Histamine H3 receptor agonists reduce L‐dopa–induced chorea, but not dystonia, in the MPTP‐lesioned nonhuman primate model of Parkinson's disease

Abstract

L-dopa-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease. The neural mechanisms underlying LID are thought to involve overactivity of striatal glutamatergic neurotransmission, with resultant underactivation of the output regions of the basal ganglia. Histamine H3 heteroreceptors can reduce glutamate and gamma-aminobutyric acid (GABA) transmission in the striatum and substantia nigra reticulata, respectively. Thus, we tested whether the histamine H3 receptor agonists immepip and imetit can alleviate LID in the MPTP-lesioned marmoset model of Parkinson's disease. Coadministration of immepip (1 mg/kg) with L-dopa (15 mg/kg) was associated with significantly less total dyskinesia than L-dopa alone. When dyskinesia was separately rated as chorea and dystonia, coadministration of L-dopa with either immepip or imetit (both 10 mg/kg) significantly reduced chorea but had no effect on dystonia. The antidyskinetic actions of the H3 agonists were not accompanied by alteration of the antiparkinsonian actions of L-dopa. However, immepip (10 mg/kg), when administered as monotherapy, significantly increased parkinsonian disability compared to vehicle. Overall, the results obtained in this study suggest that histamine H3 receptors may be involved in the neural mechanisms underlying L-dopa-induced dyskinesia in Parkinson's disease.

The other side of the histamine H3 receptor

“…At present, it is unclear how abundant D1-H3 heterodimers are, or what their functional relevance is (Box 3). Irrespective of the underlying mechanism, however, H3R agonists were found to reduce the L-DOPA-induced dyskinesia and chorea (but not dystonia) in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned marmosets [41].…”

Enhanced histamine H2 excitation of striatal cholinergic interneurons in l-DOPA-induced dyskinesia

“…The highly selective H2 receptor antagonist famotidine, when co-administered with L-DOPA in MPTP-lesioned macaque monkeys, can reduce the severity of peakdose L-DOPA-induced chorea and can prolong the anti-parkinsonian action of L-DOPA (Johnston et al, 2010). However, the mechanism for this effect and potential therapeutic limits are unknown, as H3 agonists that decrease choreic LID can also increase dystonic forms of LID (Gomez-Ramirez et al, 2006).…”

Modulation of behavior by the histaminergic system: Lessons from HDC-, H3R- and H4R-deficient mice

“…Blocking of H 3 R with thioperamide enhanced motor coordination in 6-hydroxydopaminelesioned rats (Nowak et al, 2008). H 3 R agonists, however, were beneficial for the treatment of l-Dopa-induced dyskinesia in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned marmosets, presumably because of an inhibition of glutamatergic and GABAergic neurotransmission in the striatum and substantia nigra, respectively (Gomez-Ramirez et al, 2006). An excellent review on the role of the histaminergic system in neurodegenerative diseases including PD was recently published by Panula and Nuutinen (2013) and the alterations of the neuronal histaminergic system in PD were also discussed by Shan et al (2013).…”