To determine how the histaminergic system is implicated in vestibular compensation, we studied the changes in histidine decarboxylase (HDC; the enzyme synthesizing histamine) mRNA regulation in the tuberomammillary (TM) nuclei of cats killed 1 week, 3 weeks and 3 months after unilateral vestibular neurectomy (UVN). We also used one- and two-step bilateral vestibular neurectomized (BVN) cats to determine whether HDC mRNA regulation depended on the asymmetrical vestibular input received by the TM nuclei neurons. In addition, we analysed the HDC mRNA changes in the TM nuclei and the recovery of behavioural functions in UVN cats treated with thioperamide, a pure histaminergic drug. Finally, we quantified binding to histamine H3 receptors (H3Rs) in the medial vestibular nucleus (VN) by means of a histamine H3R agonist ([3H]N-alpha-methylhistamine) in order to further investigate the sites and mechanisms of action of histamine in this structure. This study shows that UVN increases HDC mRNA expression in the ipsilateral TM nucleus at 1 week. This increased expression persisted 3 weeks after UVN, and regained control values at 3 months. HDC mRNA expression was unchanged in the one-step BVN cats but showed mirror asymmetrical increases in the two-step BVN compared to the 1 week UVN cats. Three weeks' thioperamide treatment induced a bilateral HDC mRNA up-regulation in the UVN cats, which was higher than in the untreated UVN group. Binding to histamine H3Rs in the MVN showed a strong bilateral decrease after thioperamide treatment, while it was reduced ipsilaterally in the UVN cats. That such changes of the histaminergic system induced by vestibular lesion and treatment may play a functional role in vestibular compensation is strongly supported by the behavioural data. Indeed, spontaneous nystagmus, posture and locomotor balance were rapidly recovered in the UVN cats treated with thioperamide. These results demonstrate that changes in histamine levels are related to vestibular compensation.

Excessive inhibition of the external globus pallidus (GPe) by striatal GABAergic neurons is considered a central mechanism contributing to motor symptoms of Parkinson's disease (PD). While electrophysiological findings support this view, behavioral studies assessing the beneficial effects of global GPe activations are scarce and the reported results are controversial. We used an optogenetic approach and the standard unilateral 6-hydroxydopamine nigrostriatal dopamine (DA) lesion model of PD to explore the effects of GPe photostimulation on motor deficits in mice. Global optogenetic GPe inhibition was used in normal mice to verify whether it reproduced the typical motor impairment induced by DA lesions. GPe activation improved ipsilateral circling, contralateral forelimb akinesia, locomotor hypoactivity, and bradykinesia in 6-OHDA-lesioned mice at ineffective photostimulation parameters (532 nm, 5 Hz, 3 mW) in normal mice. GPe photoinhibition (450 nm, 12 mW) had no effect on locomotor activity and forelimb use in normal mice. Bilateral photoinhibition (450 nm, 6 mW/side) reduced directed exploration and improved working memory performances indicating that recruitment of GPe in physiological conditions may depend on the behavioral task involved. Collectively, these findings shed new light on the functional role of GPe and suggest that it is a promising target for neuromodulatory restoration of motor deficits in PD.

This study is a pharmacokinetic (PK) and pharmacodynamics (PD) approach using betahistine doses levels in unilateral vestibular neurectomized cats (UVN) comparable to those used in humans for treating patients with Menière's disease. The aim is to investigate for the first time oral betahistine administration (0.2 and 2 mg/kg/day) with plasma concentrations of betahistine and its major metabolite 2-pyridylacetic acid (2-PAA) (N = 9 cats), the time course of posture recovery (N = 13 cats), and the regulation of the enzyme synthesizing histamine (histidine decarboxylase: HDC) in the tuberomammillary nuclei (TMN) of UVN treated animals (N = the same 13 cats plus 4 negative control cats). In addition the effect of co-administration of the lower betahistine dose (0.2 mg/kg/day) and selegiline (1 mg/kg/day), an inhibitor of the monamine oxidase B (MAOBi) implicated in betahistine catabolism was investigated. The PK parameters were the peak concentration (Cmax), the time when the maximum concentration is reached (Tmax) for both betahistine and 2-PAA and the area under the curve (AUC). The PD approach consisted at quantifying the surface support area, which is a good estimation of posture recovery. The plasma concentration-time-profiles of betahistine and 2-PAA in cats were characterized by early Cmax-values followed by a phase of rapid decrease of plasma concentrations and a final long lasting low level of plasma concentrations. Co administration of selegiline and betahistine increased values of Cmax and AUC up to 146- and 180-fold, respectively. The lowest dose of betahistine (0.2 mg/kg) has no effects on postural function recovery but induced an acute symptomatic effect characterized by a fast balance improvement (4-6 days). The higher dose (2 mg/kg) and the co-administration treatment induced both this acute effect plus a significant acceleration of the recovery process. The histaminergic activity of the neurons in the TMN was significantly increased under treatment with the 2 mg/kg betahistine daily dose, but not with the lower dose alone or in combination with selegiline. The results show for the first time that faster balance recovery in UVN treated cats is accompanied with high plasma concentrations of betahistine and 2-PAA, and upregulation of HDC immunopositive neurons in the TMN. The higher betahistine dose gives results similar to those obtained with the lower dose when co-administrated with an inhibitor of betahistine metabolism, selegiline. From a clinical point of view, the study provides new perspectives for Menière's disease treatment, regarding the daily betahistine dose that should be necessary for fast and slow metabolizers.

