ORIGINAL INVESTIGATION Repeated amphetamine administration in rats revealed consistency across days and a complete dissociation between locomotor and hypothalamic-pituitary-adrenal axis effects of the drug Humberto Gagliano & Raül Andero & Antonio Armario & Roser Nadal Received: 23 April 2009 / Accepted: 11 September 2009 / Published online: 7 October 2009 # Springer-Verlag 2009 Abstract Rationale Most drugs of abuse stimulate both locomotor activity and the hypothalamic-pituitary-adrenal (HPA) axis, but the relationship between the two responses within the same subjects and their reliabilities has been scarcely studied. Our objectives were to study: (1) the consistency and stability across time of locomotor and HPA activation induced by repeated d-amphetamine (AMPH); (2) the relationship between locomotor and hormonal responses to AMPH; and (3) the relationship between novelty- induced activity and both types of responses to the drug. Methods Male adult rats were exposed to a novel environ- ment to study the locomotor response. Later, they were injected with AMPH (2 mg/kg, sc) for 5 days. In Experiment 1, Plasma adrenocorticotropin (ACTH) and corticosterone levels in response to AMPH were studied on days 1, 3, and 5, and locomotor response on days 2 and 4. In Experiment 2, ACTH and corticosterone responses were studied on days 2 and 4, and locomotor response on days 1, 3, and 5. Results Across days, both locomotor and HPA responses to the drug were consistent, but independent measures, unrelated to the reactivity to novelty. As measured by the area under the curve, the HPA response to AMPH desensitized with the repeated injection, whereas the initial locomotor response to the drug increased. Conclusions Dissociation exists between HPA and loco- motor activation induced by AMPH, which seemed to be both reliable individual traits. Locomotor reactivity to novelty was related neither to HPA nor to locomotor responses to AMPH. Keywords ACTH . Corticosterone . Locomotor activity . Individual differences . Consistency . Novelty-seeking . Stress Introduction Exposure to addictive drugs exerts dramatic behavioral and physiological changes in organisms. Although most attention has been focused on motivational effects of drugs as revealed by conditioned place preference and self-administration paradigms, drug-induced activation of the hypothalamic- pituitary-adrenal (HPA) axis and locomotor activity have also been extensively studied. Regardless of their nature and particular neurochemical effects, virtually, all drugs of abuse are able to activate the HPA axis, the prototypical response to stress, and are therefore considered as stressor-like agents. In response to all kind of stressors, it is assumed that signals generated in different brain regions always converge into the paraventricular nucleus of the hypothalamus (PVN) to activate the release of corticotrophin-releasing factor (CRF) and other secretagogues to the pituitary portal blood of the median eminence (Armario H. Gagliano : R. Andero : A. Armario : R. Nadal Institute of Neurosciences, Autonomous University of Barcelona, Bellaterra, Barcelona 08193, Spain H. Gagliano : R. Andero : A. Armario Animal Physiology (School of Biosciences), Autonomous University of Barcelona, Bellaterra, Barcelona 08193, Spain R. Nadal (*) Psychobiology (School of Psychology), Bellaterra, Barcelona 08193, Spain e-mail: roser.nadal@uab.es Psychopharmacology (2009) 207:447–459 DOI 10.1007/s00213-009-1676-3