Elsevier

Neuropharmacology

Volume 46, Issue 5, April 2004, Pages 672-687
Neuropharmacology

Sex differences in cocaine-induced behavioral responses, pharmacokinetics, and monoamine levels

https://doi.org/10.1016/j.neuropharm.2003.11.017Get rights and content

Abstract

Female rats display a more robust behavioral response to acute cocaine administration than do male rats. However, a clear understanding of the biological mechanisms underlying these differences remains elusive. The present study investigated whether sexual dimorphisms in cocaine-induced motor behavior might be based on monoaminergic levels and/or cocaine pharmacokinetics. An acute injection of cocaine (5, 15, 20 or 30 mg/kg) or saline was administered to male and female rats, and behavioral activity was monitored for 3 h. Following acute cocaine or saline administration motor behavior varied according to dose and sex; overall, female rats displayed greater rearing counts and stereotypic scores, greater total locomotor counts at 15, 20, and 30 mg/kg of cocaine, and greater ambulatory counts at 20 and 30 mg/kg of cocaine than did male rats. Neurochemical determinations in post-mortem tissue showed that both male and female rats had increases in total dopamine (DA) in the caudate putamen (CPu) 15 min following cocaine administration. Additionally, male rats had a decrease in dihydroxyphenylacetic acid (DOPAC)/DA turnover. Female rats showed significant reductions in total levels of DA, DOPAC, HVA, serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), and DOPAC/DA turnover in the nucleus accumbens (NAc). Male rats displayed a reduction only in DOPAC/DA turnover and increases in 5-HT in the NAc following cocaine administration. Furthermore, sex differences in cocaine metabolism were observed where females had greater brain/blood levels of norcocaine and ecgonine methyl ester while male rats had higher blood levels of benzoylecgonine. These results suggest that sex differences in the behavioral responses to cocaine administration could be explained in part by intrinsic differences in both monoaminergic levels and metabolic processes.

Introduction

Cocaine, a psychoactive alkaloid, has a variety of pharmacological actions; however, its major effects in the central nervous system are mediated through the pre-synaptic inhibition of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) re-uptake. The resulting increase in synaptic concentrations of these monoamines causes heightened locomotor behavior in rodents. It has been postulated that mesocorticolimbic DA projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and nigrostriatal projections to the caudate putamen (CPu) mediate cocaine-induced locomotion and reward/reinforcement (reviewed in Hyman and Malenka, 2001, Spanagel and Weiss, 1999). However, emerging evidence suggests that tonic regulation of DA neurotransmission by serotonergic innervation within this pathway is also critical in mediating certain behavioral effects of cocaine (Bubar et al., 2003, Broderick and Phelix, 1997, Parsons and Justice, 1993).

An extensive body of literature describes sex differences in cocaine’s behavioral and neuroendocrine effects in rat models. For example, female rats are more sensitive to cocaine-induced psychomotor stimulation (i.e. greater locomotor behavior and stereotypy), hypothalamic-pituitary–adrenal axis (HPA) activation, and cocaine’s rewarding effects (Chin et al., 2002, Chang et al., 1999, Sell et al., 2000, Walker et al., 2001a, Walker et al., 2001b, Van Haaren and Meyer, 1991, Russo et al., 2003a). However, mechanisms modulating sex-dependent responses to cocaine remain unclear.

Sex differences in both DA and 5-HT systems exist (reviewed in Becker, 1999, Klink et al., 2002). For example, in the NAc, female rats have lower D1 DA receptor levels while in the CPu, female rats have greater striatal DA release and re-uptake than male rats (Andersen and Teicher, 2000, Walker et al., 2000, Becker and Ramirez, 1981). Moreover, female rats have higher basal levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in the NAc and CPu (Carlsson and Carlsson, 1987). It has recently been shown that there are differences in firing rates of 5-HT neurons in the dorsal raphe nucleus where male rats have higher spontaneous firing rates and lower GABAergic tonic inhibition of 5-HT firing than those of female rats (Klink et al., 2002). Additionally, female rats also have lower levels of 5-HT2A receptor mRNA in the hypothalamus and greater levels in the hippocampus (Zhang et al., 1999). To date, few studies have addressed the DA/5-HT systems as potential mediators of sex differences in cocaine’s behavioral effects. Therefore, elucidating where intrinsic/drug-induced sex differences in DA/5-HT tone reside, may provide a clearer understanding of sex differences in vulnerability to using and subsequently abusing cocaine.

Alternatively, sex differences in cocaine pharmacodynamics may also impact behavioral activity. Bowman et al. (1999) reported that although there were no sex differences in brain and blood levels of cocaine, brain and blood levels of ecgonine methyl ester (EME) were higher in female rats while male rats had higher blood benzoyleconine (BE) levels. However, these observations have not been consistently reproduced. For example, Van Haarren et al. (1997) reported that sex differences were not detected in serum BE levels after acute or chronic cocaine administration while our group demonstrated that female rats have higher serum BE levels than do male rats after acute cocaine administration (Chin et al., 2001). Moreover, no studies have addressed whether there are sex differences in the production of norcocaine, an active cocaine metabolite that binds to the monoamine transporters (Einhorn et al., 1988). As a result of the conflicting reports on cocaine metabolism, and the lack of norcocaine data, a more complete analysis of sex differences is necessary to determine if dissimilarities in motor activity are affected by bioactive metabolites. This study aims to determine the impact of sex on baseline and cocaine-induced monoaminergic levels as well as pharmacokinetic differences and their contribution to sex differences in cocaine-stimulated behaviors. A systematic study concerning these aspects of cocaine-mediated responses would provide a better understanding of possible mechanisms that contribute to sex differences in cocaine abuse.

Section snippets

Animals and housing

Eight-week-old male and female Fischer rats purchased from Charles River (Kingston, NY) were individually housed in a noise minimized facility for one week prior to experimental manipulations in standard plastic cages (20×20×41 cm3) layered with beta chips. Rats had free access to standard lab chow and water ad libitum. Rats were maintained on a 12-h light/dark cycle with lights on at 9:00 a.m. On the days of testing, only the experimenter had access to the animal room. Three separate cohorts

Effects of dose on sex differences in the behavioral response to cocaine

In both male and female rats, a main effect of cocaine dose was observed where cocaine increased all behavioral activity measured [Total counts: Males: F(4,33)=3.12, p=0.0277; Females: F(4,35)=11.55, p=0.0001; Ambulatory counts: Males: F(4,33)=3.54, p=0.0164; Females: F(4,35)=8.75, p=0.0001; Rearing counts: Males: F(4,33)=9.26, p=0.0001; Females: F(4,35)=13.53, p=0.0001; Fig. 1, Fig. 2, Fig. 3, respectively]. However, cocaine’s dose-dependent effects varied according to the rat’s sex and

Discussion

The current study demonstrates robust sex differences in cocaine-induced behavioral activities, cocaine pharmacokinetics, and monoamine content in the CPu/NAc. The general pattern of behavioral responses observed in the current study is consistent with previous results demonstrating a dose-dependent augmentation of total locomotor and ambulatory behavioral responses in female rats after acute cocaine administration when compared to male rats (Chin et al., 2001, Sell et al., 2000, Van Haaren and

Acknowledgements

The authors would like to thank Mohammed Kraish for his technical assistance. This work was supported by PS-CUNY, RCMI RR-03037, SCORE 506-GM60654, NIDA DA12136, SNRP NS-41073 (to V.Q.J.); NIDA contract N01 DA-6-7052 (to R.F.).

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