Marilyn E. Carroll

The role of impulsive behavior in drug abuse.

BackgroundImpulsivity is a multifaceted construct that has recently been recognized as a factor contributing to enhanced vulnerability to drug abuse.ObjectivesIn the present review, we focus on two facets of impulsivity (and tasks that measure them): (1) impulsive choice (delay discounting task) and (2) inhibitory failure (go/no-go, stop signal reaction time, and five-choice serial reaction time tasks). We also describe how performance on each of these tasks is associated with drug-related behavior during phases of drug abuse that capture the essential features of addiction (acquisition, escalation, and reinstatement of drug-seeking after drug access has terminated). Three hypotheses (H) regarding the relationship between impulsivity and drug abuse are discussed: (1) increased levels of impulsivity lead to drug abuse (H1), (2) drugs of abuse increase impulsivity (H2), and (3) impulsivity and drug abuse are associated through a common third factor (H3).ConclusionImpulsivity expressed as impulsive choice or inhibitory failure plays a role in several key transition phases of drug abuse. There is evidence to support all three nonexclusive hypotheses. Increased levels of impulsivity lead to acquisition of drug abuse (H1) and subsequent escalation or dysregulation of drug intake. Drugs of abuse may increase impulsivity (H2), which is an additional contributor to escalation/dysregulation. Abstinence, relapse, and treatment may be influenced by both H1 and H2. In addition, there is a relationship between impulsivity and other drug abuse vulnerability factors, such as sex, hormonal status, reactivity to nondrug rewards, and early environmental experiences that may impact drug intake during all phases of addiction (H3). Relating drug abuse and impulsivity in phases of addiction via these three hypotheses provides a heuristic model from which future experimental questions can be addressed.

Biological basis of sex differences in drug abuse: preclinical and clinical studies

Abstract. The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review, we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men; thus, different prevention and treatment strategies may be required. Similar sex differences in drug sensitivity and self-administration have been reported in laboratory animal studies. Females appear to be more vulnerable than males to the reinforcing effects of psychostimulants, opiates, and nicotine during many phases of the addiction process (e.g. acquisition, maintenance, dysregulation-escalation, relapse). Male and female animals differ in their behavioral, neurological, and pharmacological responses to drugs. Although the role of sex in the mechanisms of drug action remains unclear, preclinical and clinical studies indicate that ovarian hormones, particularly estrogen, play a role in producing sex differences in drug abuse. Future research is necessary to provide information on how to design more effective drug abuse treatment programs and resources that are sex specific.

Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats.

Abstract  Rationale: Despite numerous reports that male and female animals differ in behavioral responses to drugs, few studies have investigated sex differences in drug-reinforced behavior. Objectives: Acquisition of IV cocaine and heroin self-administration was compared in 20 female and 22 male Wistar rats. Methods: An autoshaping procedure was used to train rats to press a lever that resulted in either a 0.2 mg/kg infusion of cocaine or a 0.015 mg/kg infusion of heroin under a fixed-ratio 1 (FR 1) schedule. Daily sessions consisted of six 1-h autoshaping components followed by a 6-h self-administration component. During each autoshaping component, a retractable lever briefly (15 s) extended into the test chamber on a random interval schedule with a mean of either 90 s (cocaine groups) or 480 s (heroin groups) and either ten (cocaine groups) or five (heroin groups) computer-automated infusions were delivered each hour. During each 6-h self-administration component, the lever remained extended and each response on the lever resulted in an infusion of either cocaine (0.2 mg/kg) or heroin (0.015 mg/kg). The criterion for acquisition of cocaine self-administration was a mean of at least 100 infusions and the criterion for heroin self-administration was a mean of at least 20 infusions during the self-administration component over five consecutive sessions. Results: Female rats acquired both cocaine and heroin self-administration more rapidly than males. Acquisition of cocaine self-administration occurred in a greater percentage of female rats compared to males. Female rats self-administered more cocaine than males after acquisition criteria had been met. Conclusions: These findings indicate that female rats were more vulnerable than males to the acquisition of cocaine and heroin self-administration under the conditions of the present experiment.

