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Drug addiction is a chronic relapsing disorder, as more than 80% of former drug users relapse within a year after quit attempts have ended. This review examines incubated craving that develops over long periods of weeks to months after addictive drug use ends, when rats are given a small priming exposure to the formerly used drug, and a large amount of drug seeking occurs, reflecting large increases in craving over time. Expanded craving occurs when not only the recently-used drug, but other related or unrelated drugs of abuse elicit drug seeking that leads to relapse behavior, including common drugs like caffeine or nicotine, Thus, expanded craving is an increase in the conditions that elicit relapse, such as, a variety of drugs, and it persists weeks after drug use ends. Incubated and expanded craving occur with several drugs of abuse, and these forms of craving, can last for weeks to months and end in relapse. Voluntary physical exercise, blocked incubated cocaine craving, and expanded heroin craving elicited by multiple conditions was reduced in female and male rats. This review examines voluntary physical exercise as a long-term, self-initiated, and self-sustainable treatment that reduces long-term drug craving leading to relapse.

BACKGROUND: The rise in heroin addiction has heightened the need for novel and effective treatments. Physical exercise has been shown as an effective treatment for stimulant abuse in clinical and pre-clinical research. However, this treatment has not yet been tested on opioid addiction. This study examined the effects of physical activity (wheel running) on heroin-seeking in rats within a reinstatement paradigm (i.e., heroin relapse model). METHODS: Female and male rats were trained to self-administer intravenous heroin (0.015 mg/kg). Once trained, rats were placed into extinction (i.e., heroin abstinence) for 21 days with continuous access to a locked or unlocked running wheel. After extinction, rats were tested for drug- (heroin, caffeine, and yohimbine) and cue-primed reinstatement of heroin-seeking. RESULTS: Females completed more wheel revolutions than males across all study phases. Access to an unlocked running wheel reduced extinction and reinstatement of heroin-seeking, with greater reductions in females than males across several reinstatement conditions. In the locked wheel group, female rats showed greater reinstatement of heroin-seeking than males across several priming conditions. CONCLUSIONS: Wheel running reduced heroin-seeking in male and female rats, with females showing a more robust effect during reinstatement. The locked wheel group allowed an examination of sex differences in heroin reinstatement, which revealed that females showed greater vulnerability to heroin reinstatement than males, but with no other sex differences observed in maintenance or extinction. Overall, the results indicate that voluntary physical exercise may be an effective treatment for heroin dependence in humans.

In a previous study in female rats, voluntary wheel running attenuated incubation of cocaine craving after 30 but not 3 days (Zlebnik and Carroll Zlebnik and Carroll, Psychopharmacology 232:3507-3413, 2015). The present study in male rats, using the same procedure, showed that wheel running reduced incubated craving after both 30 and 3 days of abstinence.Male rats self-administered i.v. cocaine (0.4 mg/kg) during 6-h sessions for 10 days. They were then moved from the operant chamber to a home cage with an attached running wheel or stationary wheel, for 6 h daily for a 3- or 30-day period when cocaine craving was hypothesized to incubate. Rats were then returned to the operant chamber for a 30-min test of cocaine seeking, or "craving," indicated by responses on the former "drug" lever was formerly associated with drug stimulus lights and responses (vs. no drug stimuli), and lever responding was compared to responses on the "inactive" that was illuminated and counted lever pressing.Mean wheel revolutions were similar across the 3- and 30-day incubation groups, when both groups of rats were given access to wheel running vs. access to a stationary wheel in controls. Subsequently, when rats were tested in the operant chamber for "relapse" responding (drug-lever responding) on the lever formerly associated with drug access, cocaine craving was reduced by recent running wheel access (vs. stationary wheel access) in both the 3- and 30-day wheel exposure groups.Voluntary, self-initiated, and self-sustained physical exercise reduced cocaine craving after short- (3 days) and long-term (30 days) abstinence periods in male rats that previously self-administered cocaine. This was contrasted with reduction of cocaine seeking in females after 30-day, but not 3-day, incubation periods under the wheel running vs. stationary wheel conditions in a previous study (Zlebnik and Carroll Zlebnik and Carroll, Psychopharmacology 232:3507-3413, 2015). These initial findings suggest males may be more sensitive to incubated craving for cocaine than females.

Background Worldwide methamphetamine (METH) use has increased significantly over the last 10 years, and in the US, METH dependence has sky-rocketed among individuals with opioid use disorder. Of significant concern, METH use is gaining popularity among groups with susceptibility to developing severe substance use disorders, such as women and adolescents. Nevertheless, there is no established pharmacotherapy for METH addiction. Emerging evidence has identified the orexin/hypocretin system as an important modulator of reward-driven behavior and a potential target for the treatment of drug addiction and relapse. However, to date, there have been no investigations into the therapeutic efficacy of orexin/hypocretin receptor antagonists for METH-motivated behavior in adolescents or adults. In the present study, we examined the effects of selective antagonists of the orexin-1 (SB-334867, 20 mg/kg) and orexin-2 (TCS-OX2-29, 20 mg/kg) receptors on the reinstatement of METH seeking in both adolescent and adult male and female rats. Methods Rats were trained to self-administer METH (0.05 mg/kg/inf, iv) during two 2-h sessions/day for 5 days. Following 20 sessions of extinction over 10 days, a within-subjects design was used to test for METH seeking precipitated by METH (1 mg/kg, ip) or METH cues after systemic pretreatment with SB-334867 or TCS-OX2-29. Results SB-334867 reduced cue-induced reinstatement in males and females, regardless of age. Additionally, METH-induced METH seeking was attenuated by SB-334867 in adolescents and by TCS-OX2-29 in adults. Conclusion Selective orexin/hypocretin receptor antagonists have significant therapeutic potential for diminishing METH-seeking behavior, although their treatment efficacy may be influenced by age.

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 (0.5 mg/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.

The importance of studying sex as a biological variable in biomedical research is becoming increasingly apparent. There is a particular need in preclinical studies of addiction to include both sexes, as female animals are often excluded from studies, leaving large gaps in our knowledge of not only sex differences and potential prevention and treatment strategies but also with regard to the basic neurobiology of addiction. This review focuses on methodology that has been developed in preclinical studies to examine sex differences in the behavioral aspects and neurobiological mechanisms related to addiction across the full range of the addiction process, including initiation (acquisition), maintenance, escalation, withdrawal, relapse to drug seeking and treatment. This review also discusses strategic and technical issues that need to be considered when comparing females and males, including the role of ovarian hormones and how sex differences interact with other major vulnerability factors in addiction, such as impulsivity, compulsivity and age (adolescent versus adult). Novel treatments for addiction are also discussed, such as competing non-drug rewards, repurposed medications such as progesterone and treatment combinations. Practical aspects of conducting research comparing female and male animals are also considered. Making sex differences a point of examination requires additional effort and consideration; however, such studies are necessary given mounting evidence demonstrating that the addiction process occurs differently in males and females. These studies should lead to a better understanding of individual differences in the development of addiction and effective treatments for males and females.

