The Interaction of Histamine H3 and Dopamine D1 Receptors on Hyperkinetic Alterations in Animal Models of Parkinson's Disease

Abstract

Parkinson's disease is associated with the loss of more than 40% of dopaminergic neurons in the substantia nigra pars compacta. One of the therapeutic options for restoring striatal dopamine levels is the administration of L-3,4-dihydroxyphenylalanine (L-Dopa). However, Parkinson's disease patients on long-term L-Dopa therapy often experience motor complications, such as dyskinesias. L-Dopa-induced dyskinesias (LIDs) manifest as abnormal involuntary movements and are produced by elevated striatal dopamine levels, which lead to increased activity of the basal ganglia direct striato-nigral pathway. Dopamine D₁ receptors are more than 95% confined to neurons of the direct pathway, where they colocalize with histamine H₃ receptors. There is evidence of functional interactions between D₁ and H₃ receptors, and here we review the consequences of these interactions on LIDs.

Keywords: D1 receptor; GABA; H3 receptor; L-Dopa-induced dyskinesias; Parkinson’s disease; cerebral cortex; dopamine; glutamate; histamine; striatum.

Figure 1

Schematic view of the basal ganglia synaptic circuitry. (A) Normal circuit; (B) parkinsonian circuit; (C) dyskinetic circuit, and (D) circuit with the antidyskinetic effect of the chronic administration of the H₃R agonist immepip. Black lines represent inhibitory neuronal pathways, while red lines represent excitatory projections. The thickness of the lines and the color intensity or lightness indicate the degree of activation of each projection. The grey tone in the external segment of the globus pallidus (GPe; 1B), the substantia nigra pars reticulata (SNr; 1C), the internal segment of the globus pallidus (GPi; 1C), thalamus (1B), and the subthalamic nucleus (STN; 1C) reflect differences in activation compared to other regions shown in black. Dotted pink lines indicate dopaminergic depletion in the substantia nigra pars compacta (SNc). MSN axons project to the SNr and the GPi through a direct pathway and to the GPe, which in turn projects to the STN, forming the indirect pathway that projects to the SNr and GPi. The legends ‘L-Dopa’ and ‘L-Dopa + immepip’ for the striatum in panels C and D indicate the systemic administration of L-Dopa alone or in conjunction with the H₃R agonist immepip, respectively. ¿?, unconfirmed effect. DA, dopamine; HA, histamine; TMN, tuberomammillary nucleus.

Figure 2

Effect of the systemic administration of the H₃R agonist immepip (1 mg/kg, i.p.) on total ALO (axial, limb, and orolingual) abnormal involuntary movements (AIMs) induced by L-Dopa (6.25 mg/kg; benserazide 15 mg/kg, i.p.). ALO AIMs were individually counted and then summed per session. The statistical analysis of total AIMs was conducted with repeated-measures ANOVA followed by Bonferroni’s post hoc test (8 animals per group). &,# p < 0.01, compared to the vehicle group; * p < 0.001, compared to the L-Dopa group.

Figure 3

Schematic representation of L-Dopa-induced intracellular signaling involving the cAMP/protein kinase A (PKA) pathway (A). It is proposed that the co-administration of the H₃R agonist immepip counteracts the effects of L-Dopa and reduces dyskinesias (B).