Effects of intra-vestibular nucleus injection of the Group I metabotropic glutamate receptor antagonist AIDA on vestibular compensation in guinea pigs

Abstract

Removal of the peripheral vestibular receptor cells in one inner ear (unilateral vestibular deafferentation, UVD) results in a syndrome of ocular motor and postural disorders, many of which disappear over time in a process of behavioural recovery known as vestibular compensation. Excitatory amino acid receptors, in particular the N-methyl-D-aspartate (NMDA) receptor, have been implicated in vestibular compensation; however, the metabotropic glutamate receptors (mGluRs) have not been studied in this context. The aim of this study was to determine whether group I mGluRs in the brainstem vestibular nucleus complex (VNC) ipsilateral to the UVD are involved in vestibular compensation of the static symptoms of UVD in guinea pig. The selective group I mGluR antagonist (RS)-1-aminoindan-1,5,dicarboxylic acid (AIDA) was continuously infused into the ipsilateral VNC for 30-min pre-UVD and 30-min post-UVD by cannula, at a rate of 1 microl/h, using one of four doses: 0.1 fg, 0.1 pg, 0.1 ng or 0.1 microg (n=5 animals in each case). In control conditions, a 0.1-fg (n=4) or 0.1-microg (n=5) NaOH vehicle was infused into the ipsilateral VNC using the same protocol. In order to control for the possibility that AIDA disrupted spontaneous neuronal activity in the VNC in normal animals, 0.1 microg AIDA (n=4) or 0.1 microg NaOH (n=2) was infused into the VNC in labyrinthine-intact animals. In both groups, static symptoms of UVD (i.e. spontaneous nystagmus, SN, yaw head tilt, YHT and roll head tilt, RHT) were measured at 8, 10, 12, 15, 20, 25, 30, 35, 45 and 50 h post-UVD. In addition, the righting reflex latency (RRL) was measured in labyrinthine-intact animals in order to assess whether AIDA impaired motor coordination in labyrinthine-intact animals. In UVD animals, the highest dose of AIDA significantly reduced SN frequency and changed its rate of compensation (P<0.001 and P<0.0001, respectively). This dose of AIDA also caused a significant reduction in YHT (P<0.005) as well as a significant change in its rate of compensation (P<0.0001). However, RHT was not significantly affected. In the labyrinthine-intact animals, AIDA infusion did not induce a UVD syndrome, nor did it significantly affect RRL. These results suggest that group I mGluRs in the ipsilateral VNC may be involved in the expression of ocular motor and some postural symptoms following UVD. Furthermore, group I mGluRs may not contribute to the resting activity of vestibular nucleus neurons.

Neuropharmacology of Vestibular System Disorders

“…The neurons of the vestibular nuclei also express NMDA and non-NMDA EAA receptors [26, 49, 158]. Among other functions, these receptors mediate the main excitatory input to the vestibular nuclei neurons that originates from the primary afferents [31, 115, 148].…”

Effects of unilateral vestibular ganglionectomy on glutaminase activity in the vestibular nerve root and vestibular nuclear complex of the rat

“…Furthermore, there is evidence that glutamate receptors might function in the plasticity that follows loss of vestibular nerve input (Smith and Darlington, 1997;Li et al, 1997;Gliddon et al, 2000;Horii et al, 2001). …”

Effects of Chronic Infusion of a GABAA Receptor Agonist or Antagonist into the Vestibular Nuclear Complex on Vestibular Compensation in the Guinea Pig

“…fentanyl citrate (0.4 mg/ml), azaperone (3.2 mg/ml), and xylazine hydrochloride (58.3 mg/ml) (Fentazin; Parnell, Aukland, New Zealand). With the use of a stereotaxic apparatus, bregma was used as the reference point for the VNC stereotaxic coordinates (caudal, 12 mm;lateral, 1 mm;ventral, 10.3 mm;Gliddon et al, 2000). The cannula was inserted into the brainstem through the cerebellum and secured to the skull by dental cement.…”

“…The drugs were aliquoted, frozen at Ϫ20°C, and defrosted when required. Both drugs were diluted to the required concentration using modified cerebrospinal fluid (124 mM NaCl, 5 mM KCl, 1.2 mM KH 2 PO 4 , and 1.3 mM MgSO 4 ) (Gliddon et al, 2000). Drug solutions were tested for pH and changed to a pH 7.0 if necessary.…”