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. 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. 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. 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. 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.

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 (0.4 mg/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 (0.5 mg/kg) alone (PRO+SAL), ATO (1.5 mg/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.

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.

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. The present study examined sex differences in the acquisition and maintenance of self-administration of two widely used stimulants, cocaine and nicotine. 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. 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. Differences in acquisition amongst sexes can reveal factors that are integral to initiation of drug use, an often overlooked phase of drug addiction.

Adolescence is a transitional phase marked by a heightened vulnerability to substances of abuse. It has been hypothesized that both increased sensitivity to reward and decreased sensitivity to aversive events may drive drug-use liability during this phase. To investigate possible age-related differences in sensitivity to the aversive consequences of drug use, adolescent and adult rats were compared on self-administration of cocaine before, during, and after a 10-day period in which an aversive agent, histamine, was added to the cocaine solution. Adult and adolescent female rats were trained to self-administer intravenous cocaine (0.4 mg/kg/infusion) over 10 sessions (2 h/session; 2 sessions/day). Histamine (4 mg/kg/infusion) was then added directly into the cocaine solution for the next 10 sessions. Finally, the cocaine/histamine solution was replaced with a cocaine-only solution, and rats continued to self-administer cocaine (0.4 mg/kg) for 20 sessions. Compared with adolescent rats, adult rats showed a greater decrease in cocaine self-administration when it was punished with intravenous histamine compared with their baseline cocaine self-administration rates. These results suggest that differences in the sensitivity to negative consequences of drug use may partially explain developmental differences in drug use vulnerability.

Rationale Sweet preference is a marker of vulnerability to substance use disorders, and rats selectively bred for high (HiS) vs. low saccharin (LoS) intake display potentiated drug-seeking behaviors. Recent work indicated that LoS rats were more responsive to the negative effects of drugs in several assays. Objective The current study used the intracranial self-stimulation (ICSS) procedure to investigate the anhedonic component of morphine withdrawal in male HiS and LoS rats. Methods Rats were administered morphine (10 mg/kg) or saline for 8 days. To evaluate withdrawal effects, reward thresholds were measured 24 and 28 h following the 8th morphine injection (spontaneous withdrawal) and again for 4 days following daily acute morphine and naloxone (1 mg/kg) administration (precipitated withdrawal). Results 24 h following the final morphine injection, reward thresholds in LoS rats were significantly elevated compared to reward thresholds in LoS controls, indicating spontaneous withdrawal. This effect was not observed in HiS rats. LoS rats also showed greater elevations of reward thresholds on several days during naloxone-precipitated withdrawal compared to their HiS counterparts. Conclusions LoS rats were more sensitive to morphine withdrawal-mediated elevations in ICSS thresholds than HiS rats. While these differences were generally modest, our data suggest that severity of the negative affective component of opiate withdrawal may be influenced by genotypes related to addiction vulnerability.

Cocaine use results in anhedonia during withdrawal, but it is not clear how this emotional state interacts with an individual's vulnerability for addiction. Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug abuse vulnerability, with HiS rats being more likely to consume sweets and drugs of abuse such as cocaine and heroin (Carroll et al., 2002) than LoS rats. This study examined whether the motivational consequences of cocaine withdrawal are differentially expressed in HiS and LoS rats. HiS and LoS rats were trained to respond for a sucrose reward on a progressive ratio (PR) schedule of reinforcement and breakpoints were measured during and after chronic, continuous exposure to cocaine (30 mg/kg/day). Cocaine, but not saline, treatment resulted in lower breakpoints for sucrose during withdrawal in LoS rats only. These results suggest anhedonia during withdrawal is more pronounced in the less vulnerable LoS rats. Fewer motivational deficits during withdrawal may contribute to greater drug vulnerability in the HiS line.

Introduction Despite extensive efforts to develop effective smoking cessation interventions, 70–85% of American cigarette smokers who quit relapse within one year. Exercise has shown promise as an intervention; however, many results have been equivocal. This study explored how exercise is associated with smoking-related symptomatology, smoking behavior and impulsivity in male and female smokers. Methods Participants were recruited throughout the United States using the on-line crowdsourcing platform, Amazon’s Mechanical Turk. They completed a survey with self-report measures assessing exercise, smoking-related symptomatology, smoking behavior and impulsivity. Differences between men and women were tested using t- and chi-square tests. Regression analyses tested for associations between exercise and smoking-related symptomatology, smoking behavior and impulsivity. Results Participants (N = 604) were, on average, 32 (SD = 6.2) years old, mostly Caucasian, with at least some college education and approximately half were women. Women exercised slightly less than men and had more negative affect, craving, physical symptoms and withdrawal. Women smoked more cigarettes per day, had greater nicotine dependency and more years of smoking. Positive affect was positively associated with exercise for both men and women; however, this association was significantly stronger in women. Negative affect and withdrawal were inversely associated with exercise for women only. Impulsivity was inversely associated with exercise for both men and women. Conclusion Exercise was significantly associated with several smoking-related symptomatology, smoking behavior and impulsivity variables for both men and women, suggesting that exercise may be a useful intervention for smoking cessation. Future prospective research should determine how exercise directly impacts smoking cessation.

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. 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. 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. Treatment with PRO resulted in a sex-specific reduction in impulsive action for cocaine, while not affecting cocaine self-administration.

Aerobic exercise and the attention-deficit/hyperactivity disorder medication, atomoxetine (ATO), are two monotherapies that have been shown to suppress reinstatement of cocaine-seeking in an animal model of relapse. The present study investigated the effects of combining wheel running and ATO versus each treatment alone on cocaine-seeking precipitated by cocaine and cocaine-paired cues in rats with differing susceptibility to drug abuse (i.e., high vs. low impulsive).Rats were screened for high (HiI) or low impulsivity (LoI) based on their performance on a delay-discounting task and then trained to self-administer cocaine (0.4 mg/kg/inf) for 10 days. Following 14 days of extinction, both groups were tested for reinstatement of cocaine-seeking precipitated by cocaine or cocaine-paired cues in the presence of concurrent running wheel access (W), pretreatment with ATO, or both (W+ATO).HiI rats acquired cocaine self-administration more quickly than LoI rats. While both individual treatments and W+ATO significantly attenuated cue-induced cocaine seeking in HiI and LoI rats, only W+ATO was effective in reducing cocaine-induced reinstatement compared with vehicle treatment. There were dose-dependent and phenotype-specific effects of ATO with HiI rats responsive to the low but not high ATO dose. Floor effects of ATO and W on cue-induced reinstatement prevented the assessment of combined treatment effects.These findings demonstrated greater attenuation of cue- versus cocaine-induced reinstatement by ATO and W alone and recapitulate impulsivity phenotype differences in both acquisition of cocaine self-administration and receptivity to treatment.

