Histamine H₃ receptors (H₃Rs) are co-expressed with dopamine D₁ receptors (D₁Rs) by striato-nigral medium spiny GABAergic neurons, where they functionally antagonize D₁R-mediated responses.

We examined whether the chronic administration of the H₃R 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 D₁R and H₃R co-activation on glutamate and GABA content in dialysates from the dorsal striatum of naïve rats.

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 H₃R 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.

These results indicate that chronic H₃R activation reduces LIDs, and the effects on striatal GABA and glutamate release provide evidence for a functional interaction between D₁Rs and H₃Rs.