Fluoxetine reduces intravenous cocaine self-administration in rats

Rats self-administered intravenously delivered cocaine (0.2 mg/kg) under a fixed-ratio (FR) 4 schedule during 24-hr sessions. Water was freely available from both a drinkometer and a standard water bottle. After behavior had stabilized, the rats were injected with fluoxetine HCl at 10:00 a.m. and 4:00 p.m. for 5 consecutive days. Three groups of 5 rats each received a different dose of fluoxetine (2.5, 5 or 10 mg/kg) via the IV cannula. In three other groups of rats a glucose and saccharin solution (G + S) was substituted for water in the automatic drinking device and saline was substituted for cocaine. These three groups of rats received the same fluoxetine doses as the cocaine self-injecting groups. In two additional groups of 5 rats each, the cocaine dose was changed to 0.1 or 0.4 mg/kg, and 5 mg/kg fluoxetine injections were given. The two higher doses of fluoxetine (5 and 10 mg/kg) reduced cocaine infusions (0.2 mg/kg) by at least 50 percent on all 5 days of treatment, and cocaine infusions returned to baseline levels within 48 hr after fluoxetine treatments were terminated. Behavior maintained by the G + S solution was also reduced by the two higher fluoxetine doses; however, this reduction did not reliably occur until the last two days of fluoxetine administration. The G + S intakes returned to baseline levels within 24 hr after fluoxetine treatment. Fluoxetine also reduced cocaine infusions in the group of rats that received the lower unit dose of cocaine (0.1 mg/kg); however, it had almost no effect on behavior maintained by a higher cocaine dose (0.4 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

A concurrently available nondrug reinforcer prevents the acquisition or decreases the maintenance of cocaine-reinforced behavior

Lever-Pressing responses of 55 rats were reinforced with IV-delivered cocaine (0.2 mg/kg) or saline under conditions of continuous access for 15 24-h sessions. The rats also responded on tongue-operated drinking devices for deliveries of a 3% (w/v) glucose +0.125% (w/v) sacharin (G+S) solution or water. The effects of removing these substances on behavior maintained by G+S, water, cocaine, or saline were compared in 11 groups. Terminating cocaine access produced a decrease in G+S drinking and an increase in food and water intake. In contrast, a group of rats that did not initially self-administer G+S showed increases in G+S drinking when cocaine was removed, and G+S-maintained responding persisted when cocaine was reinstated. Substitution of water for G+S produced a nearly two-fold increase in cocaine-reinforced behavior but no change in IV-delivered saline self-administration in a control group. A group that did not initially self-administer cocaine increased its infusion rate to over 400 infusions per day as soon as G+S was replaced with water. The effect of presenting cocaine to a group that responded for G+S alone was to decrease G+S intake, but there was only a a transient decrease in water intake in the control group. Likewise, presentation of G+S to a group of rats self-administering cocaine resulted in a decrease in infusions, but saline infusions did not change in a control group. Generally, there was an increase in food and water intake during cocaine removal, but food and water intake did not vary systematically with the removal or presentation of G+S. The results suggest that behavior reinforced by IV-delivered cocaine can be substantially altered by the discontinuation or presentation of G+S, an orally self-administered nondrug reinforcer.

Deconstructing relative reinforcing efficacy and situating the measures of pharmacological reinforcement with behavioral economics : a theoretical proposal

Abstract. Background: Relative reinforcing efficacy has been assumed to be a homogeneous phenomenon referring to the behavior-strengthening or behavior-maintaining effects of a drug reinforcer. However, a variety of studies suggest that relative reinforcing efficacy may be heterogeneous. Objectives: The purpose of this theoretical proposal is to examine the difficulties associated with this conception of reinforcing efficacy and to explore whether relative reinforcing efficacy is a homogenous concept or whether it is composed of several functionally related heterogeneous phenomena. In examining this issue, we explore whether behavioral economic theory may address some of the challenges to the current conception of relative reinforcing efficacy and use this theory to suggest how the differing measures of reinforcing efficacy may relate to one another. Results: Results indicate that peak-response rate and breakpoint are related to the economic measure of maximal output and elasticity of demand, respectively. Preference is related to and predicted by the relative location of the demand curves obtained under single schedule conditions. This behavioral economic analysis may provide a theoretical understanding of reinforcement that can reconcile results of studies that both support and fail to support the notion of reinforcing efficacy as a homogenous phenomenon. Conclusions: If this theoretical proposal is validated by additional studies, then like other natural phenomena found to be heterogeneous, the study of drug reinforcers may require the adoption of several new scientific terms, such as those used in behavioral economics, each of which has analytical precision and refers to homogeneous phenomena.

Sex differences in the vulnerability to drug abuse: a review of preclinical studies

Clinical and preclinical findings indicate that males and females differ on several aspects of drug reinforcement. Females are more vulnerable than males during transition periods of drug use that are characteristic of drug addiction and relapse. Females are also more sensitive than males to the reinforcing effects of stimulants. It has been suggested that ovarian hormones contribute to the mechanisms of action underlying these sex differences. This review examines the preclinical literature on sex differences and ovarian hormonal influences on drug self-administration in animals. It summarizes the findings on the effects of these variables during different phases of drug addiction. Possible differences in the mechanisms of action of drugs of abuse due to interactions with sex differences or ovarian hormonal factors are considered. The animal literature on sex differences in drug abuse treatment effectiveness is also discussed.