Individually, both treatment with progesterone and concurrent access to an exercise wheel reduce cocaine self-administration under long-access conditions and suppress cocaine-primed reinstatement in female rats. In the present study, wheel running and progesterone (alone and combined) were assessed for their effects on reinstatement of cocaine-seeking primed by yohimbine, cocaine, and cocaine-paired cues. Male and female rats were implanted with an intravenous catheter and allowed to self-administer cocaine (0.4 mg/kg/inf, iv) during 6-h sessions for 10 days. Subsequently, the groups of male and female rats were each divided into two groups that were given concurrent access to either a locked or unlocked running wheel under extinction conditions for 14 days. Next, all four groups were tested in a within-subjects design for reinstatement of cocaine-seeking precipitated by separate administration of cocaine-paired stimuli, yohimbine, or cocaine or the combination of yohimbine + cocaine-paired stimuli or cocaine + cocaine-paired stimuli. These priming conditions were tested in the presence of concurrent wheel access (W), pretreatment with progesterone (P), or both (W + P). In agreement with previous results, females responded more for cocaine than males during maintenance. Additionally, concurrent wheel running attenuated extinction responses and cocaine-primed reinstatement in females but not in males. Across all priming conditions, W + P reduced reinstatement compared to control conditions, and for cocaine-primed reinstatement in male rats, the combined W + P treatment was more effective than W or P alone. Under certain conditions, combined behavioral (exercise) and pharmacological (progesterone) interventions were more successful at reducing cocaine-seeking behavior than either intervention alone.

Adolescence marks a period of increased vulnerability to the development of substance use disorders. High sweet preference is a genetically mediated behavioral trait that also predicts vulnerability to substances of abuse. Previous research has shown that while adolescent rats selectively bred for high (HiS) saccharin intake acquire cocaine self-administration at the same rate as adult HiS rats, adolescent rats bred for low saccharin intake (LoS) acquire cocaine self-administration faster than adult LoS rats.This study was conducted to investigate the interaction of the addiction vulnerability factors of peri-adolescence and saccharin preference on cocaine intake using an animal model of escalation of cocaine consumption over 6-h/day sessions.Peri-adolescent and adult HiS and LoS female rats self-administered i.v. cocaine (0.4 mg/kg/inf) during short-access (2-h/day) sessions for 2 days. Next, a long-access (6-h/day) period (LgA) commenced and lasted 16 days. Following LgA, session length was returned to 2-h/day for a second short access phase.LoS peri-adolescent rats escalated cocaine intake over the LgA period and consumed more drug than LoS adult rats; however, peri-adolescent and adult HiS rats consumed similar amounts of cocaine during this period. Additionally, adult HiS rats self-administered more cocaine than adult LoS rats during the LgA period, while there was no phenotypic difference between the rat lines during peri-adolescence for the LgA period. During the first short-access phase, peri-adolescent rats self-administered more cocaine than adult rats.These results emphasize the importance of adolescent drug abuse prevention by illustrating that phenotypic protection from addiction may not be expressed until adulthood.

Background Previous research has found that rats behaviorally screened for high (vs. low) wheel running were more vulnerable to cocaine abuse. To assess the extent to which a genetic component is involved in this drug-abuse vulnerability, rats selectively bred for high or low voluntary running (HVR or LVR, respectively) were examined for differences in cocaine seeking in the present study. Methods Female rats were trained to lever press for food and then were assessed for differences in acquisition of cocaine (0.4 mg/kg; i.v.) self-administration across 10 sessions. Once acquired, rats self-administered cocaine for a 14-day maintenance phase, followed by a 14-day extinction phase when cocaine was no longer available. Subsequently, reinstatement of cocaine seeking was examined with priming injections of cocaine (5, 10 & 15 mg/kg), caffeine (30 mg/kg), yohimbine (2.5 mg/kg) and cocaine-paired cues. Results A greater percentage of LVR rats met the acquisition criteria for cocaine self-administration and in fewer sessions than HVR rats. No differences in responding for cocaine were observed between phenotypes during maintenance. However, during extinction LVR rats initially responded at higher rates and persisted in cocaine seeking for a greater number of sessions. No phenotype differences were observed following drug and cue-primed reinstatement of cocaine seeking. Conclusions In general, LVR rats were more sensitive to the reinforcing effects of cocaine than HVR rats during periods of transition into and out of cocaine self-administration. Thus, LVR rats sometimes showed a greater vulnerability cocaine seeking than HVR rats.

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, 0.03 mg/kg/infusion) for 14 days followed by 21 days 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) was 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.

In previous studies, female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle. The purpose of this study was to examine sex and hormonal influences on oral cocaine self-administration in male and female rhesus monkeys in the follicular vs. luteal phases of the menstrual cycle, with concurrent access to an alternative nondrug reward, saccharin (SACC) vs. water. Concurrent access to cocaine (0.2, 0.4, and 0.8 mg/ml) and SACC or water was available from two drinking spouts under concurrent fixed-ratio (FR) 2, 4, and 8 schedules during daily 3-h sessions. Cocaine deliveries were similar in males and females in the females’ luteal phase, but cocaine deliveries were higher in females during the follicular phase than the luteal phase and compared to males. When SACC was available, cocaine deliveries were reduced in females in the follicular phase of the cycle, and cocaine intake (mg/kg) was reduced in males and in females’ follicular and luteal phases. Access to concurrent SACC (vs. water) reduced cocaine intake (mg/kg) in males and in females during both menstrual phases, and the magnitude of the reduction in cocaine intake was greatest during the females’ follicular phase. Thus, a nondrug alternative reward, SACC, is a viable alternative treatment for reducing cocaine’s rewarding effects on male and female monkeys, and reductions in cocaine seeking were optimal in the females’ luteal phase.

Rats that have been selectively bred for high (HiS) saccharin intake demonstrate elevated drug-seeking behavior in several phases of addiction compared to those bred for low (LoS) saccharin intake. HiS rats also consume greater amounts of highly palatable substances compared to LoS rats; however, little is known about the neurobiological substrates moderating the divergent behaviors found between the HiS and LoS lines. Orexins are neuropeptides that have been implicated in the conditioned cue aspects of drug abuse and overconsumption of palatable substances, and differential orexin activity in the HiS and LoS phenotypes may enhance our understanding of the close relationship between food and drug reward, and ultimately food and drug addiction. The lateral hypothalamus (LH) and perifornical area (PFA) are brain regions that have been implicated in regulating feeding behavior and addiction processes, and they contain orexinergic neurons that project broadly throughout the brain. Thus, we investigated orexin and c-Fos expression in the LH and PFA using immunohistochemistry in HiS and LoS rats following either control or cocaine (15 mg/kg) injections. Results indicated that HiS rats have higher orexin-positive cell counts compared to LoS rats in both the LH and PFA, regardless of cocaine (vs. saline) treatment. In contrast, neuronal activity indicated by c-Fos expression did not differ in either of these brain areas in HiS vs. LoS rats. These results suggest that the orexin system may be involved in aspects of genetically-mediated differences in vulnerability to compulsive, reward-driven behaviors.

