Reducing short- and long-term cocaine craving with voluntary exercise in male rats.

Background: 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.

Methods: Male rats self-administered i.

Voluntary exercise as a treatment for incubated and expanded drug craving leading to relapse to addiction: Animal models.

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.

Age-specific treatment effects of orexin/hypocretin-receptor antagonism on methamphetamine-seeking behavior.

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.

Association of exercise with smoking-related symptomatology, smoking behavior and impulsivity in men and women.

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.

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.

Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5.

In comparison to men, women initiate drug use at earlier ages and progress from initial use to addiction more rapidly. This heightened intake and vulnerability to drugs of abuse is regulated in part by estradiol, although the signaling mechanisms by which this occurs are not well understood. Recent findings indicate that within the nucleus accumbens core, estradiol induces structural plasticity via membrane-localized estrogen receptor α, functionally coupled to metabotropic glutamate receptor subtype 5 (mGluR5).

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.

How to study sex differences in addiction using animal models.

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.

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.

Sex and menstrual cycle effects on chronic oral cocaine self-administration in rhesus monkeys: Effects of a nondrug alternative reward.

Background: In previous studies, female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle.

Objectives: 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.

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.

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.

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.

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.

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.

Cocaine-induced reward enhancement measured with intracranial self-stimulation in rats bred for low versus high saccharin intake.

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).

Effects of age, but not sex, on elevated startle during withdrawal from acute morphine in adolescent and adult rats.

Investigations into animal models of drug withdrawal have largely found that emotional signs of withdrawal (e.g. anxiety, anhedonia, and aversion) in adolescents are experienced earlier and less severely than in their adult counterparts.

Cocaine self-administration punished by intravenous histamine in adolescent and adult rats.

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.

Discrepant effects of acute cocaine on impulsive choice (delay discounting) in female rats during an increasing- and adjusting-delay procedure.

Rationale: The relationship between impulsive choice and cocaine use in humans has been well established, although the causal role between these variables is complex. To disentangle this relationship, studies using rats have focused on how acute or chronic cocaine alters impulsive choice. A predominance of studies has focused on chronic cocaine regimens, but few have assessed acute cocaine's effects on impulsive choice.

Intracranial self-stimulation reward thresholds during morphine withdrawal in rats bred for high (HiS) and low (LoS) saccharin intake.

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.

Cocaine withdrawal in rats selectively bred for low (LoS) versus high (HiS) saccharin intake.

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.

Effects of the combination of wheel running and atomoxetine on cue- and cocaine-primed reinstatement in rats selected for high or low impulsivity.

Background: 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.

Effects of combined exercise and progesterone treatments on cocaine seeking in male and female rats.

Background: 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.

Methods: Male and female rats were implanted with an intravenous catheter and allowed to self-administer cocaine (0.