforcement. Thus, although higher rate alternative reinforcement appears to more effectively suppress drug seeking, should it become unavailable, it can have the unfortunate effect of increasing relapse.