Methamphetamine (METH) use has increased substantially in the last 10 years and poses a serious health concern, especially for young populations. Drug abuse primarily begins during adolescence, when uninhibited and excessive and drug intake is a common occurrence; thus, understanding the developmental patterns of addiction during this critical period is an essential step in its prevention. In the present study, the effect of age on the vulnerability to METH abuse was examined using a rat model of bingeing (i.e., escalation).Adolescent and adult rats were compared during short (ShA, 2-h) and long-access (LgA, 6-h) to METH self-administration. On postnatal (PN) days 23 (adolescents) and 90 (adults), rats were implanted with i.v. catheters and trained to lever press for infusions of METH (0.05mg/kg) during 2-h sessions. Once the rats reached a steady rate of METH self-administration, they were divided into ShA or LgA groups and allowed to self-administer METH for 15 additional days.Results indicated that adolescent rats earned significantly more infusions than adults under the LgA condition, but the age groups did not differ during ShA. Adolescents, but not adults, also significantly increased (i.e., escalated) METH self-administration across the 15 days of testing under the LgA condition. Further analysis indicated excessive responding during infusions in the LgA METH-exposed adolescents compared to the other groups, suggesting elevated impulsivity or motivation for drug.These results demonstrate that adolescents are more vulnerable to the escalation of METH than adults during LgA.

Background Sex differences in methamphetamine (METH) use (females > males) have been demonstrated in clinical and preclinical studies. This experiment investigated the effect of sex on the reinstatement of METH-seeking behavior in rats and determined whether pharmacological interventions for METH-seeking vary by sex. Treatment drugs were modafinil (MOD), an analeptic, and allopregnanolone (ALLO), a neuroactive steroid and progesterone metabolite. Method Male and female rats were trained to self-administer i.v. infusions of METH (0.05 mg/kg/infusion). Next, rats self-administered METH for a 10-day maintenance period. METH was then replaced with saline, and rats extinguished lever-pressing behavior over 18 days. A multi-component reinstatement procedure followed whereby priming injections of METH (1 mg/kg) were administered at the start of each daily session, preceded 30 min by MOD (128 mg/kg, i.p.), ALLO (15 mg/kg, s.c.), or vehicle treatment. MOD was also administered at the onset of the session to determine if it would induce the reinstatement of METH-seeking behavior. Results Female rats had greater METH-induced reinstatement responding compared to male rats following control treatment injections. MOD (compared to the DMSO control) attenuated METH-seeking behavior in male and female rats; however, ALLO only reduced METH-primed responding in females. MOD alone did not induce the reinstatement of METH-seeking behavior. Conclusions These results support previous findings that females are more susceptible to stimulant abuse compared to males, and ALLO effectively reduced METH-primed reinstatement in females. Further, results illustrate the utility of MOD as a potential agent for prevention of relapse to METH use in both males and females.

This review summarizes findings from human and animal research investigating the influence of progesterone and its metabolites allopreganolone and pregnanolone (progestins) on the effects of cocaine and other drugs of abuse. Since a majority of these studies have used cocaine, this will be the primary focus; however, the influence of progestins on other drugs of abuse will also be discussed. Collectively, findings from these studies support a role for progestins in (1) attenuating the subjective and physiological effects of cocaine in humans, (2) blocking the reinforcing and other behavioral effects of cocaine in animal models of drug abuse, and (3) influencing behavioral responses to other drugs of abuse such as alcohol and nicotine in animals. Administration of several drugs of abuse in both human and nonhuman animals significantly increased progestin levels, and this is explained in terms of progestins acting as homeostatic regulators that decrease and normalize heightened stress and reward responses which lead to increased drug craving and relapse. The findings discussed here highlight the complexity of progestin-drug interactions, and they suggest a possible use for these agents in understanding the etiology of and developing treatments for drug abuse.

Rationale Evidence suggests that the progesterone metabolite allopregnanolone (ALLO) decreases cocaine seeking in animal models of relapse. Objective The purpose of this study was to examine the effects of ALLO on an animal model of cocaine and sucrose bingeing (escalation). Allopregnanolone's effects on yohimbine-induced sucrose intake were also examined. In a separate group of animals, dose interactions between ALLO and cocaine were examined with an abbreviated procedure, a short access progressive ratio (PR) schedule for cocaine reinforcement. Methods Female rats were treated with ALLO (15 mg/kg, s.c.) or vehicle (VEH) and trained to lever press for cocaine infusions (0.4 mg/kg) under an extended-access procedure. In a separate condition, other ALLO- and VEH-treated female rats self-administered orally delivered liquid sucrose. Allopregnanolone and VEH treatment was then discountinued and the sucrose-maintained rats were administered priming injections of saline, yohimbine, or yohimbine+ALLO. For the PR condition, rats were first treated with VEH until reaching stability at four doses of cocaine (0.2, 0.4, 0.8, and 1.6 mg/kg in mixed order). Subsequently, rats re-established their baseline cocaine intake at the four cocaine doses following treatment with each of two counterbalanced doses of ALLO (15 and 30 mg/kg). Results ALLO significantly blocked the escalation of cocaine self-administration but did not reliably affect intake of sucrose under a similar condition or affect cocaine intake at several doses under a PR schedule. Yohimbine significantly increased sucrose intake while ALLO failed to attenuate this increase. Conclusion These findings indicate that ALLO protects against binge-like patterns of cocaine intake but does not reduce sugar intake that is acutely increased by yohimbine in females.

Increasing evidence indicates the presence of sex differences in many aspects of drug abuse. Most studies reveal that females exceed males during the initiation, escalation, extinction, and reinstatement (relapse) of drug-seeking behavior, but males are more sensitive than females to the aversive effects of drugs such as drug withdrawal. Findings from human and animal research indicate that circulating levels of ovarian steroid hormones account for these sex differences. Estrogen (E) facilitates drug-seeking behavior, while progesterone (P) and its metabolite, allopregnanalone (ALLO), counteract the effects of E and reduce drug seeking. Estrogen and P influence other behaviors that are affiliated with drug abuse such as drug-induced locomotor sensitization and conditioned place preference. The enhanced vulnerability to drug seeking in females vs. males is also additive with the other risk factors for drug abuse (e.g., adolescence, sweet preference, novelty reactivity, and impulsivity). Finally, treatment studies using behavioral or pharmacological interventions, including P and ALLO, also indicate that females show greater treatment effectiveness during several phases of the addiction process. The neurobiological basis of sex differences in drug abuse appears to be genetic and involves the influence of ovarian hormones and their metabolites, the hypothalamic pituitary adrenal (HPA) axis, dopamine (DA), and gamma-hydroxy-butyric acid (GABA). Overall, sex and hormonal status along with other biological risk factors account for a continuum of addiction-prone and -resistant animal models that are valuable for studying drug abuse prevention and treatment strategies.

