Long-Term Blockade of Cocaine Self-Administration and Locomotor Activation in Rats by an Adenoviral Vector-Delivered Cocaine Hydrolase.

A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH-injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH-treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaine-induced locomotion, whereas control rats showed a dose-dependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse.

Progesterone attenuates impulsive action in a Go/No-Go task for sucrose pellets in female and male rats.

Impulsivity, or a tendency to act without anticipation of future consequences, is associated with drug abuse. Impulsivity is typically separated into two main measures, impulsive action and impulsive choice. Given the association of impulsivity and drug abuse, treatments that reduce impulsivity have been proposed as an effective method for countering drug addiction. Progesterone has emerged as a promising treatment, as it is associated with decreased addiction-related behaviors and impulsive action. The goal of the present study was to determine the effects of progesterone (PRO) on impulsive action for food: a Go/No-Go task. Female and male rats responded for sucrose pellets during a Go component when lever pressing was reinforced on a variable-interval 30-s schedule. During the alternate No-Go component, withholding a lever press was reinforced on a differential reinforcement of other (DRO) behavior 30-s schedule, where a lever press reset the DRO timer. Impulsive action was operationally defined as the inability to withhold a response during the No-Go component (i.e. the number of DRO resets). Once Go/No-Go behavior was stable, responding between rats treated with PRO (0.5mg/kg) or vehicle was examined. Progesterone significantly decreased the total number of DRO resets in both males and females, but it did not affect VI responding for sucrose pellets. This suggests that PRO decreases motor impulsivity for sucrose pellets without affecting motivation for food. Thus, PRO may reduce motor impulsivity, a behavior underlying drug addiction.

Differential gene expression and chromatin accessibility in the medial prefrontal cortex associated with individual differences in rat behavioral models of opioid use disorder.

Opioid use disorder (OUD) is a neuropsychological disease that has a devastating impact on public health. Substantial individual differences in vulnerability exist, the neurobiological substrates of which remain unclear. To address this question, we investigated genome-wide gene transcription (RNA-seq) and chromatin accessibility (ATAC-seq) in the medial prefrontal cortex (mPFC) of male and female rats exhibiting differential vulnerability in behavioral paradigms modeling different phases of OUD: Withdrawal-Induced Anhedonia (WIA), Demand, and Reinstatement. Ingenuity Pathway Analysis (IPA) of RNA-seq revealed greater changes in canonical pathways in Resilient (vs. Saline) rats in comparison to Vulnerable (vs. Saline) rats across 3 paradigms, suggesting brain adaptations that might contribute to resilience to OUD across its trajectory. Analyses of gene networks and upstream regulators implicated processes involved in oligodendrocyte maturation and myelination in WIA, neuroinflammation in Demand, and metabolism in Reinstatement. Motif analysis of ATAC-seq showed changes in chromatin accessibility to a small set of transcription factor (TF) binding sites as a function either of opioid exposure (i.e., morphine versus saline) generally or of individual vulnerability specifically. Some of these were shared across the 3 paradigms and others were unique to each. In conclusion, we have identified changes in biological pathways, TFs, and their binding motifs that vary with paradigm and OUD vulnerability. These findings point to the involvement of distinct transcriptional and epigenetic mechanisms in response to opioid exposure, vulnerability to OUD, and different stages of the disorder.

Substitutability of nicotine and sucrose in rats: A behavioral economic analysis.

Despite considerable evidence suggesting that sweet foods are a substitute for nicotine in humans, no formal behavioral economic analysis of this interrelationship has been conducted in nonhumans. The purpose of the present study was to examine this phenomenon in rats using concurrent schedules of sucrose pellet, chow pellet, and nicotine reinforcer delivery. Rats responded on separate levers that delivered sucrose pellets, chow pellets, or nicotine infusions under concurrent fixed-ratio (FR) 1 schedules for each commodity within a closed economy. Following stable food and nicotine intake, the unit price of either sucrose or nicotine (the primary commodity) was increased while the two alternative commodities remained unchanged. Substitution was quantified using a behavioral economic cross-price model, as well as a novel commodity relation index that normalizes consumption of dissimilar commodities. Asymmetrical partial substitution was observed, wherein sucrose served as a partial substitute for nicotine, but nicotine failed to substitute for sucrose. Moreover, sucrose was a stronger partial substitute for nicotine than chow in most rats. These findings indicate that substitution of food for nicotine depends on the type of food. These findings mirror the selective increase in carbohydrate intake that can occur during smoking cessation and demonstrate a behavioral economic mechanism that may mediate it.

