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Estrous cycle differences in cocaine-induced stereotypic and locomotor behaviors in Fischer rats

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Abstract

This study was conducted to characterize female behavioral response to acute `binge' pattern cocaine administration (15 mg kg−1, i.p., three times a day, at 1 h intervals) during the different stages of the estrous cycle in Fischer rats. Cocaine administration significantly increased stereotypic behavior and locomotion in females. Animals in estrus showed significantly higher cocaine-induced stereotypic and locomotive behavioral responses than those in other stages of the cycle. Plasma levels of the cocaine metabolite benzoylecgonine during metestrus–diestrus were significantly higher than during estrus and proestrus probably reflecting more rapid biotransformation of cocaine. Therefore, it is likely that the hormonal fluctuations associated with the estrous cycle modulate both cocaine metabolism and the behavioral responses to cocaine in female rats. This in turn may have important implications in gender differences in behavioral responses to cocaine.

Introduction

Cocaine, a psychostimulant, is one of the most widely abused drugs in Western countries. Although cocaine has a variety of pharmacological actions, one of its major effects is binding to the dopamine transporter to prevent dopamine re-uptake into presynaptic neurons, thus, increasing synaptic concentrations of dopamine [20], which in turn cause behavioral effects in animals and subjective effects in humans 39, 40. Cocaine produces dramatic psychomotor activity in rats. These responses include increased stereotypic behaviors such as sniffing, repetitive head and forelimb movements, and rearing, as well as increased cocaine-induced locomotor activity.

Although recent progress has been made in understanding the neurobiological basis of cocaine abuse, more extensive studies are needed at the behavioral level in the female, where the understanding of the effects of drug addiction in the CNS are limited. Ovarian hormones affect a variety of reproductive 1, 27, 28, 29and non-reproductive behaviors [32]possibly by their actions in the dopamine and opioid systems 11, 12, 13, 14, 18, 35. These systems have been shown to be an integral part of the cascade of events that may lead to and–or be involved in the effects on the CNS associated with cocaine addiction. These hormones are known to fluctuate during the estrous cycle. Thus, in females, steroids may play an important role in modulating the response to cocaine or other addictive drugs in the CNS. This, in turn, may be a basis for gender differences in the responses to drugs of abuse. In this study we wanted to characterize the behavioral responses of female rats to cocaine during the different stages of the estrous cycle. Elucidating the response to cocaine across the reproductive cycle in female rats may have implications for the prevention and treatment of substance abuse in humans. Furthermore, this study will extend our understanding of possible gender differences in the CNS response to cocaine.

Section snippets

Animals

A total of two cohorts (each with 24 animals) of 8 week old female Fischer rats purchased from Charles River were single-housed in a standard cage placed within an electronic monitor to record locomotor activity [42], in a stress-minimized facility with free access to food and water, and maintained on a 12-h light–dark cycle. Rats were acclimated, with daily handling for ≈5 min, for 10 days before the start of the experiment. Vaginal lavage (30 min after lights on) of each rat for 10

Stereotypic behaviors

Mean stereotypic behavioral scores for each rating after the first and second injections for all cocaine-treated and all saline-treated female rats are shown in Fig. 1A. Across all time points, cocaine-treated animals had a mean stereotypy score of 7±0.1, a score that reflects continuous pivoting and sniffing. The mean cumulative stereotypy scores after the first and second injection for groups of rats in the different stages of the estrous cycle in each treatment condition are shown in Fig. 1

Discussion

Cocaine induction of locomotor activity and stereotypic behaviors has been previously demonstrated in male rats 7, 10, 15, 16, 22, 41, 42, 43, 44. In this study we show that cocaine-treated female rats also had significantly higher levels of stereotypic behaviors and locomotor activity than saline treated control rats. Unterwald et al. [42], reported that in male Fischer rats, treated with the same cocaine administration paradigm for 14 days, cocaine-induced locomotor activity increased after

Acknowledgements

This work was supported by NIH-NIDA P50-DA05130 (M.J.K.), NIH-NIDA K05-DA0049 (M.J.K.), and a fellowship from The Altman Foundation (V.Q.J.) and RR-03037 (V.Q.J.).

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