Symptom-related changes of endocannabinoid and palmitoylethanolamide levels in brain areas of R6/2 mice, a transgenic model of Huntington’s disease Tiziana Bisogno a , Alberto Martire b , Stefania Petrosino a,c , Patrizia Popoli b, * , Vincenzo Di Marzo a, * a Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli (Naples), Italy b Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanita `, Viale Regina Elena 299, 00161 Rome, Italy c Dipartimento di Scienze Farmaceutiche, Universita ` degli Studi di Salerno, Fisciano, Italy Received 29 May 2007; received in revised form 18 June 2007; accepted 28 June 2007 Available online 4 July 2007 Abstract Previous studies have shown an impairment of the endocannabinoid system in experimental models of Huntington’s disease. In transgenic R6/ 2 mice, created by inserting exon 1 of the human IT15 mutant gene into the mouse, and exhibiting 150 CAG repeats as well as signs of HD, a progressive decline of CB 1 receptor expression and an abnormal sensitivity to CB 1 receptor stimulation have been reported. Here, by using isotope-dilution liquid chromatography–mass spectrometry, we investigated whether the levels of three endogenous neuroprotective substances, the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and palmitoylethanolamide (PEA), are altered in different brain areas of transgenic R6/2 versus wild-type (WT) mice at two different disease phases, i.e. in pre-symptomatic (4.5 weeks) or overtly symptomatic (10 weeks) R6/2 mice versus age-matched WT mice (n = 4/group). Except for a 25% decrease in 2-AG levels in the cortex, no significant changes in endocannabinoid and PEA levels were observed in pre-symptomatic R6/2 versus WT mice. By contrast, in symptomatic R6/2 mice the levels of all three compounds were significantly (30–60%) decreased in the striatum, whereas little changes were observed in the hippocampus, and a 28% decrease of 2-AG levels, accompanied by a 50% increase of AEA levels, was found in the cortex. These findings show that endocannabinoid levels change in a disease phase- and region-specific way in the brain of R6/2 mice and indicate that an impaired endocannabinoid system is a hallmark of symptomatic HD, thus suggesting that drugs inhibiting endocannabinoid degradation might be used to treat this disease. # 2007 Elsevier Ltd. All rights reserved. Keywords: Cannabinoid; Anandamide; 2-Arachidonoylglycerol; CB1 receptor; Basal ganglia; Locomotion; Cortex 1. Introduction Huntington’ s disease (HD) is an autosomal neurodegenera- tive disease, inherited dominantly, characterized by motor disturbances, dementia, psychiatric symptoms and early death. HD is caused by a mutation (a CAG trinucleotide expansion) in exon 1 of the IT15 gene coding for huntingtin on chromosome 4 (The Huntington’s Disease Collaborative Research Group, 1993). The expanded CAG repeat is translated into a polyglutamine (poliQ) expansion in the N-terminal region of huntingtin, that is, in this mutant version, very toxic for neurons, especially for GABAergic, medium-sized spiny neurons (MSNs) of the striatum. The pathogenesis of this selective neuronal degeneration is still unclear, even though several animal models (both ‘‘pathogenetic’’ and genetic) are available to study the www.elsevier.com/locate/neuint Neurochemistry International 52 (2008) 307–313 * Corresponding authors. Tel.: +39 081 8675093; fax: +39 081 8041770. E-mail addresses: patrizia.popoli@iss.it (P. Popoli), vdimarzo@icmib.na.cnr.it (V. Di Marzo). 0197-0186/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2007.06.031