Paradoxical effects of d-amphetamine in infant and adolescent mice: role of gender and environmental risk factors

Abstract

The psychostimulant d-amphetamine (AMPH) increases generalised activity in adult subjects, while exerting a paradoxical “calming effect” in children with Attention-deficit Hyperactivity Disorder (AD/HD). A number of animal models have been developed to characterise the neurobiological basis of this AMPH action. In this line, the present review summarises recent work on the effects of AMPH on behavioural and physiological parameters in developing mice with a special emphasis on the role of gender and environmental risk factors. Behavioural and neuroendocrine responses to AMPH administration (0, 1, or 3 mg/kg, IP) and their relation to changes in the environment, represented by social stimuli, were studied in infant CD-1 mouse pups of both sexes at three different developmental ages (3, 8, or 18 postnatal (pnd) days). Mouse pups were assessed either in baseline condition or following 24 h maternal deprivation. AMPH exerted a paradoxical effect on CORT secretion only in maternally deprived subjects while affecting behaviour mainly in deprived female subjects, which showed a generalised shift to the left in the dose-response curve to this drug. Unwanted perseverative motor effects and possible dependence states represent side effects of AMPH administration. Further knowledge on these aspects comes from another set of studies where a shortened conditioned place preference (CPP) paradigm was employed to assess the reinforcing properties of AMPH (0, 1, 3.3, or 10 mg/kg) in developing mice on 14–17, 21–24, and 28–31 pnd. Data indicate that AMPH-CPP develops early, mice being able, already at two weeks of age, to acquire a place preference that relies on adult-like sensory, motor, and associative capacities. AMPH-CPP appears earlier in females, compared to males. A detailed analysis of acute d-amphetamine effects evidenced that the drug produces a dose-dependent increase in locomotor activity and in several responses (including stereotypes). These effects appear much larger at both post weaning stages than in preweanlings and are significantly more pronounced in females than in males. Overall these data suggest that AMPH action is dependent on the baseline level of activity and indicate a strong role of gender in the effects of this drug measured early on during development, with females showing greater sensitivity to this drug. A better understanding of AMPH action during the early ontogenetic phases, particularly its interaction with environmental factors, might extend our knowledge on the neurobiological basis of AD/HD, possibly improving the clinical efficacy of psychostimulant drugs.

Introduction

d-amphetamine (AMPH) is a psychostimulant well known for its ability to increase random, nondirected activity both in animals and in humans. A number of years ago it was reported that, differently from adults, when this drug is administered to preweaning rats, it produces no visible increase in motor activity while enhancing approach and contact behaviours with conspecifics [1]. In humans, a number of studies have detailed the effectiveness of psychostimulants like AMPH in reducing symptoms of inattentiveness and hyperactivity–impulsivity characterising children affected by Attention deficit/Hyperactivity Disorder (AD/HD) [2]. AD/HD is a childhood psychiatric disorder affecting about 1% of the childhood population whose primary symptoms are distractibility, impulsivity and overactivity [3]. A role for dopamine and other monoamine disfunctions in AD/HD has been suspected ever since it was shown that dopamine depletion following ventral–tegmental-area lesions [4] as well as massive dopamine depletion by 6-OHDA in juvenile rats produce hyperactivity that is reversible by AMPH [5], [6]. Neuropsychological, neurophysiological and neuroimaging studies in individuals with AD/HD have attempted to understand the mechanisms of action of psychostimulants. Although much research has been devoted to this problem, the mechanism of action of AMPH remains poorly understood. Neuroimaging studies of children with AD/HD have revealed abnormalities in the anterior frontal cortex and basal ganglia, which are involved in executive function and motor control, respectively [2].

Clinical research has to rely on animal models to summarise and simplify the understanding of a disorder and to perform experiments which would not be possible in children for ethical reasons [2]. It has been argued that the best animal model is one that mimics, although in a simpler form than the full-blown clinical case, the fundamentals of the behavioural characteristics of people with AD/HD [7]. A number of animal models have been developed to study AD/HD: rats reared in social isolation, exposed to environmental pollutants, or genetic models (SHR; Naples High/Low excitability rats) to mention only a few [7], [8], [9], [10]. Most altricial mammals present periods of hyperactivity during ontogenesis when AMPH effects can be tested [11], [12]. Periadolescent rats, for example, have been shown to be hyperactive, engaging in more conspecifics play behaviour than younger or older rats and show age-specific alterations in selective attention or stimulus processing [13]. Because of these peculiarities, periadolescent rats have been proposed as an animal model of AD/HD. In terms of psychopharmacological responsiveness, when compared with younger or older subjects, periadolescent rats exhibit an attenuated responsiveness to AMPH, but are more responsive to the catecholaminergic antagonist haloperidol (for a review, see [13], [14]). This pattern of temporary hyposensitivity might be ascribed to the maturation of autoinhibitory dopamine autoreceptors in mesolimbic brain regions [13]. Andersen and colleagues [15] have also demonstrated dramatic changes in dopamine receptor density during adolescence. Further, they have shown that these differences are gender-specific, with males showing a greater degree of striatal and accumbens overproduction and elimination of D1 receptors. These data may be relevant also for humans as the course of AD/HD peaks during childhood, males being more often diagnosed than females, and wanes with the transition from childhood to adolescence [16], [17], [18].

In this framework, the present review summarises more recent work performed in our laboratory on developing mice. Specifically, we were interested in testing gender effects in the response to AMPH and their possible interaction with environmental challenges, such as maternal deprivation. AMPH administration has been shown to be responsible for locomotor-enhancing effects (including compulsive stereotyped movements) as well as for the production of positive reinforcement effects, thus a paradigm such as the conditioned place preference (CPP) procedure—capable to reveal both these aspects—was also employed. Because previous work had been already carried out in periadolescent rats and mice [14], [19], [20], [21], we chose to test AMPH effects from birth to the time period right before periadolescence using male and female mice.