Elsevier

Behavioural Brain Research

Volume 154, Issue 2, 5 October 2004, Pages 409-415
Behavioural Brain Research

Research report
Intranigral injection of the H3 agonist immepip and systemic apomorphine elicit ipsilateral turning behaviour in naive rats, but reduce contralateral turning in hemiparkinsonian rats

https://doi.org/10.1016/j.bbr.2004.03.007Get rights and content

Abstract

There is evidence that histamine H3 receptors co-localise with dopamine D1 receptors on the terminals of striato-nigral neurones. In this work we studied the effect of the local activation of H3 receptors present in substantia nigra pars reticulata (SNr) on turning behaviour following apomorphine administration to either naive or hemiparkinsonian rats. In naive rats the intranigral (SNr) injection of the H3 receptor agonist immepip (3.2 or 32 ng/1 μl) resulted in ipsilateral turning following systemic apomorphine (0.5 mg/kg, subcutaneous). The effect of immepip was related to the dose and prevented by the H3 antagonist thioperamide (5 mg/kg, intraperitoneal). Conversely, in rats with 6-hydroxydopamine (6-OHDA) lesions to either substantia nigra pars compacta or the medial forebrain bundle (mfb), apomorphine-induced contralateral turning was reduced by intranigral immepip, an effect prevented by systemic thioperamide. Our data show that H3 receptors present in SNr regulate the synaptic output of the basal ganglia, most likely by reducing GABA release from striato-nigral terminals. These results may be relevant for the understanding of the role of histamine and H3 receptors in the control of motor behaviour both in normal and pathophysiological conditions, such as Parkinson’s disease in which histaminergic innervation and histamine levels in substantia nigra have been shown to increase.

Introduction

In the mammalian central nervous system, histamine regulates a variety of central functions, such as wakefulness, feeding, drinking, the neuroendocrine system, body temperature, analgesia and motor activity. Histamine actions are mediated by G protein-coupled receptors, four such receptors (H1–H4) have been cloned, and three of them (H1–H3) are widely distributed in the brain [6], [14], [15]. The H3 receptor was discovered originally as an autoreceptor regulating the release and synthesis of histamine, but current knowledge indicates that it is also involved in the presynaptic regulation of the release of acetylcholine, dopamine, noradrenaline, serotonine [15], glutamate [6], [20] and GABA [4], [11].

High densities of H3 receptors are present in the substantia nigra pars reticulata (SNr) and the striatum [3], [22], nuclei that belong to the basal ganglia, a major neuronal system intimately involved in motor behaviour [12]. The striatum is the major nucleus of the basal ganglia in that it is the target of inputs from most areas of the cortex and provides output to the other components of the system. GABAergic projection neurones make up over 90% of all the neurones in the striatum and can be divided into two principal populations on the basis of additional neurotransmitters and by the areas to which they project. Thus, one such population contents substance P and dynorphin and project mainly to the SNr, whereas a second population co-releases enkephalin and project to the globus pallidus. Dopamine D1 receptors appear to be associated largely with the former and D2 receptors with the latter [12], [32]. The vast majority of striatal neurones express the H3 receptor mRNA [23], and there is evidence that striato-nigral GABAergic projection neurones co-express D1 and H3 receptors [25]. This co-localisation extends to striato-nigral terminals and intrastriatal collaterals, and a functional interaction between presynaptic D1 and H3 receptors has been shown in slices from rat striatum and SNr where H3 receptor activation markedly and selectively inhibits the component of depolarisation-induced [3H]-GABA release dependent on concomitant D1 receptor stimulation [4], [11].

Intracerebroventricular histamine induces hypoactivity, reversed by the H3 antagonist thioperamide [8] and thioperamide itself increases locomotor activity in mast cell-deficient W/Wv mice [27], suggesting the involvement of the histaminergic system in the control of movement. Since the importance of the permissive role of dopamine D1 receptors in the so-called ‘direct’ (striato-nigral) pathway through the basal ganglia is well documented [12], [13], the supposition would be that the activation of histamine H3 receptors present on the striato-nigral terminals should reduce the activity of the direct pathway by diminishing GABA release. In this work we therefore set out to study the effect of local activation of SNr H3 receptors on turning behaviour, known to be originated by an imbalance of the basal ganglia synaptic output between the brain hemisphere.

Section snippets

Animals

Wistar male rats (bred in Cinvestav facilities) were maintained under thermoregulated (22±2 °C) and light-controlled conditions (light on between 6:00 and18:00 h), with food and water ad libitum. All procedures used in this study were reviewed and approved by the Cinvestav Animal Care Committee. All efforts were made to minimise animal suffering and to use only as many animals were required for proper statistical analysis.

