Research reportIntranigral injection of the H3 agonist immepip and systemic apomorphine elicit ipsilateral turning behaviour in naive rats, but reduce contralateral turning in hemiparkinsonian rats
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 []-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)
- et al.
An altered histaminergic innervation to the sustantia nigra in Parkinson’s disease
Exp. Neurol
(2000) - et al.
Distribution and modulation of histamine H3 receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson’s disease
Neurobiol. Dis
(2001) - et al.
Pharmacological activity of VUF 9153, an isothiourea histamine H3 receptor antagonist
Eur. J. Pharmacol
(1993) - et al.
The physiology of brain histamine
Prog. Neurobiol
(2001) - et al.
Histamine and spontaneous motor activity: biphasics changes receptor involved and participation of striatal dopamine system
Life Sci
(1998) - et al.
Thioperamide, the selective histamine H3 receptor antagonist, attenuates stimulant-induced locomotor activity in the mouse
Eur. J. Pharmacol
(1994) - et al.
Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent []-GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata
Neuroscience
(1997) Molecular effects of dopamine on striatal-projection pathways
Trends Neurosci
(2000)- et al.
Effects of histamine H3 ligand on levodopa induced turning behavior of hemiparkinsonian rats
Parkinsonism Relat. Disord
(2000) - et al.
Brain penetration of the histamine H3 receptor antagonists thioperamide and clobenpropit in rat and mouse determined with ex vivo []iodophenpropit binding
Brain Res
(1996)
Histamine H3 receptor activation inhibits glutamate release from rat striatal synaptosomes
Neuropharmacology
A detailed mapping of the histamine H3 receptor and its gene transcripts in rat brain
Neuroscience
Marked increase in histamine H3 receptors in the striatum and substantia nigra after 6-hydroxydopamine-induced denervation of dopaminergic neurons: an autoradiographic study
Neurosci. Lett
Effects of thioperamide, a histamine H3 receptor antagonist, on locomotor activity and brain histamine content in mast cell-deficient W/Ww mice
Life Sci
Unilateral 6-hydroxydopamine lesions of meso-striatal dopamine neurons and their physiological sequelae
Prog. Neurobiol
The unilateral 6-hydroxydopamine lesion model in behavioral brain research. Analysis of function deficits, recovery and treatments
Prog. Neurobiol
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