RESEARCH ARTICLE Jordi Bove´ Æ Jordi Serrats Æ Guadalupe Mengod Roser Corte´s Æ Eduardo Tolosa Æ Concepcio´ Marin Neuroprotection induced by the adenosine A 2A antagonist CSC in the 6-OHDA rat model of parkinsonism: effect on the activity of striatal output pathways Received: 12 November 2004 / Accepted: 2 February 2005 / Published online: 21 June 2005 Ó Springer-Verlag 2005 Abstract In Parkinson’s disease (PD), the striatal dopamine depletion and the following overactivation of the indirect pathway of the basal ganglia leads to very early disinhibition of the subthalamic nucleus (STN) that may contribute to the progression of PD by gluta- matergic overstimulation of the dopaminergic neurons in the substantia nigra. Adenosine A 2A antagonism has been demonstrated to attenuate the overactivity of the striatopallidal pathway. To investigate whether neuro- protection exerted by the A 2A antagonist 8-(3-chloro- styryl)caffeine (CSC) correlates with a diminution of the striatopallidal pathway activity, we have examined the changes in the mRNA encoding for enkephalin, dynor- phin, and adenosine A 2A receptors by in situ hybrid- ization induced by subacute systemic pretreatment with CSC in rats with striatal 6-hydroxydopamine(6-OHDA) administration. Animals received CSC for 7 days until 30 min before 6-OHDA intrastriatal administration. Vehicle-treated group received a solution of dimethyl sulfoxide. CSC pretreatment partially attenuated the decrease in nigral tyrosine hydroxylase immunoreactiv- ity induced by 6-OHDA, whereas no modification of the increase in preproenkephalin mRNA expression in the dorsolateral striatum was observed. The neuroprotective effect of the adenosine A 2A antagonist CSC in striatal 6- OHDA-lesioned rats does not result from a normaliza- tion of the increase in striatal PPE mRNA expression in the DL striatum, suggesting that other different mech- anisms may be involved. Keywords Parkinson Æ Adenosine A 2A receptors Æ Enkephalin Æ Dynorphin Introduction Parkinson’s disease (PD) is a neurodegenerative disorder that progresses over years affecting prominently the dopaminergic neurons of the substantia nigra pars compacta (SNc). Indeed, most of the disabling motor symptoms of PD are due to this neuronal loss and the concomitant dramatic reduction of the dopamine con- tent in the striatum. Although several dopaminomimetic drugs are useful in relieving motor symptoms, none of them clearly diminishes or prevents the progression of the disease. Recently, adenosine A 2A receptor antagonists have appeared to have an anti-parkinsonian effect in several experimental models of PD (Kanda et al. 1998, 2000; Grondin et al. 1999; Koga et al. 2000; Pinna et al. 2001), and to reverse levodopa-induced motor fluctuations (Bove´ et al. 2002). Adenosine A 2A receptors are mainly expressed in the striatum (Jarvis and Williams 1989; Ongini and Fredholm 1996; Moreau and Huber 1999; Svenningsson et al. 1999; Kaelin-Lang et al. 2000; El Yacoubi et al. 2001) and colocalized with preproen- kephalin mRNA (Schiffmann et al. 1991; Augood and Emson 1994; Augood 1999) and dopamine (DA) D-2 receptor mRNA (Fink et al. 1992; Pollack et al. 1993; Johansson et al. 1997) in the striatopallidal medium spiny neurons that constitute the so-called indirect pathway of the basal ganglia. In PD (Miller and DeLong 1987; Bergman et al. 1990) and in experimental models (Mitchell et al. 1989; DeLong 1990), it has been dem- onstrated that this output pathway is overactive. This J. Bove´ Æ E. Tolosa Æ C. Marin (&) Laboratori de Neurologia Experimental, A ´ rea de Neurocie`ncies, Fundacio´ Clinic-Hospital Clı´nic, Institut d’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), Villarroel 170, 08036 Barcelona, Spain E-mail: cmarin@clinic.ub.es Tel.: +34-93-2275400 Fax: +34-93-4515272 J. Serrats Æ G. Mengod Æ R. Corte´s Departament de Neuroquı´mica, Institut d’Investigacions Biome`diques de Barcelona, CSIC-IDIBAPS Barcelona, Spain Exp Brain Res (2005) 165: 362–374 DOI 10.1007/s00221-005-2302-1