Neuropharmacology 39 (2000) 334–346 www.elsevier.com/locate/neuropharm A unique hormonal and behavioral hyporesponsivity to both forced novelty and d-amphetamine in periadolescent mice Walter Adriani, Giovanni Laviola * Section of Behavioral Pathophysiology, Labor. F.O.S., Istituto Superiore di Sanita `, viale Regina Elena 299, I-00161 Rome, Italy Accepted 26 May 1999 Abstract The identification of critical ontogenetic periods of increased vulnerability to the effects of drugs of abuse could have a great psychobiological and clinical-therapeutical importance. Potential age-related differences in the response of the hypothalamic-pitu- itary-adrenal (HPA) axis to both stress and psychostimulants has been tested here in an animal model of adolescence. Periadolescent (PND 33–43) and Adult (PND60) mice of both sexes were injected with d-amphetamine (AMPH, 0, 2, or 10 mg/kg i.p.) and immediately faced with a mild psychological stress experience, i.e. placement in a novel environment. A detailed time-course analysis of both hormonal and behavioral profiles was performed, with animals being sacrificed for trunk-blood collection at different time-points during the test (before the injection, NT group; 15, 30, or 120 min after the injection). Basal corticosterone (CORT) levels (NT group) were consistently higher in periadolescents than in adults. As a whole, a marked increment of blood CORT levels was found in mice of both ages exposed to forced novelty. However, important age-related differences were also observed, with Saline-injected periadolescents still exhibiting elevated levels of locomotion at the end of the 120-min test session and failing to show the increasing profile of CORT release over the baseline that was typical of adults. Upon an AMPH 2 administration, periadolescents exhibited a much lower profile of locomotor hyperactivity than adults, and also failed to show an increase across the course of the session in CORT release, that was observed in adults. When treated with the high AMPH 10 dose, a marked locomotor hyperactivity was found in periadolescents, which however showed much lower levels of the stereotyped licking and gnawing behavior, that was typical of adults. The present results suggest a unique profile of integrated behavioral and physiological hyporesponsivity in mice during periadolescence. The latter also represents a very useful model for the study of the issue of psychobiological risk factors involved in vulnerability to drugs of abuse in human adolescents.  2000 Elsevier Science Ltd. All rights reserved. Keywords: Adolescence; Forced novelty; Amphetamine; Corticosterone; Mice 1. Introduction According to Zuckerman (1979, 1994), certain human individuals are characterized by a particular behavioral trait, such as a prominent seeking for novel sensations, which are hypothesized to be rewarding. Sensation seek- ers are also often involved in risky and stressful activities that are avoided by others, as well as in illicit drug use (Wills et al., 1994). In an epidemiological review by Arnett (1992), human adolescents are reported to be characterized by elevated levels of novelty seeking when * Corresponding author. Tel.: + 39-06-4990-2105; fax: + 39-06- 4957-821. E-mail address: laviola@iss.it (G. Laviola) 0028-3908/00/$ - see front matter  2000 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(99)00115-X compared with adults. The continuing search for novel stimuli may justify in these subjects the elevated level of restlessness, recklessness, curiosity, and perhaps the first approach towards psychoactive drug use, that appears to be quite common among subjects around this age (Mathias, 1996; Compas et al., 1995). These data lead to the hypothesis that the experience associated with risk and novelty, as well as with psychostimulant drug use, may have a greater incentive potential among ado- lescents than among adult subjects (for discussion, see Adriani et al., 1998). In this framework, a great interest has been recently devoted to the interaction between the brain reward sys- tem, i.e. the mesolimbic dopamine pathways, and the hormonal stress-response system, namely the hypothal- amic-pituitary-adrenal (HPA) axis. Indeed, it has been