Compared to nondrug reinforcers, few studies have examined delay discounting for drug reinforcers. The purpose of the present study was to examine delay discounting in rhesus monkeys using orally delivered phencyclidine (PCP) as the reinforcer and to examine the effects of manipulating reinforcer magnitude and cost on delay discounting for PCP using an adjusting delay task. Monkeys could choose between a single delivery of PCP available immediately or a bundle of PCP deliveries available following a titrated delay. The average of the delays, or the mean adjusted delay (MAD), served as the quantitative measure of delay discounting. In Experiment 1, reinforcer magnitude was manipulated by varying the PCP concentration and the size of the delayed reinforcer (6 or 12 deliveries). The concentration-effect curve for PCP deliveries assumed an inverted U-shaped function, but varying PCP concentration had little effect on MAD values or the choice between immediate and delayed reinforcers. Increasing the size of the delayed reinforcer produced an upward and leftward shift in the concentration-effect curve. In Experiment 2, the cost of reinforcers was manipulated by increasing the fixed ratio (FR) requirement for each choice. Increasing the FR led to increased MAD values and decreased PCP self-administration.

The purpose of this study was to examine a form of impulsive behavior (impaired inhibition) using cocaine or food reward in addiction-prone and addiction-resistant rats that were bred for high saccharin (HiS) or low saccharin (LoS) intake, respectively. A Go/No-go procedure was used to examine cocaine and food reinforcement (Go component) and the inhibition of responding during a subsequent period of nonreward (No-go component). Rats were initially trained to self-administer intravenous cocaine (0.4 mg/kg) under an FR 1 schedule during daily Go/No-go sessions consisting of three components of cocaine reinforcement (Go) alternating with two nonreward components (No-go), each signaled by different stimuli. Responding and drug intake were compared under three FR values (FR 1, FR 3, and FR 5) and three cocaine doses (0.2, 0.4, and 0.8 mg/kg). A similar Go/No-go procedure was used with food reinforcement and the same three FR conditions. During the Go components for intravenous cocaine, female rats self-administered more infusions at the 0.2 and 0.4 mg/kg doses than males, indicating a sex difference in cocaine intake. During the No-go periods under the cocaine condition, HiS rats and females responded significantly more than LoS rats and males, indicating phenotype and sex differences in impaired inhibition. During the Go components with food reward, males responded more and earned more pellets than females, but there were no phenotype or sex differences in No-go responding (impulsivity). The results indicate that HiS rats and females are more prone than LoS rats and males to impulsive drug-seeking behavior.

Drug abuse and impulsive choice are related in humans. In female rats, impulsive choice predicted the rate of acquisition of IV cocaine self-administration. The objectives of the present experiments were to: (a) compare impulsive choice in males and females, (b) extend previous research on impulsive choice and acquisition of cocaine self-administration to males, and (c) compare males and females during maintenance, extinction, and reinstatement of cocaine-seeking behavior. Male and female rats were trained on an adjusting delay task in which a response on one of two levers yielded one food pellet immediately, and a response on the other resulted in three pellets after an adjusting delay that decreased after responses on the immediate lever and increased after responses on the delay lever. A mean adjusted delay (MAD) was used as the quantitative measure of impulsivity. In Experiment 1, MADs were analyzed for sex differences. In Experiment 2, acquisition of cocaine self-administration was examined in rats selected for high (HiI; MADsor =9 seconds) or low (LoI; MADsor =13 seconds) impulsivity. In Experiment 3, HiI and LoI groups were compared on maintenance and extinction of cocaine self-administration and cocaine-primed reinstatement of drug-seeking behavior. There were no sex differences in impulsive choice; however, HiI male and female rats acquired cocaine self-administration faster than their LoI counterparts. LoI females responded more on a cocaine-associated lever during maintenance and extinction than HiI females, but HiI females showed greater reinstatement of cocaine-seeking behavior than all other groups at the highest dose tested (15 mg/kg). Thus, individual differences in impulsive choice were associated with differences in cocaine-seeking behavior. Impulsive choice and sex may be additive vulnerability factors in certain phases of drug abuse.

Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans.

Animal models employing selection or selective breeding practices based on phenotypic traits related to substance use disorders have enhanced our understanding of the role genes play in the vulnerability to such compulsive behaviors. Rodent models, in particular, have shown that traits such as impulsivity and high sweet consumption, among others, are under strong genetic influence and positively associated with drug intake, similar to human populations. This chapter will review a number of rat models of phenotypic vulnerability to and protection from drug abuse. It will compare and contrast these models and assess whether they provide evidence for one or multiple addiction-prone phenotypes, and conclude by assessing the potential utility of these models in predicting clinical outcomes in treating substance use disorders.

Rats selectively bred for high saccharin consumption (HiS) self-administer more oral ethanol and i.v. cocaine than those selectively bred for low saccharin consumption (LoS). Male and female drug-seeking-prone (HiS) and -resistant (LoS) rats were used in the present experiment to test the prediction that cocaine-induced locomotor activity and sensitization varied with sex and their selective breeding status (HiS and LoS). All rats were intermittently exposed over 2 weeks to pairs of sequential saline and cocaine injections, separated by 45 min. The first 5 pairs of injections, each separated by 2–3 days (10–12 days total), were given to examine the development of cocaine-induced locomotor activity and the development of locomotor sensitization, which was determined by comparing the effects of cocaine injection 1 with injection 6 (given 2 weeks after the 5 pairs of intermittent injections). Results indicated that after the first injection pair (saline, cocaine) the HiS and LoS groups did not differ (saline vs. cocaine) in locomotor activity; however, after cocaine injection pairs 1, 5, and 6, HiS females were more active than HiS males and LoS females. There were also significant phenotype differences (HiS > LoS) in locomotor activity after cocaine injections 5 and 6. There was a weak sensitization effect in cocaine-induced locomotor activity in HiS females after cocaine injection 5 (compared to 1); however it was not present after injection 6 or in other groups. The lack of a strong sensitization effect under these temporal and dose conditions was inconsistent with previous reports. However, the results showing HiS > LoS and females > males on cocaine-induced activity measures are consistent with several measures of cocaine-seeking behavior (acquisition, maintenance, escalation, extinction, and reinstatement), and they suggest that cocaine-induced locomotor activity and sensitization are behavioral markers of drug-seeking phenotypes.