The relative reinforcing efficacy of nicotine in an adolescent rat model of attention-deficit hyperactivity disorder.

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is an independent risk factor for tobacco use disorder. Individuals with ADHD are more likely to begin smoking at a younger age, become a daily smoker sooner, smoke more cigarettes per day, and exhibit greater nicotine dependence than individuals without ADHD. It is unclear whether these findings are due to the reinforcing efficacy of nicotine per se being greater among individuals with ADHD. The purpose of the present study was to examine this issue using an animal model of ADHD, the spontaneously hypertensive rat (SHR) strain. Methods: Adolescent SHR and Wistar (control) rats were given access to a typically reinforcing nicotine unit dose (30 µg/kg), a threshold reinforcing nicotine dose (4 µg/kg), or saline under an FR 1 (week 1) and FR 2 (week 2) schedule during 23 h sessions to examine acquisition of self-administration. Behavioral economic demand elasticity was then evaluated at the 30 µg/kg dose through an FR escalation procedure. Results: At the 30 µg/kg dose, SHR rats exhibited a lower average response rate, lower mean active to inactive lever discrimination ratio, and lower proportion of rats acquiring self-administration compared to control rats. During demand assessment, SHR rats showed no significant difference from Wistars in demand intensity (Q0) or elasticity (α; i.e., reinforcing efficacy). In addition, no strain difference in acquisition measures were observed at the 4 µg/kg dose. Discussion: These findings suggest that the increased risk of tobacco use disorder in adolescents with ADHD may not be attributable to a greater reinforcing efficacy of nicotine, and that other aspects of tobacco smoking (e.g., non-nicotine constituents, sensory factors) may play a more important role. A policy implication of these findings is that a nicotine standard to reduce initiation of tobacco use among adolescents in the general population may also be effective among those with ADHD.

Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity.

Impulsive choice has enduring trait-like characteristics and is defined by preference for small immediate rewards over larger delayed ones. Importantly, it is a determining factor in the development and persistence of substance use disorder (SUD). Emerging evidence from human and animal studies suggests frontal cortical regions exert influence over striatal reward processing areas during decision-making in impulsive choice or delay discounting (DD) tasks. The goal of this study was to examine how these circuits are involved in decision-making in animals with defined trait impulsivity. To this end, we trained adolescent male rats to stable behavior on a DD procedure and then re-trained them in adulthood to assess trait-like, conserved impulsive choice across development. We then used chemogenetic tools to selectively and reversibly target corticostriatal projections during performance of the DD task. The prelimbic region of the medial prefrontal cortex (mPFC) was injected with a viral vector expressing inhibitory designer receptors exclusively activated by designer drugs (Gi-DREADD), and then mPFC projections to the nucleus accumbens core (NAc) were selectively suppressed by intra-NAc administration of the Gi-DREADD actuator clozapine-n-oxide (CNO). Inactivation of the mPFC-NAc projection elicited a robust increase in impulsive choice in rats with lower vs. higher baseline impulsivity. This demonstrates a fundamental role for mPFC afferents to the NAc during choice impulsivity and suggests that maladaptive hypofrontality may underlie decreased executive control in animals with higher levels of choice impulsivity. Results such as these may have important implications for the pathophysiology and treatment of impulse control, SUDs, and related psychiatric disorders.

The reinforcement threshold and elasticity of demand for nicotine in an adolescent rat model of depression.

