Chronic d-amphetamine induces sexually dimorphic effects on locomotion, recognition memory, and brain monoamines

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Abstract

While acute and chronic d-amphetamine (AMPH) treatments produce greater scores for locomotor activity in female rats in comparison with male rats, little is known about AMPH-induced gender differences on cognition. The objectives of the present study were to (1) investigate during a withdrawal period following chronic AMPH treatment whether performance of two memory tasks, object recognition (OR) and object placement (OP) are altered, and (2) determine if an AMPH challenge dose after a withdrawal period amplifies previously reported gender differences in locomotor activity and neurochemistry. Sprague–Dawley male and female adult rats were included in a chronic AMPH treatment (10 injections, 1 every other day; males: 3 mg/kg, females 2.6 mg/kg). Locomotor activity was quantified (acute, chronic, and after a 16-day withdrawal period). Neurotransmitter levels in brain areas were evaluated after an AMPH challenge dose on the 16th withdrawal day. During the withdrawal period, OR (2- and 4-h delays) was impaired in AMPH-treated males but they did not show any impairment in OP; AMPH females also showed impairments in OR (only 4-h delay). AMPH females showed more locomotion after acute and chronic treatment but AMPH-induced hyperactivity was comparable for females and males after a challenge dose. Following a challenge dose of AMPH after a withdrawal period, gender differences in dopaminergic and serotonergic neurotransmission in the striatum were found. These gender differences elicited by AMPH in monoaminergic pathways may be related to sex differences on behavioral components involved in locomotion and OR memory.

Introduction

Sex steroids exert potent influences on the nervous system during critical developmental periods and into adulthood by organizing and reorganizing the neuronal circuitry involved in neuroendocrine and behavioral functions (Matsumoto, 1991). Gender differences have been reported for anatomic or functional characteristics of several neurotransmitter systems including the dopamine system (Becker, 1999). Gender differences in this system may have a major impact on numerous complex brain functions since dopamine pathways are involved in motor control, reward circuits, sexual behavior, affective state, and cognitive tasks Camp and Robinson, 1988, Becker and Beer, 1986, Alexander et al., 1990, Kimura, 1996, Koob et al., 1998. There is also a convergence of neural circuits associated with learning/memory and with those responsible for drug addiction (for review see Nestler, 2001). Drugs of addiction activate the mesolimbic dopamine system, which includes connections between basal ganglia and nucleus accumbens and prefrontal cortex Koob et al., 1998, Alexander et al., 1990. In rodents, the caudate/striatum modulates different types of learning Viaud and White, 1989, Packard et al., 1994. In humans, the caudate is thought to be involved in complex cognitive functioning and a recent study found that in women, but not men, better cognitive performance was associated with higher dopamine availability in the caudate and putamen (Harper Mozley et al., 2001). Prefrontal cortex also represents one of the main brain areas involved in working memory, specifically visual recognition memory (Ennaceur et al., 1997).

In experimental animals, sexual dimorphisms have been reported in the initial response to psychomotor drugs and following repeated drug exposure. Locomotor activity and stereotypical components of behavior are higher in female rats in comparison with male rats following either acute or chronic amphetamine (AMPH) treatments (Camp and Robinson, 1988; for review see Becker, 1999). It has also been reported that female rodents show a variety of different responses to psychostimulants drugs, including increased motivation to self-administration for cocaine and methamphetamine Lynch and Carroll, 1999, Roth et al., 2002 and enhanced sensitivity to conditioned place preference for cocaine (Quinones-Jenab et al., 2001). It is not clear whether these gender differences in psychomotor/reward aspects of behavior also extend to other brain functions and, more importantly, to cognitive functions. The aim of the first part of the paper was to verify AMPH effects and sex differences on locomotion (acute and chronic treatments). We also investigated the functional effects on working memory of this AMPH treatment in female and male rats during a withdrawal period from chronic AMPH treatment. We used the one trial object-recognition (OR) paradigm developed by Ennaceur and Delacour (1988), as well as a modification of this test used to evaluate spatial memory, the Object Placement (OP) test (Ennaceur et al., 1997). These tests assess both exploration and working memory (spatial and nonspatial visual memory) by using delays between the sample trial and the recognition trial. Other authors have reported sex differences in neurochemistry following a withdrawal period (Camp and Robinson, 1988), but there is no data regarding the effect of an AMPH challenge after a withdrawal period. Therefore, we further exposed the rats to an AMPH challenge dose after a 16-day withdrawal period and quantified monoamine levels in brain areas in order to determine whether a challenge dose with AMPH intensifies gender differences in the withdrawal period.

Section snippets

Animals

Intact adult male and female Sprague–Dawley rats (females: 190–200 g, males 240–270 g) were obtained from Harlan, single housed under a 14:10 light/dark cycle (lights on 7:00 a.m.) with water and food ad libitum. Experiments started 2 weeks after arrival.

All animal use followed the NIH Guide for the Care and Use of Laboratory Animals, and the experimental protocol was approved by the Institutional Animal Care and Use Committee at Hunter College of the City University of New York.

Drug treatment

For chronic

Locomotion

The effect of repeated, intermittent AMPH treatment on locomotion is reported in Fig. 2. Locomotion was quantified in control and AMPH-treated rats after the 1st and the 10th injections. Repeated measures ANOVA (sex×treatment×injection #) revealed a significant effect of sex. [F(1,32)=16.32, P<.001]: females had more total counts than males, a treatment effect [F(1,32)=116.86, P<.000001]: AMPH groups had more total counts than control groups, a sex×treatment effect [F(1,32)=6.01, P<.02]:

Discussion

The primary goal of the present study was to investigate if the gender differences in locomotor and stereotypical behavior induced by AMPH administration extend to functional cognitive performance in the OR test (nonspatial visual memory) and OP test (spatial visual memory). These tests are useful to assess both object exploration and working memory using different delay periods between the sample and the recognition trial. These different intertrial delays produce different degrees of

Acknowledgements

This work was supported by funds from MIDARP (R24 DA12136, NIDA), SCORE (SO6 GM60654), and RISE (R25 GM60665) grants. We wish to thank R. Kesraj, A. Lalmansingh, and L. Jacome for helping with behavioral observations. A portion of these results was presented at the 64th Annual Scientific Meeting of the College on Drug Dependence (2002), Quebec City, Canada.

References (37)

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