Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration

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Abstract

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).

Introduction

Cocaine is a highly addictive illicit drug that produces rapid, euphoric effects shortly after it is administered via insufflation (Oliveto et al., 2001), intravenous injection Resnick and Kestenbaum, 1977, Walsh et al., 1996, or smoking (Foltin and Fischman, 1991). In order to experience the same euphoric effect over time, the user consumes more of the drug, often soon after the last administration. However, the euphoria produced by the first cocaine dose is not duplicated when subsequent doses are spaced too closely Brower et al., 1986, Foltin et al., 2003, Trinkoff et al., 1990, and this frequently causes the user to take the drug in ‘binges’ or cycles of frequent, repeated dosing (Gawin and Kleber, 1985). These patterns of use result in chronic exposure to the drug that can lead to uncontrolled accelerated patterns of drug intake (e.g., escalation), which are defining features of addiction Edwards, 1986, Gawin, 1991, Marlatt et al., 1988. In 2002, an estimated two million people or 0.9% of the population in the United States were current cocaine users (National Survey on Drug Use and Health (NSDUH), 2002). Of these users, 25.2% were classified as cocaine abusers or cocaine dependent (NSDUH, 2002). Therefore, identifying factors that may contribute to the progression from cocaine use to cocaine addiction, such as the escalation in drug intake, may be important for developing prevention and treatment strategies for cocaine addiction.

Sex is one factor that may be important to consider when designing strategies to prevent and treat cocaine addiction. For example, women reported greater negative physiological effects (e.g., nervousness) following cocaine use than men (Kosten et al., 1996). Women also took longer to detect the subjective effects of cocaine, and they reported less euphoria and dysphoria following cocaine administration compared to men (Lukas et al., 1996). Similar sex differences were reported in the subjective responses to smoked cocaine (Sofuoglu et al., 1999) and repeated ‘binge’-smoked cocaine (Evans et al., 1999). It is possible that women may be more likely than men to escalate their cocaine use and to use the drug in an uncontrolled, erratic manner to achieve the euphoria they first experienced since their subjective euphoric responses to the drug are initially diminished relative to males.

Preclinical data have revealed sex differences during all phases of drug addiction in animal models of drug self-administration, and these differences typically occurred during transition periods of drug use (e.g., acquisition, controlled to uncontrolled intake, relapse). For example, female rats took less time than male rats to acquire intravenous cocaine, heroin (Lynch and Carroll, 1999), nicotine (Donny et al., 2000), and methamphetamine (Roth and Carroll, 2004) self-administration. During the maintenance of stimulant self-administration, female rats worked harder than males for single injections of cocaine (Roberts et al., 1989) or methamphetamine (Roth and Carroll, 2004), as indicated by higher breakpoints (BP) (maximum behavioral output) under progressive ratio (PR) schedules. Female rats regulated their intake of intravenous cocaine to a lesser extent than male rats (Lynch et al., 2000), and they exhibited greater levels of reinstatement for cocaine self-administration than males following a cocaine-free period (Lynch and Carroll, 2000).

One method that has been used to examine the progression from controlled drug intake to uncontrolled, escalated drug intake in animal models of drug self-administration was to vary the total time the animals had access to drug self-administration each day Ahmed and Koob, 1998, Ahmed and Koob, 1999. Results from studies using this method revealed that animals given extended access (6 h/day) to cocaine self-administration displayed elevated dose–response curves under equal access conditions compared to animals peviously given limited access (1 h/day) Ahmed and Koob, 1998, Ahmed and Koob, 1999. These studies were extended to examine the effects of access conditions on the escalation and reinstatement of heroin self-administration (Ahmed et al., 2000). Rats given long (11 h) versus short (1 h) access to heroin self-administration also displayed an increased escalation in heroin intake, a slower extinction response following the cessation of heroin availability, and an increased reinstatement of heroin self-administration following exposure to stress (Ahmed et al., 2000). Mantsch et al. (2001) also used an extended access procedure to examine individual differences in cocaine self-administration in rats. The authors compared high responders (HR) and low responders (LR) to novelty during several phases of cocaine self-administration (e.g., acquisition, maintenance, escalation) during daily 10-h sessions. Higher levels of responding in HR versus LR rats were found under the extended access (10 h/day) conditions only at low cocaine doses, and they were surmountable by increasing the dose (Mantsch et al., 2001). In contract, recent work by Paterson and Markou (2004) using similar procedures with nicotine did not find escalation in male rats.

A differential access paradigm similar to that used by Ahmed and Koob, 1998, Ahmed and Koob, 1999 was used in the present study to examine sex differences in the escalation of cocaine intake. Male and female rats were given either short access (ShA; 1 h) or long access (LgA; 6 h) to daily cocaine self-administration. Subsequently, daily access conditions were made equal (3 h) for all groups of rats, and dose–response curves for cocaine were obtained and compared across access groups. Males and females were compared to determine if differential access to cocaine self-administration affected the escalation of cocaine and if sex differences existed in the sensitivity to factors that contribute to the escalation of cocaine intake (e.g., extended access conditions).

Section snippets

Animals

Thirty-three sexually mature (>90 days old), female (n=17) and male (n=16) Wistar (Harlan Sprague–Dawley) rats were used as subjects. Female rats weighed approximately 240–400 g, and male rats weighted approximately 340–540 g at the beginning of the experiment. Rats were same-sex pair housed for a minimum of 5 days upon arrival to the laboratory in plastic home cages with ad libitum access to food and water. After the acclimation period, each rat was implanted with a chronic indwelling catheter

Differential access period (Days 1–21)

Fig. 1 illustrates the mean (±S.E.M.) number of cocaine (0.5 mg/kg/infusion) infusions self-administered over the 21-day differential access period for each group of rats. Statistical analysis revealed that there was a significant main effect of sex [F(1,692)=3.56, P<.05] and access condition [F(1,692)=149.01, P<.05], but not day (i.e., 1–21) on number of infusions self-administered across the 21-day differential access period. There were no significant interactions among sex, day, and/or

Discussion

Previous escalation studies have been focused mainly upon male rats. In this study, we extended the escalation paradigm to female rats. In general, under equal access conditions, rats that had previously been allowed LgA to cocaine self-administration displayed dose–response curves that were shifted vertically upward relative to the ShA rats. However, female rats were more sensitive than male rats to the extended access conditions, as indicated by a significant increase in the number of cocaine

Acknowledgements

The authors are grateful to Dr. Kelly P. Cosgrove, Erin B. Larson, Andrew D. Morgan, and Jennifer Perry for critically reviewing the manuscript. We are also grateful to Annemarie Loth for her technical assistance in collecting data for this study. This study was supported by NIDA grants K05 DA15267 and R01 DA03240 (M.E.C.) and F31 DA14161 and T32 DA07097 (M.E.R.).

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