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Chronic H3R activation reduces L-Dopa-induced dyskinesia, normalizes cortical GABA and glutamate levels, and increases striatal dopamine D1R mRNA expression in 6-hydroxydopamine-lesioned male rats

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Abstract

Rationale

Dyskinesias induced by L-3,4-dihydroxyphenylalanine, L-Dopa (LIDs), are the major complication in the pharmacological treatment of Parkinson’s disease. LIDs induce overactivity of the glutamatergic cortico-striatal projections, and drugs that reduce glutamatergic overactivity exert antidyskinetic actions. Chronic administration of immepip, agonist at histamine H3 receptors (H3R), reduces LIDs and diminishes GABA and glutamate content in striatal dialysates (Avila-Luna et al., Psychopharmacology 236: 1937-1948, 2019).

Objectives and methods

In rats unilaterally lesioned with 6-hydroxydopamine in the substantia nigra pars compacta (SNc), we examined whether the chronic administration of immepip and their withdrawal modify LIDs, the effect of L-Dopa on glutamate and GABA content, and mRNA levels of dopamine D1 receptors (D1Rs) and H3Rs in the cerebral cortex and striatum.

Results

The administration of L-Dopa for 21 days induced LIDs. This effect was accompanied by increased GABA and glutamate levels in the cerebral cortex ipsi and contralateral to the lesioned SNc, and immepip administration prevented (GABA) or reduced (glutamate) these actions. In the striatum, GABA content increased in the ipsilateral nucleus, an effect prevented by immepip. L-Dopa administration had no significant effects on striatal glutamate levels. In lesioned and L-Dopa-treated animals, D1R mRNA decreased in the ipsilateral striatum, an effect prevented by immepip administration.

Conclusions

Our results indicate that chronic H3R activation reduces LIDs and the overactivity of glutamatergic cortico-striatal projections, providing further evidence for an interaction between D1Rs and H3Rs in the cortex and striatum under normal and pathological conditions.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

AIMs:

Abnormal involuntary movements

D1Rs:

Dopamine D1 receptors

H3Rs:

Histamine H3 receptors

L-Dopa :

L-3,4-dihydroxyphenylalanine

LIDs:

L-Dopa-induced dyskinesias

MSN:

Medium spiny neurons

SNc:

Substantia nigra pars compacta

SNr:

Substantia nigra pars reticulata

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Acknowledgements

We thank MVZ Hugo Lecona Butrón for support with the housing, care, maintenance, and monitoring of the health of the experimental animals in INR-LGII. We also thank MVZ Javier Pérez Gallaga and Biol. Mónica Guadalupe Santamaria Olmedo for technical support.

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Authors and Affiliations

  1. Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calzada México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México

    Alberto Avila-Luna, Arturo Gálvez-Rosas, Alfonso Alfaro-Rodriguez, Camilo Ríos & Antonio Bueno-Nava

  2. Laboratorio de Neurofisiología Química de la Discapacidad, Coordinación de Neurociencias Básicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calz. México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México

    Alberto Avila-Luna, Arturo Gálvez-Rosas, Alexander Aguirre-Pérez & Antonio Bueno-Nava

  3. Departamento de Medicina Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, SSa, Calzada México-Xochimilco 289, Arenal de Guadalupe, Ciudad de México, 14389, México

    Alberto Hidalgo-Bravo

  4. Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, SSa, Insurgentes Sur 3877, La Fama, Ciudad de México, 14269, México

    Camilo Ríos

  5. Laboratorio de Neurofarmacología Molecular, Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, Calzada del Hueso 1100, Col. Villa Quietud, Ciudad de México, 04960, México

    Camilo Ríos

  6. Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Av. IPN 2508, Zacatenco, Ciudad de México, 07360, México

    José-Antonio Arias-Montaño

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Highlights

• Chronic administration of the H3R agonist immepip decreases L-Dopa-induced dyskinesias

• L-Dopa administration increases cortical GABA and glutamate levels

• Chronic immepip normalizes cortical GABA and glutamate levels

• Chronic H3R activation reduces cortico-striatal glutamatergic overactivity

Supplementary information

ESM 1

Figure S1. Representative chromatograms for glutamate, glutamine, and GABA. Panel A shows standards (10 μM). Panel B shows a striatal sample.

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Avila-Luna, A., Gálvez-Rosas, A., Aguirre-Pérez, A. et al. Chronic H3R activation reduces L-Dopa-induced dyskinesia, normalizes cortical GABA and glutamate levels, and increases striatal dopamine D1R mRNA expression in 6-hydroxydopamine-lesioned male rats. Psychopharmacology 240, 1221–1234 (2023). https://doi.org/10.1007/s00213-023-06339-1

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