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 w ith Attention-deficit Hyperactivity Disorder (AD/HD). A number of animal mo dels 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 f actors. Behavioural and neuroendocrine responses to AMPH administration (0, 1, or 3 mg/kg, IP) and their relation to changes in the environment, repre sented by social stimuli, were studied in infant CD-1 mouse pups of both se xes 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 o nly in maternally deprived subjects while affecting behaviour mainly in dep rived 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. F urther knowledge on these aspects comes from another set of studies where a shortened conditioned place preference (CPP) paradigm was employed to asse ss the reinforcing properties of AMPH (0, 1, 3.3, or 10 mg/kg) in developin g 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 pr eference that relies on adult-like sensory, motor, and associative capaciti es. AMPH-CPP appears earlier in females, compared to males. A detailed anal ysis of acute D-amphetamine effects evidenced that the drug produces a dose -dependent increase in locomotor activity and in several responses (includi ng stereotypes). These effects appear much larger at both post weaning stag es than in preweanlings and are significantly more pronounced in females th an in males. Overall these data suggest that AMPH action is dependent on th e baseline level of activity and indicate a strong role of gender in the ef fects of this drug measured early on during development, with females showi ng greater sensitivity to this drug. A better understanding of AMPH action during the early ontogenetic phases, particularly its interaction with envi ronmental factors, might extend our knowledge on the neurobiological basis of AD/HD, possibly improving the clinical efficacy of psychostimulant drugs . (C) 2000 Elsevier Science Ltd. All rights reserved.