Experimental Neurology 2011-11-01

Functional changes in postsynaptic adenosine A(2A) receptors during early stages of a rat model of Huntington disease.

Marco Orrú, Janaina Menezes Zanoveli, César Quiroz, Huu Phuc Nguyen, Xavier Guitart, Sergi Ferré

Index: Exp. Neurol. 232(1) , 76-80, (2011)

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Abstract

Huntington disease (HD) is a neurodegenerative disorder involving preferential loss of striatal GABAergic medium spiny neurons. Adenosine A(2A) receptors (A(2A)Rs) are present in the striatum at both presynaptic and post-synaptic levels. Blocking pre-synaptic A(2A)Rs, localized in glutamatergic terminals that contact striatal GABAergic dynorphinergic neurons, reduces glutamate release, which could be beneficial in HD. On the other hand, blockade of post-synaptic A(2A)Rs, localized in striatal GABAergic enkephalinergic neurons, could exacerbate the motor dysfunction. To evaluate the function of pre- or post-synaptic A(2A)Rs in HD we used selective antagonists for these receptors in a transgenic rat model of HD. Locomotor activity after systemic administration of the postsynaptic A(2A)R antagonist KW-6002 was used to investigate the function of post-synaptic A(2A)Rs. The role of pre-synaptic A(2A)Rs was instead evaluated by measuring the reduction of the electromyographic response of mastication muscles during electrical stimulation of the orofacial motor cortex after the systemic administration of the presynaptic A(2A)R antagonist SCH-442416. The ability of KW-6002 to produce locomotor activation was lost at 6 and 12 month-old of age in heterozygous and homozygous transgenic rats, but not in wild-type littermates. Nevertheless, no significant changes were observed up to 12 months of age in the potency of SCH-442416 to decrease the electromyographic response after cortical electrical stimulation. These results agree with a selective impairment of the striatal GABAergic enkephalinergic neuronal function during pre-symptomatic stages in HD. Since presynaptic A(2A)R function is not impaired, this receptor could probably be used as a target for the symptomatic treatment of the disease.Published by Elsevier Inc.