BACKGROUND: The Food and Drug Administration (FDA) is considering setting a nicotine standard for tobacco products to reduce their addictiveness. Such a standard should account for the apparent greater vulnerability to nicotine addiction in some subpopulations, such as adolescents with depression. The present study examined whether the reinforcement threshold and elasticity of demand (i.e., reinforcing efficacy) for nicotine in a genetic inbred rat model of depression (Flinders Sensitive Line [FSL]) differs from an outbred control strain. METHODS: Acquisition of nicotine self-administration (NSA) across a wide range of nicotine doses was measured in both FSL and Sprague-Dawley (SD) control adolescent rats. At the highest dose, elasticity of demand was also measured. Nicotine pharmacokinetics was examined to determine whether it might modulate NSA, as it does smoking in humans. RESULTS: FSL rats acquired self-administration quicker and showed more inelastic demand (greater reinforcing efficacy) than SDs at the highest unit dose. However, there was no strain difference in the reinforcement threshold of nicotine. FSL rats exhibited faster nicotine clearance, larger volume of distribution, and lower plasma and brain nicotine concentrations. However, these differences were not consistently related to strain differences in NSA measures. CONCLUSION: These findings are consistent with studies showing greater dependence and reinforcing efficacy of cigarettes in smokers with depression and those with relatively fast nicotine metabolism. However, these findings also suggest that a nicotine standard to reduce initiation of tobacco use should be similarly effective in both the general adolescent population and those with depression.

Comparison of the Relative Abuse Liability of Electronic Cigarette Aerosol Extracts and Nicotine Alone in Adolescent Rats: A Behavioral Economic Analysis.

Background: Characterizing the determinants of the abuse liability of electronic cigarettes (ECs) in adolescents is needed to inform product regulation by the United States Food and Drug Administration (FDA). We recently reported that Vuse Menthol EC aerosol extract containing nicotine and a range of non-nicotine constituents (e.g., menthol, propylene glycol) had reduced aversive effects compared to nicotine alone in adolescent rats, whereas Aroma E-Juice EC aerosol extract did not. The current study used a behavioral economic approach to compare the relative abuse liability of these EC extracts and nicotine alone in an i.v. self-administration (SA) model in adolescents. Methods: Adolescents were tested for the SA of EC extracts prepared using an ethanol (ETOH) solvent or nicotine and saline, with and without 4% ETOH (i.e., the same concentration in the EC extracts) in 23 h/day sessions. Results. Although acquisition of SA was faster for nicotine + ETOH compared to all other formulations, the elasticity of demand for all nicotine-containing formulations was similar. Conclusions: EC aerosol extracts did not have greater abuse liability than nicotine alone in adolescents. These data suggest that nicotine may be the primary determinant of the abuse liability of these ECs in youth, at least in terms of the primary reinforcing effects of ECs mediated within the central nervous system.

Status and Future Directions of Preclinical Behavioral Pharmacology in Tobacco Regulatory Science.

Behavioral pharmacology is a branch of the experimental analysis of behavior that has had great influence in drug addiction research and policy. This paper provides an overview of recent behavioral pharmacology research in the field of tobacco regulatory science, which provides the scientific foundation for the Food and Drug Administration Center for Tobacco Products (FDA CTP) to set tobacco control policies. The rationale and aims of tobacco regulatory science are provided, including the types of preclinical operant behavioral models it deems important for assessing the abuse liability of tobacco products and their constituents. We then review literature relevant to key regulatory actions being considered by the FDA CTP, including regulations over nicotine and menthol content of cigarettes, and conclude with suggesting some directions for future research. The current era of tobacco regulatory science provides great opportunities for behavioral pharmacologists to address the leading cause of preventable death and disease worldwide.

Substitutability of nicotine alone and an electronic cigarette liquid using a concurrent choice assay in rats: A behavioral economic analysis.