Environmental factors, including social interaction, can alter the effects of drugs of abuse on behavior. The present study was conducted to examine the effects of social stimuli on oral phencyclidine (PCP) self-administration by rhesus monkeys. Ten adult rhesus monkeys (M. mulatta) were housed side by side in modular cages that could be configured to provide visual, auditory, and olfactory stimuli provided by another monkey located in the other side of a paired unit. During the first experiment, monkeys self-administered PCP (0.25 mg/ml) and water under concurrent fixed ratio (FR) 16 schedules of reinforcement with either a solid or a grid (social) partition separating each pair of monkeys. In the second experiment, a PCP concentration-response relationship was determined under concurrent progressive ratio (PR) schedules of reinforcement during both the solid and grid partition conditions. Under the concurrent FR 16 schedules, PCP and water self-administration were significantly higher during exposure to a cage mate through a grid partition than when a solid partition separated the monkeys. The relative reinforcing strength of PCP, as measured by PR break points, was greater during the grid partition condition compared to the solid partition condition indicated by an upward shift in the concentration-response curve. To determine whether the social stimuli provided by another monkey led to activation of the hypothalamic-pituitary-adrenal (HPA) axis, which may have evoked the increase of PCP self-administration during the grid partition condition, a third experiment was conducted to examine cortisol levels under the two housing conditions. A modest, but nonsignificant increase in cortisol levels was found upon switching from the solid to the grid partition condition. The results suggest that social stimulation among monkeys in adjoining cages leads to enhanced reinforcing strength of PCP.

Adolescence and excessive intake of saccharin have each been previously associated with enhanced vulnerability to drug abuse. In the present study, we focused on the relationship between these two factors using male adolescent and adult rats selectively bred for high (HiS) and low (LoS) levels of saccharin intake. On postnatal day 25 (adolescents) or 150 (adults), rats were implanted with an intravenous catheter and trained to self-administer cocaine (0.4 mg/kg) using an autoshaping procedure that consisted of two 6-h sessions. In the first 6 h, rats were given non-contingent cocaine infusions at random intervals 10 times per hour, and during the second 6-h session, rats were allowed to self-administer cocaine under a fixed ratio 1 (FR 1) lever-response contingency. Acquisition was defined as a total of at least 250 infusions over 5 consecutive days, and rats were given 30 days to meet the acquisition criterion. Subsequently, saccharin phenotype scores were determined by comparing 24-h saccharin and water consumption in two-bottle tests to verify HiS/LoS status. Adolescent LoS rats had a faster rate of acquisition of cocaine self-administration than adult LoS rats; however, adolescent and adult HiS rats acquired at the same rate. Both HiS and LoS adolescents had significantly higher saccharin phenotype scores than HiS and LoS adults, respectively. Additionally, saccharin score was negatively correlated with the number of days to meet the acquisition criterion for cocaine self-administration, but this was mostly accounted for by the HiS adolescents. These results suggest that during adolescence, compared with adulthood, rats have both an increased avidity for sweets and vulnerability to initiate drug abuse.

Estradiol benzoate (EB) facilitates the acquisition and reinstatement of cocaine-seeking behavior when administered to ovariectomized (OVX) rats. In contrast, progesterone (P) decreases acquisition of cocaine self-administration, but the effects of P on the reinstatement of drug seeking are not known. The purpose of the present study was to compare the effects of EB and P on the reinstatement of cocaine-seeking behavior in female rats. Rats received either OVX or sham surgery (SH) and were trained to lever press for intravenous cocaine infusions (0.4 mg/kg) under a fixed ratio 1, 20-s time-out schedule during daily 2-hr sessions. After 14 days of stable responding, saline replaced cocaine, and a 21-day extinction period began. After extinction, rats were separated into 5 treatment groups (OVX+EB, OVX+EB+P, OVX+vehicle [VEH], SH+P, or SH+VEH), and VEH, EB, or EB+P was administered 30 min prior to each session for 5 days. After 3 days of hormone treatment, rats received a saline or cocaine (10 mg/kg) injection, and reinstatement of lever responding was assessed. Reinstatement responding in the OVX+EB group was greater relative to the OVX+EB+P, SH+P, and OVX+VEH groups, which had low levels of cocaine-primed responding. The SH+VEH and OVX+EB groups displayed similar high levels of cocaine-elicited reinstatement. The suppression of cocaine-induced reinstatement following P treatment suggests a role for P in the prevention of relapse to cocaine self-administration in female cocaine users.

Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug-abuse vulnerability, with HiS rats being more likely to consume sweets and cocaine than LoS rats. Still, the nature of these differences is poorly understood. This study examined whether the motivational consequences of cocaine exposure are differentially expressed in HiS and LoS rats by measuring intracranial self-stimulation (ICSS) thresholds following acute injections of cocaine (10 mg/kg). Reductions in ICSS thresholds following cocaine injection were greater in HiS rats than in LoS rats, suggesting that the reward-enhancing effects of cocaine are greater in the drug-vulnerable HiS than LoS rats. Higher cocaine-induced reward, indicated by lower ICSS thresholds, may explain the higher rates of drug consumption in sweet-preferring animal models, providing a clue to the etiology of cocaine addiction in vulnerable populations.

Recent research has demonstrated that aerobic exercise can attenuate craving for drugs of abuse and reduce escalation and reinstatement of drug-seeking behavior in animal models. The present study examined the effects of aerobic exercise on the development of the incubation of cocaine-seeking behavior or the progressive increase in cocaine seeking over a protracted withdrawal period from cocaine self-administration.Female rats were trained to self-administer cocaine (0.4 mg/kg/inf) during daily 6-h sessions for 10 days. Subsequently, access to cocaine and cocaine-paired cues was discontinued during a 3- or 30-day withdrawal period when rats had access to either a locked or unlocked running wheel. At the end of the withdrawal period, rats were reintroduced to the operant conditioning chamber and reexposed to cocaine-paired cues to examine cocaine-seeking behavior under extinction conditions.Rats with access to a locked running wheel during 30 days of withdrawal had significantly greater cue-induced cocaine-seeking behavior than rats that had access to an unlocked running wheel for 30 days. Further, there was robust incubation of cocaine seeking in rats with access to a locked running wheel as cocaine seeking was notably elevated at 30 vs. 3 days of withdrawal. However, cocaine-seeking behavior did not differ between rats with access to an unlocked running wheel for 30 vs. 3 days, indicating that incubation of cocaine seeking was suppressed following access to exercise for 30 days.Aerobic exercise during extended withdrawal from cocaine self-administration decreased incubation of cue-induced cocaine-seeking behavior and may reduce vulnerability to relapse.

