Amphetamine triggers an increase in met-enkephalin simultaneously in brain areas and immune cells María A. Assis a,1 , César Collino b,c , María de L. Figuerola d , Claudia Sotomayor b , Liliana M. Cancela a, ⁎ a Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina b Departamento de Bioquímica Clínica, CIBIC-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina c Centro de Química Aplicada, CEQUIMAP, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina d Centro de Investigaciones Endocrinólogicas (CEDIE), CONICET, Hospital de Niños Ricardo Gutiérrez, Gallo 1360, 1425, Buenos Aires, Argentina Received 21 October 2005; received in revised form 16 May 2006; accepted 17 May 2006 Abstract We analyzed effects of amphetamine on proenkephalin-derived peptides in brain areas and immune cells in rats. Acute, as well as a repeated amphetamine treatment, decreased the concanavalin-A-induced lymphocyte proliferation, concomitantly with an increase of free met-enkephalin in nucleus accumbens, prefrontal cortex, spleen, thymus and splenic macrophages. Proenkephalin protein increased in prefrontal cortex, thymus (32 kDa isoform), nucleus accumbens and spleen (44 kDa isoform), while proenkephalin mRNA levels decreased in brain stem. The influence of met-ENK in key brain areas for sensitization and in immune organs is consistent with the idea that changes on met-ENK could underlie amphetamine's effects on brain and IS. © 2006 Elsevier B.V. All rights reserved. Keywords: Psychostimulants; Proenkephaline; Sensitization; T-cell proliferation; Rat 1. Introduction Drug addiction is a devastating illness with deleterious consequences not only on behavior, but also on immune system (IS) functions, rendering the individuals more vulnerable to infectious diseases. It is currently known that drugs of abuse clearly perturb immune functions as do stress, mood and emotion (Woiciechowsky et al., 1999; Pruett, 2001; Galinowski et al., 1992; Baldwing et al., 1998; Padgett and Glaser, 2003). Furthermore, the interchangeability between psychostimulant drugs and stress observed at behavioral level, showing long-lasting changes in dopami- nergic neurons and in the pituitary functions (Diaz-Otañez et al., 1997; Knych and Eisenberg, 1979; Saal et al., 2003), was also found in the IS (Basso et al., 1999). Sensitization is a well known adaptive process which has been associated to the long-lasting behavioral consequences following exposure to psychostimulants (Robinson and Berridge, 2000; Vezina et al., 2002). Several of the changes Journal of Neuroimmunology 178 (2006) 62 – 75 www.elsevier.com/locate/jneuroim Abbreviations: IS, immune system; DA, dopamine; NAc, nucleus accumbens; PfC, prefrontal cortex; ENK, enkephalin; AMPH, amphet- amine; Con A, concanavalin-A; VEH, vehicle; ZT, zeitgeber; RIA, radioimmunoassay; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; FITC, fluorescein isothiocyanate; MoAb, monoclonal antibody; PE, R- phycoerythrin; CREB, cAMP-response element binding protein; AP-1, activator protein-1. ⁎ Corresponding author. Tel.: +54 351 4344974x161; fax: +54 351 4334420. E-mail address: lcancela@fcq.unc.edu.ar (L.M. Cancela). 1 Fellowship from CONICET. 0165-5728/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2006.05.009