BACKGROUND: For the Food and Drug Administration to effectively regulate tobacco products, the contribution of non-nicotine tobacco constituents to the abuse liability of tobacco must be well understood. Our previous work compared the abuse liability of electronic cigarette refill liquids (EC liquids) and nicotine (Nic) alone when each was available in isolation and found no difference in abuse liability (i.e., demand elasticity). Another, and potentially more sensitive measure, would be to examine abuse liability in a choice context, which also provides a better model of the tobacco marketplace. METHODS: Demand elasticity for Nic alone and an EC liquid were measured when only one formulation was available (alone-price demand) and when both formulations were concurrently available (own-price demand), allowing an assessment of the degree to which each formulation served as a substitute (cross-price demand) when available at a low fixed-price. RESULTS: Own-price demand for both formulations were more elastic compared to alone-price demand, indicating that availability of a substitute increased demand elasticity. During concurrent access, consumption of the fixed-price formulation increased as the unit-price of the other formulation increased. The rate of increase was similar between formulations, indicating that they served as symmetrical substitutes. CONCLUSION: The cross-price model reliably quantified the substitutability of both nicotine formulations and indicated that the direct CNS effects of non-nicotine constituents in EC liquid did not alter its abuse liability compared to Nic. These data highlight the sensitivity of this model and its potential utility for examining the relative abuse liability and substitutability of tobacco products.

Propylene glycol, a major electronic cigarette constituent, attenuates the adverse effects of high-dose nicotine as measured by intracranial self-stimulation in rats.

BACKGROUND: Non-nicotine tobacco constituents may contribute to the abuse liability of tobacco products. We previously reported that electronic cigarette (EC) refill liquids containing nicotine and a range of non-nicotine constituents attenuated the anhedonic/aversive effects of nicotine in an intracranial self-stimulation (ICSS) model. The alcohol propylene glycol (PG) is a primary ingredient in these and other EC liquids, yet its abuse potential has not been established. The goal of this study was to evaluate the effects of parenteral administration of PG alone and PG combined with nicotine on ICSS in rats. METHODS AND RESULTS: PG alone did not affect ICSS at concentrations up to 100%. PG (25% or 60%) did not affect nicotine's reinforcement-enhancing (ICSS threshold-decreasing) effects at low to moderate nicotine doses, but attenuated nicotine's reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at a high nicotine dose. PG concentrations similar to those in EC liquid doses used in our previous studies (1% or 3%) modestly attenuated the ICSS threshold-elevating effects of a high nicotine dose. CONCLUSIONS: PG attenuated elevations in ICSS thresholds induced by high-dose nicotine, which may reflect an attenuation of nicotine's acute aversive/anhedonic and/or toxic effects. PG may have contributed to the attenuated ICSS threshold-elevating effects of EC liquids reported previously. Further examination of PG in models of addiction and toxicity is needed to understand the consequences of EC use and to inform the development of EC product standards by the FDA.

Sex-specific attenuation of impulsive action by progesterone in a go/no-go task for cocaine in rats.

RATIONALE: Previous work indicated that progesterone (PRO) reduced impulsive choice for cocaine in female but not male rats (Smethells et al. Psychopharmacology 233:2999-3008, 2016). Impulsive action, typically measured by responding for a reinforcer during a signaled period of nonavailability of natural reinforcers, predicts initiation and escalation of drug use in animals and humans. The present study examined impulsive action for cocaine using PRO in male and female rats trained on a go/no-go task. OBJECTIVE: Rats were trained on a go/no-go task to respond for cocaine infusions (0.4 mg/kg/inf). During the "go" component, responding was reinforced on a VI 30-s schedule, whereas during the "no-go" component, withholding a response was reinforced on a differential reinforcement of other behavior (DRO) 30-s schedule. A response during the no-go component resets the DRO timer and served as a measure of impulsive action. After baseline responding was established, rats were pretreated with vehicle (VEH) or PRO (0.5 mg/kg), and DRO resets and responding during the go component for cocaine were compared in males vs. females. RESULTS: DRO resets were significantly lower following PRO treatment compared to VEH in female, but not male, rats. Response rates and overall infusions during the go component were not significantly altered by PRO in either females or males. CONCLUSION: Treatment with PRO resulted in a sex-specific reduction in impulsive action for cocaine, while not affecting cocaine self-administration.