Rats selectively bred for high saccharin (HiS) intake consume more alcohol and acquire intravenous (i.v.) cocaine self-administration more rapidly than their low saccharin (LoS)-consuming counterparts. The present experiment was designed to determine whether HiS and LoS rats differed in other aspects of drug abuse. The purpose of the present experiment was to use a two-lever dose self-selection procedure to investigate the regulation/dysregulation of i.v. cocaine self-administration in female HiS and LoS rats. HiS and LoS rats were trained to self-administer eight different doses of cocaine during daily 5-h sessions, with the cocaine doses ranging from 0.2 to 1.6 mg/kg in steps of 0.2 mg/kg. The dose size increased after a response on one lever (infusion duration lengthened by 3 s) and decreased after a response on the other lever (infusion duration shortened by 3 s), with a lower limit of 0 s and with an upper limit of 24 s (a corresponding range of 0 to 1.6 mg/kg); the animals increased or decreased their self-administered dose in nine discrete steps. The HiS rats showed less precise regulation of their postinfusion interval (PII) than LoS rats based on the size of the previously self-administered cocaine dose. Correlations between these variables were lower for HiS than for LoS rats during the acquisition and maintenance phases, and HiS rats had lower PIIs than LoS rats after many of the cocaine doses. The HiS rats also self-administered significantly more cocaine infusions during the maintenance phase than the LoS rats, especially at the highest dose. These data indicate that HiS rats are more likely to self-administer more cocaine infusions, at higher doses, and with less precise dose-time regulation than LoS rats. Thus, rats selectively bred for HiS showed less inhibitory control over their cocaine intake than LoS rats, suggesting that a genetic predisposition for saccharin preference is related to the rewarding effects of i.v. cocaine.

Preclinical and clinical studies indicate that females are more vulnerable to relapse than males, and the neurobiological effects of estrogen are thought to mediate, in part, the sex differences in cocaine-taking behavior. The goal of the present study was to investigate the involvement of estrogen receptor alpha (ERalpha) and beta (ERbeta) in estrogen-mediated increases in cocaine-induced reinstatement of extinguished cocaine-seeking behavior in ovariectomized (OVX) female rats. Rats were initially trained to self-administer cocaine (0.4 mg/kg/inf, i.v.) under a fixed-ratio 1 (FR 1) schedule of reinforcement during daily 2-h sessions. After a 10-day maintenance period, cocaine solutions were replaced with saline, and self-administration was extinguished over a 14-day period. OVX rats were then treated with either the mixed ERalpha/beta agonist estradiol benzoate (EB), the ERalpha-selective agonist, propyl-pyrazole-triol (PPT), the ERbeta-selective agonist, diarylpropionitrile (DPN), or a vehicle control (dimethyl sulfoxide, DMSO). Treatment lasted a total of 9 days, and during this time, rats were assessed for nonreinforced reinstatement of extinguished cocaine-seeking behavior after priming injections of saline or cocaine (5, 10, or 15 mg/kg, i.p.). OVX rats showed no differences in self-administration during maintenance or extinction. OVX rats treated with EB exhibited greater responding for cocaine during reinstatement compared to OVX+DMSO controls. Selective activation of ERbeta with DPN also increased cocaine-induced reinstatement responding, whereas selective activation of ERalpha with PPT did not affect cocaine-seeking behavior. These results indicate that estrogen influences the propensity for reinstatement of extinguished cocaine-seeking behavior, and that estrogen-mediated enhancement of cocaine-induced reinstatement responding involves the activation of ERbeta.

Substantive evidence indicates that there are sex differences in the reinforcing effects of drugs, and gonadal steroid hormones, such as estrogen and progesterone, likely contribute to these differences. Among females, subjective effects of drugs differ as a function of menstrual cycle phase. The purpose of the present study was to compare oral self-administration of phencyclidine (PCP) in female rhesus monkeys (Macaca mulatta) across different phases of the menstrual cycle. Since the 28-day menstrual cycle of non-human primates is similar to that of humans, this model could provide important evidence supporting the implication that changes in the levels of gonadal hormones across menstrual phase can alter a drug's reinforcing effects. Oral self-administration of several concentrations of PCP (0.125, 0.25, and 0.5 mg/ml) was examined in three sexually mature female monkeys during 3-h experimental sessions. Menstrual cycle phase was determined by onset of menses and verified by examining vaginal cytology. PCP self-administration was greater during the luteal phase at the 0.125 and 0.25 mg/ml concentrations, which is normally characterized by high levels of progesterone and moderate levels of estrogen, than during the follicular phase, when levels of estrogen are increasing and progesterone levels are low. When examined within each phase, numbers of PCP deliveries were highest during the mid-luteal phase, compared to the early and mid-follicular phases. No differences in self-administration were observed between early and mid-follicular phases, but a significant difference in PCP deliveries was found between mid- and late luteal phases at the lowest concentration of PCP tested. The results from this study suggest that PCP's reinforcing effects in female monkeys differ as a function of menstrual cycle phase.

Rationale: Rats selectively bred for high saccharin (HiS) intake consume more alcohol, acquire intravenous (i.v.) cocaine self-administration more rapidly, and show more dysregulated patterns of cocaine self- administration than their low saccharin-consuming (LoS) counterparts. Objectives: The purpose of the present study was to determine whether HiS and LoS rats also differ in the escalation, maintenance, extinction, and reinstatement of i.v. cocaine self-administration. Materials and methods: Two experiments were con- ducted in separate groups of rats. In the first experiment, HiS and LoS female rats were allowed to self-administer cocaine (0.4 mg/kg; fixed ratio (FR) 1) under short (ShA, 2 h per day) or long (LgA, 12 h per day) access conditions for 21 days. Session lengths were subsequently equated (2 h), and FR1-maintained cocaine self-administration was examined. In the second experiment, additional groups of HiS and LoS female rats were given access to cocaine (0.4 mg/kg; FR 1) self-administration during 2-h sessions for 10 days. Subsequently, saline was substituted for cocaine, and responding was extinguished. After a 14- day extinction period, saline- and cocaine-(5, 10, and 15 mg/kg, intraperitoneal (i.p.)) induced reinstatement of drug-seeking behavior was measured. Results: HiS LgA rats escalated their cocaine intake more rapidly than LoS rats, and during the 2 h sessions after escalation cocaine self-administration was significantly higher in HiS LgA rats, compared to LoS LgA rats. HiS rats responded on the cocaine-paired lever more than LoS rats during mainte- nance, extinction, and cocaine-(15 mg/kg) induced reinstatement. Conclusions: These results suggest that HiS and LoS rats have distinct drug-seeking and drug- taking profiles. The HiS and LoS rats differ along a wide range of behavioral dimensions and represent an im- portant model to study the interactions of excessive intake of dietary substances and vulnerability to drug abuse.

