ENVIRONMENTAL CONTEXT AND DRUG HISTORY MODULATE AMPHETAMINE-INDUCED C-FOS mRNA EXPRESSION IN THE BASAL GANGLIA, CENTRAL EXTENDED AMYGDALA, AND ASSOCIATED LIMBIC FOREBRAIN M. M. OSTRANDER, a A. BADIANI, a1 H. E. W. DAY, b2 C. S. NORTON, b S. J. WATSON, b H. AKIL b AND T. E. ROBINSON a * a Biopsychology and Neuroscience Programs, Department of Psychol- ogy, The University of Michigan, 525 East University Avenue, Ann Arbor, MI 48109-1109, USA b Mental Health Research Institute, The University of Michigan, Ann Arbor, MI 48109-1109, USA Abstract—The context in which amphetamine is adminis- tered modulates its ability to induce both behavioral sensiti- zation and immediate early gene expression. When given in a novel test environment amphetamine produces greater levels of c-fos and arc mRNA expression in many brain regions relative to when it is given in the home cage. The purpose of the current study was to determine if environment and drug history interact to influence amphetamine-induced c-fos mRNA expression. Rats with a unilateral 6-hydroxydopamine lesion were treated for 7 days with saline or 0.5 mg/kg of d-amphetamine (i.v.) in a distinct and relatively novel test environment (Novel), or in their home cage (Home). Following a 10 –12-day withdrawal period, a challenge injection of either saline or 0.5 mg/kg d-amphetamine was administered. In situ hybridization histochemistry was used to examine c-fos mRNA expression in several regions of the basal ganglia, the central extended amygdala, and limbic forebrain. In most brain regions amphetamine given in the Novel environment produced greater c-fos mRNA expression than when given it was given at Home, and drug history had no effect on am- phetamine-induced c-fos mRNA expression. However, within the subthalamic nucleus, substantia nigra reticulata, and central nucleus of the amygdala prior experience with am- phetamine in the Novel but not Home environment enhanced the effect of an amphetamine challenge injection on c-fos mRNA expression. In contrast, there was a decrease in c-fos mRNA expression in amphetamine-pretreated animals, re- gardless of environmental context, in the ventral portion of the far caudal striatum. Reexposure to an environment pre- viously paired with amphetamine produced a conditioned increase in c-fos mRNA expression in portions of the cau- date-putamen, the subthalamic nucleus, the nucleus accum- bens shell and a conditioned decrease in c-fos mRNA expres- sion in the central nucleus of the amygdala. We conclude that environmental context and drug history interact to alter the basal ganglia and central extended amygdala circuitry en- gaged by subsequent exposure to amphetamine, or exposure to an environment previously paired with amphetamine. © 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved. Key words: psychostimulants, novelty, immediate early genes, sensitization, conditioning. The repeated and intermittent administration of psycho- stimulant drugs, such as amphetamine and cocaine, re- sults in a progressive and persistent increase (sensitiza- tion) in both their psychomotor activating and incentive motivational effects. The neural adaptations that underlie sensitization are thought to be important in the develop- ment of both stimulant psychosis and addiction, and there- fore, factors that promote or retard the development of behavioral sensitization are of interest (Robinson and Becker, 1986; Robinson and Berridge, 1993). We have found that both the acute psychomotor activating effects of these drugs, and their ability to induce psychomotor sen- sitization, are modulated by the context in which they are given (Badiani et al., 1995a,b; Crombag et al., 1996; Rob- inson et al., 1998). For example, when given in a distinct (Novel) test environment amphetamine and cocaine pro- duce greater psychomotor sensitization than when they are given in the home cage (Home), even when the Home is physically identical to the Novel test cage (Badiani et al., 1995a,b; Crombag et al., 1996). In exploring the neurobiological mechanisms by which context modulates drug effects we found that amphet- amine produces a more robust increase in the expression of immediate early genes (IEGs), such as c-fos or arc, when it is administered in a Novel environment than when it is administered at Home (Badiani et al., 1998; Day et al., 2001; Uslaner et al., 2001a,b; Klebaur et al., 2002). In the 1 Present address: Department of Human Physiology and Pharmacol- ogy, University of Rome “La Sapienza,” Rome, Italy. 2 Present address: Psychology Department, University of Colorado, Boulder, CO, USA. *Corresponding author. Tel: +1-734-763-4361; fax: +1-734-763- 7480. E-mail address: ter@umich.edu (T. E. Robinson). Abbreviations: BLA/LA, basolateral/lateral nuclei of the amygdala; BSTov, bed nucleus of the stria terminalis, oval nucleus; CeA, central nucleus of the amygdala; Cg1, cingulate division of medial prefrontal cortex; CPu, caudate-putamen; DA, dopamine; DL, dorsolateral; DM, dorsomedial; DYN, dynorphin; DYN-pos, dopamine D1 receptors; ENK, enkephalin; ENK-pos, dopamine D2 receptors; F g , F-value for the group factor; F i , F-value for grouprostrocaudal gradient interaction; F r , F-value for the rostrocaudal gradient factor; Fras, Fos-related antigens; Home, home cage; HPA, hypothalamic–pituitary–adrenal; IEG, immediate early gene; IL, infra- limbic division of medial prefrontal cortex; LHb, lateral habenula; NACo, nucleus accumbens core; NASh, nucleus accumbens shell; Novel, distinct test environment; 6-OHDA, 6-hydroxydopamine; PrL, prelimbic division of medial prefrontal cortex; PVN, paraventricular nucleus of the hypothalamus; PVTh, paraventricular nucleus of the thalamus; SNr, substantia nigra reticulata; STN, subthalamic nucleus; VL, ventrolateral; VM, ventromedial; VTA, ventral tegmental area. Neuroscience 120 (2003) 551–571 0306-4522/03$30.00+0.00 © 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved. doi:10.1016/S0306-4522(03)00247-1 551