Effects of nicotine-containing and "nicotine-free" e-cigarette refill liquids on intracranial self-stimulation in rats.

BACKGROUND: Animal models are needed to inform FDA regulation of electronic cigarettes (ECs) because they avoid limitations associated with human studies. We previously reported that an EC refill liquid produced less aversive/anhedonic effects at a high nicotine dose than nicotine alone as measured by elevations in intracranial self-stimulation (ICSS) thresholds, which may reflect the presence of behaviorally active non-nicotine constituents (e.g., propylene glycol) in the EC liquids. The primary objective of this study was to assess the generality of our prior ICSS findings to two additional EC liquids. We also compared effects of "nicotine-free" varieties of these EC liquids on ICSS, as well as binding affinity and/or functional activity of nicotine alone, nicotine-containing EC liquids, and "nicotine-free" EC liquids at nicotinic acetylcholine receptors (nAChRs). METHODS AND RESULTS: Nicotine alone and nicotine dose-equivalent concentrations of both nicotine-containing EC liquids produced similar lowering of ICSS thresholds at low to moderate nicotine doses, indicating similar reinforcement-enhancing effects. At high nicotine doses, nicotine alone elevated ICSS thresholds (a measure of anhedonia-like behavior) while the EC liquids did not. Nicotine-containing EC liquids did not differ from nicotine alone in terms of binding affinity or functional activity at nAChRs. "Nicotine-free" EC liquids did not affect ICSS, but bound with low affinity at some (e.g., α4ß2) nAChRs. CONCLUSIONS: These findings suggest that non-nicotine constituents in these EC liquids do not contribute to their reinforcement-enhancing effects. However, they may attenuate nicotine's acute aversive/anhedonic and/or toxic effects, which may moderate the abuse liability and/or toxicity of ECs.

Tests of behavioral-economic assessments of relative reinforcer efficacy: economic substitutes.

This experiment was conducted to test predictions of two behavioral-economic approaches to quantifying relative reinforcer efficacy. According to the first of these approaches, characteristics of averaged normalized demand curves may be used to predict progressive-ratio breakpoints and peak responding. The second approach, the demand analysis, rejects the concept of reinforcer efficacy, arguing instead that traditional measures of relative reinforcer efficacy (breakpoint, peak response rate, and choice) correspond to specific characteristics of non-normalized demand curves. The accuracy of these predictions was evaluated in rats' responding for food or fat: two reinforcers known to function as partial substitutes. Consistent with the first approach, predicted peak normalized response output values (Omax) obtained under single-schedule conditions ordinally predicted progressive-ratio breakpoints and peak responding. Predictions of the demand analysis had mixed success. Pmax and Omax were significantly correlated with PR breakpoints and peak responding (respectively) when fat, but not when food, was the reinforcer. Relative consumption of food and fat under single schedules of reinforcement did not predict preference better than chance. The normalized demand analysis is supplemented with the economic concept of diminishing marginal utility, to predict preference shifts across the range of food and fat prices examined.

Tests of behavioral-economic assessments of relative reinforcer efficacy II: economic complements.

This experiment was conducted to test the predictions of two behavioral-economic approaches to quantifying relative reinforcer efficacy. The normalized demand analysis suggests that characteristics of averaged normalized demand curves may be used to predict progressive-ratio breakpoints and peak responding. By contrast, the demand analysis holds that traditional measures of relative reinforcer efficacy (breakpoint, peak response rate, and choice) correspond to specific characteristics of non-normalized demand curves. The accuracy of these predictions was evaluated in rats' responding for food or water: two reinforcers known to function as complements. Consistent with the first approach, predicted peak normalized response output values obtained under single-schedule conditions ordinally predicted progressive-ratio breakpoints and peak response rates obtained in a separate condition. Combining the minimum-needs hypothesis with the normalized demand analysis helped to interpret prior findings, but was less useful in predicting choice between food and water--two strongly complementary reinforcers. Predictions of the demand analysis had mixed success. Peak response outputs predicted from the non-normalized water demand curves were significantly correlated with obtained peak responding for water in a separate condition, but none of the remaining three predicted correlations was statistically significant. The demand analysis fared better in predicting choice--relative consumption of food and water under single schedules of reinforcement predicted preference under concurrent schedules significantly better than chance.