6-Hydroxydopamine (6-OHDA) lesions

For unilateral lesions of the left substantia nigra pars compacta (SNc)

Effect of intranigral immepip on turning behaviour in naive rats treated with apomorphine

The administration of apomorphine (0.5 mg/kg, i.p.) to naive rats resulted in increased ambulatory activity (not quantified), but not turning behaviour. The injection of isotonic saline (1 μl) into the SNr followed by systemic apomorphine lead to minimal and non-significant turning behaviour (3±1 turns in 90 min, mean±S.E.M., n=8 animals). In contrast, the intranigral administration of the H3 agonist immepip-induced turning behaviour, ipsilateral to the cannulated side and significantly different

Discussion

We report herein that intranigral administration of the H3 agonist immepip induces ipsilateral turning in naive rats previously treated with systemic apomorphine. Conversely, in rats with 6-OHDA lesion to either substantia nigra pars compacta or medial forebrain bundle, intranigral immepip reduced apomorphine-induced contralateral turning. Both effects could be explained by a H3 receptor-mediated reduction in GABA release from striato-nigral terminals, in accordance with the action shown for

Acknowledgements

Supported by Cinvestav and Conacyt (grant 37345N to J.-A.A.-M.). We thank A. Nuñez and J.J. Sierra for their skilful technical assistance.

References (32)

Cited by (28)

  • Pharmacological antagonism of histamine H2R ameliorated L-DOPA–induced dyskinesia via normalization of GRK3 and by suppressing FosB and ERK in PD

    2019, Neurobiology of Aging
    Citation Excerpt :

    The value of p < 0.05 was considered statistically significant. Dysregulation of HA in PD has been suggested to contribute to pathophysiology leading to LID (Ferrada et al., 2008; Garcia-Ramirez et al., 2004; Johnston et al., 2010; Lim et al., 2015). We hypothesized that LID could be reduced with HA-H2R antagonism by GRK-mediated regulation of the signaling cues.

  • Histamine H<inf>3</inf> Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons

    2018, Neuroscience
    Citation Excerpt :

    Subsequent studies indicated that histamine H3 receptors fail to affect baseline levels of dopamine (Fox et al., 2005; Giannoni et al., 2010; Aquino-Miranda et al., 2015), but reliably modulate extracellular dopamine elevations evoked by pharmacological stimuli (Munzar et al., 2004; Nowak et al., 2008; Alfaro-Rodriguez et al., 2013). In addition, H3 receptors have been shown to modulate behaviors typically regulated by dopaminergic neurotransmission, such as alcohol consumption reinstatement (Nuutinen et al., 2015), alcohol-mediated reward (Nuutinen et al., 2011; Morais-Silva et al., 2016), amphetamine self-administration (Munzar et al., 2004), amphetamine-induced locomotor activity (Munzar et al., 2004; Banks et al., 2009), and apomorphine-induced turning behavior in mice with unilateral striatal ablation (Garcia-Ramirez et al., 2004), among others. It is important to point out, however, that other uncontrolled parameters perhaps exist influencing how these receptors act to regulate the dopaminergic system under different experimental conditions.

  • The H<inf>3</inf>receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats

    2014, European Journal of Pharmacology
    Citation Excerpt :

    In normal rats, H3 agonists can induce ipsilateral rotation when injected unilaterally into the substantia nigra. However, in 6-OHDA-lesioned rats, the intra-cerebroventricular (icv) or intra-nigral application of an H3 agonist inhibits the contralateral rotational response to apomorphine suggesting a potential adverse effect on motor function (Garcia-Ramirez et al., 2004; Liu et al., 2008). However, so far only a single study has examined the systemic administration of H3 agonists relevant to PD in either 6-OHDA-lesioned rats or MPTP-treated primates.

  • Cellular distribution of the histamine H<inf>3</inf> receptor in the basal ganglia: Functional modulation of dopamine and glutamate neurotransmission

    2013, Basal Ganglia
    Citation Excerpt :

    Several H3R agonists decrease l-dopa and apomorphine-induced turning behaviour in 6-hydroxydopamine lesioned rats [26,63] as well as l-dopa-induced chorea in MPTP-lesioned monkeys [28]. These effects could be due to H3R-mediated decrease of GABA release in the SNr [64] (but see [65]). In reserpinized mice, H3 receptor stimulation decreases locomotion induced by dopaminergic agonists [47].

View all citing articles on Scopus
View full text