Wheel-running attenuates intravenous cocaine self-administration in rats: Sex differences

This experiment examines the effect of access to a running-wheel on intravenous cocaine self-administration in male and female rats. Rats maintained at 85% of their free-feeding body weight were first exposed to the running-wheel alone during the 6-h sessions until behavior stabilized for 14 days. Intravenous cannulae were then implanted, and the rats were trained to self-administer a low dose of cocaine (0.2 mg/kg) under a fixed-ratio (FR 1) schedule during the 6-h sessions, while the wheel remained inactive and cocaine self-administration stabilized (cocaine-only condition). Next, the wheel access and cocaine self-administration were concurrently available followed by a period of cocaine-only. Behavior was allowed to stabilize for 10 days at each phase. During wheel access, cocaine infusions decreased by 21.9% in males and 70.6% in females compared to the cocaine-only condition; the effect was statistically significant in females. Infusions increased to baseline levels when wheel access was terminated. When cocaine infusions were concurrently available, wheel revolutions were reduced by 63.7% and 61.5% in males and females, respectively, compared to the wheel-only condition. This result did not differ due to sex, but it was statistically significant when data from males and females were combined. These results indicate that wheel-running activity had a greater suppressant effect on cocaine self-administration in females than in males, and in females, wheel-running and cocaine self-administration are substitutable as reinforcers.

Role of estrogen in the acquisition of intravenously self-administered cocaine in female rats.

Previous work from this laboratory has revealed that female rats acquired cocaine self-administration at a faster rate than male rats and that a greater percentage of females acquired self-administration [Psychopharmacology 144 (1999) 77.]. It has been suggested that sex differences in stimulant self-administration may be related to ovarian hormones, particularly estrogen. To investigate this possibility, we compared four groups (n = 10) of female rats: ovariectomized (OVX) treated with either estradiol benzoate (EB) or vehicle (VEH), and sham-operated intact (SH) females treated with either the antiestrogen tamoxifen (TAM) or VEH. An autoshaping procedure was used to train rats to lever press for intravenous infusions of cocaine (0.2 mg/kg). The criterion for cocaine acquisition was a mean of 100 self-administered infusions over five consecutive 6-h sessions. Results revealed that 70% of the OVX + EB group and 80% of the SH + VEH group acquired self-administration, while only 30% of the OVX + VEH group and 50% of the SH + TAM group met the acquisition criterion. Rats that had estrogen chemically or surgically blocked exhibited significantly less responding for cocaine over the acquisition testing period, and fewer of these rats met the acquisition criterion compared to intact rats and to OVX rats with estrogen (EB) replacement. The percentages for females with estrogen (70% and 80%) vs. those without (OVX, 30%) were similar to those reported for intact females (70%) and males (30%) in the previous study [Psychopharmacology (2000)]. Taken together, these results suggest that estrogen is a key factor influencing drug-seeking behavior in female rats, and it may underlie sex differences in drug-reinforced responding.

Reinstatement of cocaine self-administration in rats: sex differences

Abstract  Rationale: Results obtained with both humans and animals suggest that rates of relapse, or levels of reinstatement responding, may differ between males and females. However, the results obtained with humans are equivocal, and few studies have compared male and female animals on reinstatement responding. Objectives: The present experiment was designed to compare male (n=8) and female (n=8) rats on reinstatement of extinguished cocaine-reinforced responding. Methods: Reinstatement of responding was examined using a priming model in which lever pressing for cocaine (0.2 mg/kg) was extinguished by replacing cocaine infusions (2 h) with saline infusions (5 h). After responding extinguished during hour 3, reinstatement of responding was tested by administering one of several priming injections of cocaine (0.32, 1.0 and 3.2 mg/kg) or an equal volume of saline. Results: Although males and females did not differ in the number of saline infusions self-administered after either saline or 0.32 mg/kg cocaine-priming injections, female rats self-administered significantly more saline infusions than males after 1.0 mg/kg and 3.2 mg/kg cocaine-priming injections. Additionally, the effects of 0.32 mg/kg cocaine-priming injections were significantly different from those of saline-priming injections for female, but not male, rats. There was no significant difference between males and females in total cocaine self-administered during hours 1 and 2. Conclusions: These findings indicate that female rats are more sensitive than males during the reinstatement phaseof drug abuse.