Sex differences in attenuation of nicotine reinstatement after individual and combined treatments of progesterone and varenicline.

Tobacco use is the largest cause of preventable mortality in the western world. Even after treatment, relapse rates for tobacco are high, and more effective pharmacological treatments are needed. Progesterone (PRO), a female hormone used in contraceptives, reduces stimulant use but its effects on tobacco addiction are unknown. Varenicline (VAR) is a commonly used medication that reduces tobacco use. The present study examined sex differences in the individual vs. combined effects of PRO and VAR on reinstatement of nicotine-seeking behavior in a rat model of relapse. Adult female and male Wistar rats self-administered nicotine (NIC, 0.03mg/kg/infusion) for 14days followed by 21days of extinction when no cues or drug were present. Rats were then divided into 4 treatment groups: control (VEH+SAL), PRO alone (PRO+SAL), VAR alone (VEH+VAR) and the combination (PRO+VAR). Reinstatement of nicotine-seeking behavior induced by priming injections of NIC or caffeine (CAF), presentation of cues (CUES), and the combination of drugs and cues (e.g. NIC+CUES, CAF+CUES) were tested after extinction. Male and female rats did not differ in self-administration of nicotine or extinction responding, and both showed elevated levels of responding to the CAF+CUES condition. However, males, but not females, reinstated active lever-pressing to the NIC+CUES condition, and that was attenuated by both VAR and VAR+PRO treatment. Thus, males were more sensitive to NIC+CUE-induced reinstatement than females, and VAR alone and VAR combined with PRO effectively reduced nicotine relapse.

Sex differences in the acquisition and maintenance of cocaine and nicotine self-administration in rats.

RATIONALE: Consistent sex differences are observed in human drug addiction, with females often exceeding males on drug intake. However, there is still a need for animal models for some aspects of addiction such as acquisition of drug self-administration and the subsequent development of drug-seeking. OBJECTIVES: The present study examined sex differences in the acquisition and maintenance of self-administration of two widely used stimulants, cocaine and nicotine. METHODS: Male and female rats self-administered cocaine (0.4 mg/kg/infusion) or nicotine (0.03 mg/kg/infusion) daily under a fixed-ratio 1 (FR 1) schedule until acquisition criteria were met (maximum of 30 sessions). The self-administration criterion for cocaine was ≥20 infusions in a 2-h session and ≥5 infusions in a 1-h session for nicotine. Sex differences were assessed by examining the percentage of rats that met acquisition criteria, the number of sessions to meet criteria, and the number of infusions earned during the maintenance phase. RESULTS: A significantly higher percentage of male rats acquired both cocaine and nicotine self-administration than females, and males met acquisition criteria in fewer sessions. However, after criteria were met, females self-administered more cocaine than males during the first 5 days of maintenance. There were no sex differences in nicotine infusions post-acquisition. CONCLUSIONS: Differences in acquisition amongst sexes can reveal factors that are integral to initiation of drug use, an often overlooked phase of drug addiction.

Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine.