Withdrawal from orally self-administered phencyclidine (PCP) has been shown to alter operant baselines of food-maintained responding. The goal of the present study was to determine whether there are sex differences in these alterations. Seven female and 7 male rhesus monkeys (Macaca mulatta) were given concurrent access to PCP and water under fixed ratio (FR) 8 schedules during 2 daily sessions that alternated with 2 sessions during which pellet deliveries were contingent on lever presses under an FR 64 schedule. After operant responding stabilized, PCP was replaced by water for 10 days, and food access remained under the same schedule. Subsequently, concurrent PCP and water access was reintroduced for 10 days. This procedure was repeated with 3 PCP concentrations (0.125, 0.25, and 0.50 mg/ml) and 3 FR requirements for food-reinforced responding (64, 128, and 256). Disruptions in operant responding for food served as a quantitative measure of withdrawal severity. During PCP withdrawal, males showed a greater suppression of food-maintained behavior than females at the 2 highest PCP concentrations and the lowest FR requirement tested. Males responded more than females for PCP; however, when weight was taken into consideration, PCP intake (milligrams per kilogram) in males and females was equal. The data suggest that males may experience more severe withdrawal effects than females, and the duration of the adverse effects of withdrawal lasts longer in males than in females. This study is the 1st to use nonhuman primates to document sex differences in withdrawal severity as measured by a quantifiable baseline.

Estrogen effects on cocaine-induced reinstatement of lever responding were examined in sham-operated, vehicle-treated (SH + VEH), ovariectomized (OVX + VEH), and OVX female Wistar rats with estrogen replacement (OVX + EB). The effect of long- (64 ± 1.56 days) and short-term (9 days) EB treatment on reinstatement of cocaine-seeking behavior was compared in Experiment 1 and 2, respectively, in order to compare the effect of EB when it was present during the development vs. expression of reinstatement of cocaine-seeking behavior. Rats were trained to self-administer 0.4 mg/kg/inf cocaine. After the acquisition criteria were met, rats continued to respond for cocaine for 2 h/day for a 14-day maintenance period. Cocaine was then replaced with saline and the 21-day extinction period commenced. Subsequently, rats were tested for reinstatement of lever responding on the previously drug-paired lever after alternating daily injections of saline or cocaine. In both experiments, there were no differences between groups in self-administration behavior during training, maintenance, or extinction. In Experiment 1, SH + VEH and chronically treated OVX + EB rats had greater cocaine-induced reinstatement than OVX + VEH rats. In Experiment 2, short-term treated OVX + EB rats also showed enhanced cocaine-induced reinstatement compared to OVX + VEH rats. The results indicate that EB-mediated enhancement of cocaine-induced reinstatement is dependent on EB presence during the expression of reinstatement but not during the formation of stimulus–reward associations during the development of cocaine-reinforced behavior.

Studies with male rats indicate that long access (LgA) vs short access (ShA) to i.v. cocaine and heroin self-administration leads to an escalation of drug intake and a subsequent upward shift of the dose-response function.The purpose of this experiment was to extend these results to male and female rhesus monkeys and oral phencyclidine (PCP) self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules.Adult rhesus monkeys (seven females and nine males) orally self-administered PCP (0.25 mg/ml) and water under concurrent FR 16 FR 16 schedules during daily ShA 3-h sessions. Since females weighed less than males, each liquid delivery (0.6 ml) represented a higher unit dose mg/kg for females than males, but drug concentration mg/ml remained constant. Concurrent PR PR schedules were then used to obtain a concentration-response function (0.125, 0.25, 0.5, and 1.0 mg/ml). Next, PCP and water were available during LgA 6-h sessions under concurrent FR 16 FR 16 schedules for 21 days. The monkeys were then retested under the concurrent FR 16 FR 16 and PR PR conditions during ShA sessions.Under the initial ShA concurrent FR 16 FR 16 schedules, females and males did not differ on PCP deliveries or intake (mg/kg); however, during LgA, males and females had more PCP deliveries compared with ShA. During LgA, males exceeded females in PCP deliveries, but females were higher than males in mg/kg PCP intake. Also, PCP (but not water) deliveries and mg/kg PCP intake significantly increased from the first 3 days to the last 3 days of the 21-day LgA period in both males and females. The subsequent ShA FR 16 FR 16 performance did not differ by sex, but it was significantly elevated above the first ShA period in both sexes. The concentration-response function for PCP break point under the PR PR schedules and PCP intake (mg/kg) were significantly shifted upward during the second (vs first) ShA period, and females' mg/kg intake significantly exceeded males'.Male and female rhesus monkeys both showed escalation of PCP self-administration during LgA to PCP and during ShA that occurred after (vs before) LgA. Both showed vertical upward shifts in the concentration x intake (mg/kg) function under the PR schedule, and females exceeded males on this measure. These findings with PCP and monkeys are consistent with vertical upward shifts of cocaine dose-response functions in previous escalation studies in male rats and reports of sex differences (FM) during several other phases of drug abuse.

Preclinical data have indicated that extended access to cocaine self-administration (e.g., 6-12 h/day) facilitates an escalation in daily cocaine intake that is not seen when rats are given shorter (e.g., 1-2 h/day) access to cocaine for self-administration. Data from studies with rats have shown that females self-administer more cocaine than males during all phases of drug abuse (e.g., acquisition, maintenance, and reinstatement). The purpose of this study was to examine potential differences between males and females in the escalation of intravenous cocaine intake following a differential access (e.g., 1 vs. 6 h) period of cocaine self-administration. Four groups of rats were compared: (1) long-access (LgA; 6 h) females; (2) LgA males; (3) short-access (ShA; 1 h) females; and (4) ShA males. Animals were given LgA or ShA to intravenous cocaine (0.5 mg/kg/infusion) self-administration under an Fr 1 schedule for 21 days. Subsequently, access conditions were made equal (3 h) across groups, and dose-response curves for cocaine were compared. Results revealed that the LgA groups' dose-response curves were significantly elevated above those of ShA groups. Additionally, the dose-response curve of LgA female rats was significantly elevated above that of LgA male rats. These results suggest that female rats are more sensitive than male rats to factors that contribute to the escalation of cocaine intake (e.g., extended access conditions).

Evidence is accumulating that the etiology, epidemiology, consequences and mechanisms that underlie drug abuse are different in males and females. In this review, we present examples of sex differences in all phases of drug abuse, including acquisition, steady-state maintenance, escalation, dysregulation, withdrawal, relapse and treatment. Most reported findings are based on laboratory research in animals, but there are corroborating reports from human clinical and epidemiological studies. In all phases of drug abuse, females seem to be more sensitive to the rewarding effects of drugs than males, and estrogen is a major factor that underlies these sex differences.