Chronic administration of the histamine H.sub.3 receptor agonist immepip decreases l-Dopa-induced dyskinesias in 6-hydroxydopamine-lesioned rats

Rationale Histamine H.sub.3 receptors (H.sub.3Rs) are co-expressed with dopamine D.sub.1 receptors (D.sub.1Rs) by striato-nigral medium spiny GABAergic neurons, where they functionally antagonize D.sub.1R-mediated responses. Objectives and methods We examined whether the chronic administration of the H.sub.3R agonist immepip modifies dyskinesias induced by l-3,4-dihydroxyphenylalanine, l-Dopa (LIDs), in rats lesioned with 6-hydroxydopamine in the substantia nigra pars compacta, and the effect of D.sub.1R and H.sub.3R co-activation on glutamate and GABA content in dialysates from the dorsal striatum of naïve rats. Results The systemic administration (i.p.) of l-Dopa for 14 days significantly increased axial, limb, and orolingual abnormal involuntary movements (AIMs) compared with the vehicle group. The chronic administration of the H.sub.3R agonist immepip alongside l-Dopa significantly decreased axial, limb, and orolingual AIMs compared with l-Dopa alone, but AIMs returned to previous values on immepip withdrawal. Chronic immepip was ineffective when administered prior to l-Dopa. The chronic administration of immepip significantly decreased GABA and glutamate content in striatal dialysates, whereas the administration of l-Dopa alone increased GABA and glutamate content. Conclusions These results indicate that chronic H.sub.3R activation reduces LIDs, and the effects on striatal GABA and glutamate release provide evidence for a functional interaction between D.sub.1Rs and H.sub.3Rs.