Two repurposed medications have been proposed to treat cocaine abuse. Progesterone, a gonadal hormone, and atomoxetine, a medication commonly used to treat attention deficit/hyperactivity disorder, have both been separately shown to reduce cocaine self-administration and reinstatement (i.e., relapse). The goal of the present study was to examine sex differences in the individual effects of PRO and ATO as well as the combination PRO+ATO treatment on cocaine (COC), caffeine (CAF), and/or cue-primed reinstatement of cocaine-seeking. Adult male and female Wistar rats lever-pressed under a FR 1 schedule for cocaine infusions (0.4mg/kg/inf). After 14 sessions of stable responding in daily 2-h sessions, rats underwent a 21-day extinction period when no drug or drug-related stimuli were present. Rats were then separated into four groups that received PRO (0.5mg/kg) alone (PRO+SAL), ATO (1.5mg/kg) alone (VEH+ATO), control (VEH+SAL) or combination (PRO+ATO) treatments prior to the reinstatement condition. Reinstatement of cocaine-seeking to cues and/or drug injections of cocaine or caffeine was tested after extinction. During maintenance, females self-administered more cocaine than males, but no sex differences were seen during extinction. Females showed greater cocaine-seeking than males after a CAF priming injection. Individual treatment with ATO did not decrease reinstatement under any priming condition; however, the combination treatment decreased cocaine-seeking under the COC+CUES priming condition in males, and both PRO alone and the combination treatment decreased cocaine-seeking in the CAF+CUES condition in females. Overall, PRO alone was only effective in reducing reinstatement in females, while the combination treatment was consistently effective in reducing reinstatement in both sexes.

Sex differences in the reduction of impulsive choice (delay discounting) for cocaine in rats with atomoxetine and progesterone.

RATIONALE: Impulsive choice, or an inability to delay immediate gratification, has been strongly linked to the development and persistence of drug abuse. Indeed, delaying drug use itself may underlie drug addiction and relapse. Thus, employing treatments that are efficacious in reducing impulsive choice (atomoxetine; ATO) or drug-seeking behavior (progesterone; PRO) may be an effective means of treating drug addiction. OBJECTIVE: The current study assessed sex differences in the effects of PRO, ATO, and their combination in a delay discounting paradigm for cocaine and for sucrose pellets. METHOD: Male and female rats chose between a small-immediate or a large-delayed (0, 7.5, 15, 30, 60 s) outcome in an impulsive choice procedure for sucrose pellets (1 vs. 3 pellets) or for iv cocaine infusions (0.3 vs. 0.9 mg/kg). Following baseline assessment of impulsive choice, rats received daily treatment of vehicle (VEH), PRO (0.5 mg/kg), ATO (1.5 mg/kg), or a combination (PRO + ATO) until a second assessment of impulsive choice was determined. RESULTS: Compared to the VEH group, females were less impulsive for cocaine following PRO or the PRO + ATO combined treatment, whereas males were less impulsive for cocaine following ATO. No treatment effects were observed on impulsive choice for sucrose pellets. CONCLUSIONS: The present results indicate that impulsive choice for cocaine is reduced by PRO in females and by ATO in males. These findings suggest both treatments may be an effective intervention in treating cocaine abuse, but that their effectiveness differs by sex.

Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments.

The purpose of this review is to discuss recent findings related to sex differences in behavioral dyscontrol that lead to drug addiction, and clinical implications for humans are discussed. This review includes research conducted in animals and humans that reveals fundamental aspects of behavioral dyscontrol. The importance of sex differences in aspects of behavioral dyscontrol, such as impulsivity and compulsivity, is discussed as major determinants of drug addiction. Behavioral dyscontrol during adolescence is also an important consideration, as this is the time of onset for drug addiction. These vulnerability factors additively increase drug-abuse vulnerability, and they are integral aspects of addiction that covary and interact with sex differences. Sex differences in treatments for drug addiction are also reviewed in terms of their ability to modify the behavioral dyscontrol that underlies addictive behavior. Customized treatments to reduce behavioral dyscontrol are discussed, such as (1) using natural consequences such as non-drug rewards (e.g., exercise) to maintain abstinence, or using punishment as a consequence for drug use, (2) targeting factors that underlie behavioral dyscontrol, such as impulsivity or anxiety, by repurposing medications to relieve these underlying conditions, and (3) combining two or more novel behavioral or pharmacological treatments to produce additive reductions in drug seeking. Recent published work has indicated that factors contributing to behavioral dyscontrol are an important target for advancing our knowledge on the etiology of drug abuse, intervening with the drug addiction process and developing novel treatments.