Gonadal steroids mediate the opposite changes in cocaine-induced locomotion across adolescence in male and female rats

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Abstract

Evidence from both human studies and animal models indicates that cocaine elicits more behavioral stimulation in females than males. The present study sought to determine whether sex-specific responses to cocaine emerge during adolescence and to determine if gonadal steroid action during puberty affects adult responsiveness to cocaine. We administered cocaine using an escalating dose model in male and female rats at ages postnatal (PN) 28, 42, and 65 days. To assess the effects of pubertal gonadal steroid action, we compared the effects of binge cocaine administration on intact and prepubertally gonadectomized male and female rats in adulthood. Cocaine responses changed in opposite directions in males and females as they progressed through adolescence. At most doses, adolescent males were more responsive than adult males whereas adult females were more responsive than adolescent females. Ambulatory activity was age-dependent in males whereas non-ambulatory activity was age-dependent in females. Prepubertal gonadectomy increased behavioral responsiveness to the highest dose of cocaine in males whereas it decreased behavioral responsiveness to lower doses of cocaine in females. We conclude that sex differences in behavioral responses to cocaine arise during adolescence from a concurrent decrease in male responsiveness and increase in female responsiveness. Our results suggest that gonadal steroids exert lasting and opposing effects on the sensitivity of males and females to psychostimulants during development.

Introduction

Females demonstrate unique vulnerabilities to cocaine when compared to males (McCance-Katz et al., 1999, Robbins et al., 1999). Although more men than women are current users (SAMHSA, 2005), women prefer more highly addictive routes of administration such as smoking or intravenous injections rather than intranasal use (McCance-Katz et al., 1999). Women report greater substance-dependence associated symptoms (Chen and Kandel, 2002), higher anxiety following cocaine use (Kosten et al., 1996) and increased cue-induced craving compared to men (Robbins et al., 1999). Animal models of addiction have provided evidence that these differences reflect in part biological differences. Adult female rats consistently show greater behavioral responses to cocaine or amphetamine than adult males (Becker et al., 1982, Camp et al., 1986, Camp and Robinson, 1988, Chin et al., 2002, Glick et al., 1983, Schneider and Norton, 1979, Sell et al., 2000, Van Haaren and Meyer, 1991, Walker et al., 2001). Female rats may also initiate cocaine self-administration more rapidly and achieve higher break point values than males when provided with equal access to drug (Carroll et al., 2002) although contradictory results also exist (Caine et al., 2004; reviewed in Roth et al., 2004). Sex differences in dopaminergic function have been identified and likely contribute to these effects (Walker et al., 2000, Walker et al., 2006).

Numerous reports suggest that gonadal hormones modulate behavioral responsiveness to cocaine. Cocaine-induced locomotor activity varies across the estrus cycle of female rats: cocaine responses are blunted during diestrus compared to the proestrus and estrus phases (Quiñones-Jenab et al., 1999, Sell et al., 2000, Walker et al., 2002). Ovariectomy decreases female responsiveness to cocaine (Chin et al., 2002, Walker et al., 2001). Castration may slightly increase stimulant-induced behavioral responsiveness in males although specific results have been inconsistent and highly mixed (Chin et al., 2002, Dluzen et al., 1986, Hu and Becker, 2003, Savageau and Beatty, 1981, Van Luijtelaar et al., 1996, Walker et al., 2001).

The studies cited above that were conducted in animals gonadectomized as adults provide valuable information about activational hormonal effects. However, they cannot demonstrate if gonadal hormones influence cocaine responsiveness through organizational effects at specific windows during development. Two studies in females show that either prepubertal ovariectomy or androgen treatment at birth both lower locomotor responses to amphetamine during adulthood (Forgie and Stewart, 1993, Forgie and Stewart, 1994). However, in females, it is difficult to discriminate between the contributions of activational and organizational effects from these studies, as estradiol has such a marked effect on locomotor responses to amphetamine (Becker, 1999, Becker and Beer, 1986). Furthermore, similar studies have not been conducted in males. Organizational effects of gonadal steroids throughout adolescence may contribute significantly to the sex differences in stimulant responsiveness observed in adulthood but these have not been compared in males and females.

Organizational effects during puberty may be particularly relevant to addiction as adolescence has been identified as a critical period for drug abuse (Chambers et al., 2003, Laviola et al., 1999, Spear, 2000). The onset of drug taking behavior typically occurs during adolescence (Chambers et al., 2003, Spear, 2000). Adolescents may also progress from first substance use to dependence faster than adults (Clark et al., 1998). In animal models, subtle differences in dosing, drug administration paradigms and methods of data collection have made it difficult to ascertain how adolescents respond to stimulants in comparison to adults. Several studies suggest that adolescents may respond more (Caster et al., 2005, Catlow and Kirstein, 2005) or less (Lanier and Isaacson, 1977, Laviola et al., 1995) than adults to acute stimulant treatment. Additionally, It is unclear whether the sex differences seen in adulthood result from a developmental increase in female responsiveness, a decrease in male responsiveness or a combination of the two.

The present study characterized the emergence of sex differences in cocaine-stimulated behavioral responsiveness across adolescence by treating PN 28, 42, and 65 male and female rats with a progressively increasing dose regimen of cocaine during a single session to simulate a binge pattern of drug taking. We have previously observed robust age-related differences in males using this paradigm (Caster et al., 2005). Differences in behavioral responses were determined by an analysis of automated open-field horizontal activity and a trained observer recorded stereotyped behaviors. To assess the role of gonadal hormones in this process, sham-operated and prepubertally gonadectomized animals were subjected to the same binge cocaine paradigm after reaching adulthood. We hypothesized that the behavioral response to cocaine would decrease across adolescence in males but increase in females and that gonadectomy would exert sex-specific effects by increasing male responsiveness but reducing female responsiveness.

Section snippets

Subjects

Male and female Sprague–Dawley rats were acquired from Charles River Laboratories (Raleigh, NC) and separated into plastic self-ventilated cages by age and sex. Animals were housed in a vivarium with a 12 hour light:dark cycle and given ad libitum access to food and water. For experiment 1, rats PN 28, 42, and 65 were used to correspond to early adolescence, mid adolescence, and adulthood, respectively (Spear, 2000). These animals were shipped and received on PN 21, 35, and 58 and given one

Habituation and novelty-induced behavior

Horizontal activity during habituation to the novel open-field test chamber was resolved as ambulatory and non-ambulatory (fine movements) activity. Fig. 1 shows the behaviors over time and session totals. Consistent with previous reports, females exhibited more exploratory behavior than males during the one hour test session. ANOVA indicated a main effect of sex for ambulations [F(1,63) = 20.0, P < 0.001] and fine movements [F(1,63) = 11.8, P < 0.001] and post-hoc analysis indicated females did more

Discussion

The present study demonstrates that sex differences in cocaine-induced behavioral activation arise during adolescence. Females had greater responses to cocaine in all behavioral measures in adulthood. These differences in cocaine-stimulated behavior in adulthood result from increased activation with age in females and decreased activation with age in males. Additionally, different behavioral profiles changed with age for males and females. While ambulatory activity decreased with age in males,

Acknowledgments

This work was generously supported by NIDA grant #DA09079.

These experiments comply with all applicable United States laws and regulations.

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