After unilateral vestibular neurectomy (UVN) many molecular and neurochemical mechanisms underlie the neurophysiological reorganizations occurring in the vestibular nuclei (VN) complex, as well as the behavioral recovery process. As a key regulator, the histaminergic system appears to be a likely candidate because drugs interfering with histamine (HA) neurotransmission facilitate behavioral recovery after vestibular lesion. This study aimed at analyzing the post-lesion changes of the histaminergic system by quantifying binding to histamine H3 receptors (H3R; mediating namely histamine autoinhibition) using a histamine H3 receptor agonist ([(3)H]N-α-methylhistamine). Experiments were done in brain sections of control cats (N = 6) and cats submitted to UVN and killed 1 (N = 6) or 3 (N = 6) weeks after the lesion. UVN induced a bilateral decrease in binding density of the agonist [(3)H]N-α-methylhistamine to H3R in the tuberomammillary nuclei (TMN) at 1 week post-lesion, with a predominant down-regulation in the ipsilateral TMN. The bilateral decrease remained at the 3 weeks survival time and became symmetric. Concerning brainstem structures, binding density in the VN, the prepositus hypoglossi, the subdivisions of the inferior olive decreased unilaterally on the ipsilateral side at 1 week and bilaterally 3 weeks after UVN. Similar changes were observed in the subdivisions of the solitary nucleus only 1 week after the lesion. These findings indicate vestibular lesion induces plasticity of the histamine H3R, which could contribute to vestibular function recovery.

Over the last decade, striatal cholinergic interneurons (ChIs) have reemerged as key actors in the pathophysiology of basal-ganglia-related movement disorders. However, the mechanisms involved are still unclear. In this study, we address the role of ChI activity in the expression of parkinsonian-like motor deficits in a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion model using optogenetic and pharmacological approaches. Dorsal striatal photoinhibition of ChIs in lesioned ChAT(cre/cre) mice expressing halorhodopsin in ChIs reduces akinesia, bradykinesia, and sensorimotor neglect. Muscarinic acetylcholine receptor (mAChR) blockade by scopolamine produces similar anti-parkinsonian effects. To decipher which of the mAChR subtypes provides these beneficial effects, systemic and intrastriatal administration of the selective M1 and M4 mAChR antagonists telenzepine and tropicamide, respectively, were tested in the same model of Parkinson's disease. The two compounds alleviate 6-OHDA lesion-induced motor deficits. Telenzepine produces its beneficial effects by blocking postsynaptic M1 mAChRs expressed on medium spiny neurons (MSNs) at the origin of the indirect striatopallidal and direct striatonigral pathways. The anti-parkinsonian effects of tropicamide were almost completely abolished in mutant lesioned mice that lack M4 mAChRs specifically in dopamine D1-receptor-expressing neurons, suggesting that postsynaptic M4 mAChRs expressed on direct MSNs mediate the antiakinetic action of tropicamide. The present results show that altered cholinergic transmission via M1 and M4 mAChRs of the dorsal striatum plays a pivotal role in the occurrence of motor symptoms in Parkinson's disease.

Unilateral vestibular deafferentation results in strong microglial and astroglial activation in the vestibular nuclei (VN) that could be due to an inflammatory response. This study was aimed at determining if markers of inflammation are upregulated in the VN after chemical unilateral labyrinthectomy (UL) in the rat, and if the inflammatory response, if any, induces the expression of neuroprotective factors that could promote the plasticity mechanisms involved in the vestibular compensation process. The expressions of inflammatory and neuroprotective factors after chemical or mechanical UL were also compared to verify that the inflammatory response was not due to the toxicity of sodium arsanilate.

In Parkinson's disease, nigrostriatal dopamine (DA) degeneration is commonly associated with motor symptomatology. However, non-motor symptoms affecting cognitive function, such as behavioural flexibility and inhibitory control may also appear early in the disease. Here we addressed the role of DA innervation of the dorsomedial striatum (DMS) in mediating these functions in 6-hydroxydopamine (6-OHDA)-lesioned mice using instrumental conditioning in various tasks. Behavioural flexibility was studied in a simple reversal task (nose-poke discrimination) or in reversal of a two-step sequence of actions (central followed by lateral nose-poke). Our results show that mild DA lesions of the DMS induces behavioural flexibility deficits in the sequential reversal learning only. In the first sessions following reversal of contingency, lesioned mice enhanced perseverative sequence of actions to the initial rewarded side then produced premature responses directly to the correct side omitting the central response, thus disrupting the two-step sequence of actions. These deficits may be linked to increased impulsivity as 6-OHDA-lesioned mice were unable to inhibit a previously learned motor response in a cued response inhibition task assessing proactive inhibitory control. Our findings show that partial DA denervation restricted to DMS impairs behavioural flexibility and proactive response inhibition in mice. Such striatal DA lesion may thus represent a valuable animal model for exploring deficits in executive control documented in early stage of Parkinson's disease.