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

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.