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Implication of the Endocannabinoid System in the Locomotor Hyperactivity Associated with Congenital Hypothyroidism

Departamento de Bioquímica y Biología Molecular (T.A., M.d.M.A., A.S.), Facultad de Medicina, Departamento de Psicobiología (M.A.G., J.A.L.-M., M.N., F.R.d.F.), Facultad de Psicología, Universidad Complutense de Madrid, 28040 Madrid, Spain; Instituto de Investigaciones Biomédicas (A.P.-C.), Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid, 28049 Madrid, Spain; and Fundación Instituto Mediterráneo para el Avance de la Biomedicina y la Investigación (A.B., F.R.d.F.), Hospital Carlos Haya, 29010 Málaga, Spain

Address all correspondence and requests for reprints to: A. Santos, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense 28040 Madrid, Spain. E-mail: piedras3{at}med.ucm.es; or A. Perez-Castillo, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma, Arturo Duperier 4, 28029 Madrid, Spain. E-mail: aperez{at}iib.uam.es.

Alterations in motor functions are well-characterized features observed in humans and experimental animals subjected to thyroid hormone dysfunctions during development. Here we show that congenitally hypothyroid rats display hyperactivity in the adult life. This phenotype was associated with a decreased content of cannabinoid receptor type 1 (CB₁) mRNA in the striatum and a reduction in the number of binding sites in both striatum and projection areas. These findings suggest that hyperactivity may be the consequence of a thyroid hormone deficiency-induced removal of the endocannabinoid tone, normally acting as a brake for hyperactivity at the basal ganglia. In agreement with the decrease in CB₁ receptor gene expression, a lower cannabinoid response, measured by biochemical, genetic and behavioral parameters, was observed in the hypothyroid animals. Finally, both CB₁ receptor gene expression and the biochemical and behavioral dysfunctions found in the hypothyroid animals were improved after a thyroid hormone replacement treatment. Thus, the present study suggests that impairment in the endocannabinoid system can underlay the hyperactive phenotype associated with hypothyroidism.

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