Chronic administration of the histamine H3 receptor agonist immepip decreases l-Dopa-induced dyskinesias in 6-hydroxydopamine-lesioned rats
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.
Objectives and methods
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.
KeywordsDopamine Histamine D1 receptor H3 receptor Dyskinesia Striatum Parkinson’s disease l-Dopa Immepip
We thank MVZ Hugo Lecona Butrón for the support with housing, care, maintenance, and monitoring of the health of the experimental animals at the Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra. We thank MVZ Javier Pérez Gallaga for the technical support. The authors wish to thank Dr. Ivonne M. Heuze de Icaza for her support with the experimental animals.
Effect of the administration of L-Dopa (6.25 mg/kg) and the co-administration of L-Dopa and the H3R agonist immepip (1 mg/kg) in 6-OHDA-lesioned rats. Note that the administration of immepip reduces LIDs in 6-OHDA-lesioned rats (MP4 38915 kb)
Effects of the chronic administration of immepip+L-Dopa for 14 days, and immepip withdrawal on day 15. Drugs administration was as described for Video 1 (MP4 31326 kb)
- Alfaro-Rodriguez A, Alonso-Spilsbury M, Arch-Tirado E, Gonzalez-Pina R, Arias-Montano J-A, Bueno-Nava A (2013) Histamine H3 receptor activation prevents dopamine D1 receptor-mediated inhibition of dopamine release in the rat striatum: a microdialysis study. Neurosci Lett 552:5–9CrossRefGoogle Scholar
- Bastide MF, Meissner WG, Picconi B, Fasano S, Fernagut PO, Feyder M, Francardo V, Alcacer C, Ding YM, Brambilla R, Fisone G, Stoessl AJ, Bourdenx M, Engeln M, Navailles S, De Deurwaerdere P, Ko WKD, Simola N, Morelli M, Groc L, Rodriguez MC, Gurevich EV, Quik M, Morari M, Mellone M, Gardoni F, Tronci E, Guehl D, Tison F, Crossman AR, Kang UJ, Steece-Collier K, Fox S, Carta M, Cenci MA, Bezard E (2015) Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson’s disease. Prog Neurobiol 132:96–168CrossRefGoogle Scholar
- González-Sepúlveda M, Rosell S, Hoffmann HM, Castillo-Ruiz MM, Mignon V, Moreno-Delgado D, Michel V, Díaz J, Sabriá J, Ortiz J (2013) Cellular distribution of the histamine H3 receptor in the basal ganglia: functional modulation of dopamine and glutamate neurotransmission. Basal Ganglia 3:109–121CrossRefGoogle Scholar
- Moreno E, Hoffmann H, Gonzalez-Sepulveda M, Navarro G, Casado V, Cortes A, Mallol J, Vignes M, McCormick PJ, Canela EI, Lluis C, Moratalla R, Ferre S, Ortiz J, Franco R (2011) Dopamine D-1-histamine H-3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway. J Biol Chem 286:5846–5854CrossRefGoogle Scholar
- Olfert E, Cross B, Mc William A (1993) Guide for the care and use of experimental animals. Can Council Anim Care 1:211Google Scholar
- Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, LondonGoogle Scholar
- Rangel-Barajas C, Silva I, Lopez-Santiago LM, Aceves J, Erlij D, Floran B (2011) L-dopa-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata. Neurobiol Dis 41:51–61CrossRefGoogle Scholar
- Rodriguez-Ruiz M, Moreno E, Moreno-Delgado D, Navarro G, Mallol J, Cortes A, Lluis C, Canela EI, Casado V, McCormick PJ, Franco R (2017) Heteroreceptor complexes formed by dopamine D1, histamine H3, and N-methyl-D-aspartate glutamate receptors as targets to prevent neuronal death in Alzheimer’s disease. Mol Neurobiol 54:4537–4550CrossRefGoogle Scholar