liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Central vestibular compensation: the role of the GABAB receptor
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The remarkable capacity for adaptive plastic changes in response to changed internal or external conditions is a distinctive feature of the vestibular system. Even in adults the system can be modified throughout life due to altered conditions caused by disease. trauma, medical treatment or normal ageing. Central nervous plastic changes following a unilateral peripheral vestibular loss are summarised by the term 'vestibular compensation'. This concept has become the most extensively investigated experimental model in studies of vestibular plasticity. The vestibular system governs a number of reflexes of which one is maintaining a stable gaze when the head moves - the vestibuloocular reflex. Since this reflex is relatively easy to quantify with non-invasive methods it constitutes an excellent tool for studying vestibular function in health and disease. Furthermore, the underlying neuronal circuitry of the reflex is phylogenetically ancient.

γ-Aminobutyric acid (GABA) is the most widely distributed inhibitory neurotransmitter in the vertebrate central nervous system. It acts via the classical GABAA and the more recently discovered GABAB receptors, the physiological functions of which are just beginning to emerge. The studies that provide the basis for this thesis systematically investigate the functional significance of the GABAB receptors for vestibular compensation during several stages after unilateral vestibular loss in rats. Firstly, the long-term maintenance of the partially normalised vestibular function weeks- months after the sensory loss was investigated (I and 11). Subsequently, the compensation that normalises the function of the vestibular system within a few days after the loss was investigated (III). Finally, in order to be able to investigate the acute stage, minutes - hours after unilateral vestibular loss, a method for reversible inactivation of the vestibular sensory input was developed (IV). In addition to information about the role of GABAB receptor function during this stage. the method also revealed the immediate behavioural consequences following a sudden transient vestibular loss as well as compensatory modulations that outlasted the inactivation of the sensory input (IV).

In summary, this thesis demonstrates a concrete physiological role of the GABAB receptors in a well-characterised neural system related to a specific behaviour. A direct causal relationship between the GABAB receptors and the physiological changes underlying compensation from a unilateral peripheral vestibular loss is established for all stages of the compensatory process. The physiological effect is partly mediated through an endogenous tonic control of the receptor. Furthermore, this thesis elucidates the immediate behavioural consequences of an acute transient loss of sensory vestibular input.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2003. , 59 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 765
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25687Local ID: 10063ISBN: 91-7373-522-1 (print)OAI: oai:DiVA.org:liu-25687DiVA: diva2:246235
Public defence
2003-01-16, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-19Bibliographically approved
List of papers
1. Effects of the GABA agonists baclofen and THIP on long-term compensation in hemilabyrinthectomised rats
Open this publication in new window or tab >>Effects of the GABA agonists baclofen and THIP on long-term compensation in hemilabyrinthectomised rats
1998 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 795, no 1-2, 307-311 p.Article in journal (Refereed) Published
Abstract [en]

Horizontal eye movements, elicited by sinusoidal rotation in darkness, were recorded with a magnetic search coil technique in pigmented rats, hemilabyrinthectomised 8–12 weeks before the investigation. Separate gains during rotation towards the lesioned side (LS) and the intact side (IS) were calculated by a computer program, demonstrating an asymmetry. Systemic single administration of the GABAB agonist baclofen caused a dose-related temporary rebalancing of the compensatory eye movements to the LS and the IS. At an optimal dose of 14 μmol/kg b.wt symmetry was achieved by excitation of eye movements during rotation to the LS and depression during rotation to the IS. Administration of the GABAA agonist THIP did not obviously reduce the asymmetry. It is suggested that stimulation of GABAB receptors modifies the tonic imbalance between the bilateral vestibular nuclei and/or the central processing of the input from the peripheral sensory organs.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84752 (URN)10.1016/S0006-8993(98)00329-1 (DOI)
Available from: 2012-10-19 Created: 2012-10-19 Last updated: 2017-12-07Bibliographically approved
2. GABAB receptors contribute to vestibular compensation after unilateral labyrinthectomy in pigmented rats
Open this publication in new window or tab >>GABAB receptors contribute to vestibular compensation after unilateral labyrinthectomy in pigmented rats
2000 (English)In: Experimental Brain Research, ISSN 0014-4819, E-ISSN 1432-1106, Vol. 134, no 1, 32-41 p.Article in journal (Refereed) Published
Abstract [en]

The horizontal vestibulo-ocular reflex was studied in pigmented rats, which had been unilaterally, chemically labyrinthectomised 6–144 days previously. During this partially compensated stage after unilateral labyrinthectomy (UL), both static and dynamic deficits remain. The former was evaluated by recording of spontaneous eye movements in darkness, and the latter by estimating the slow-phase velocity (SPV) gain of compensatory eye movements during horizontal vestibular stimulation. The GABAB agonist baclofen caused a reversal of the remaining ipsilesional drift of the eyes in darkness into a nystagmus with a contralesional slow phase. The GABAB antagonist CGP 36742 caused a decompensation by exaggerating the remaining ipsilesional eye drift. Further, baclofen equilibrated or reversed the asymmetry between ipsi- and contralesional SPV gains during horizontal sinusoidal rotations at 0.2 Hz and 0.8 Hz. This was achieved by an increase in the ipsilesional gain and a decrease in the contralesional gain. The phase lead during sinusoidal rotation (0.2 Hz) was larger following rotation to the lesioned side than to the intact side in UL rats. This asymmetry was reversed by baclofen. CGP 36742 inhibited the effects of baclofen, while the antagonist per se aggravated SPV gain and phase lead asymmetries in UL rats during vestibular stimulation. Per- and post-rotatory nystagmus induced by velocity step stimulation revealed an imperfect velocity-storage function in UL animals, which was modulated by baclofen. An investigation of the baclofen effect on SPV gain asymmetry during different time intervals after chemical UL showed a completely developed effect on the 6th day. Bilateral flocculectomy did not alter the effects of baclofen on UL animals. It is concluded that physiological stimulation of GABAB receptors contributes to minimise the vestibulo-oculomotor asymmetry during the partially compensated period after UL. Administration of an agonist or an antagonist changes the asymmetry towards the ipsi- or contralesional side, possibly by altering the spontaneous neuronal activity in the bilateral medial vestibular nuclei. The results are compatible with a hypothesis, supported by in vitro slice experiments, that the efficacy of GABAB receptors is up-regulated on the ipsilesional side and down-regulated on the contralesional side.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25256 (URN)10.1007/s002210000438 (DOI)9695 (Local ID)9695 (Archive number)9695 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
3. Early compensation of vestibulo-oculomotor symptoms after unilateral vestibular loss in rats is related to GABAB receptor function
Open this publication in new window or tab >>Early compensation of vestibulo-oculomotor symptoms after unilateral vestibular loss in rats is related to GABAB receptor function
2002 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 111, no 3, 625-634 p.Article in journal (Refereed) Published
Abstract [en]

The horizontal vestibulo-oculomotor reflex was studied in pigmented rats during the first 5 days after a unilateral chemical or surgical vestibular deafferentation. Spontaneous eye movements in darkness and slow phase velocity gain of compensatory eye movements during horizontal sinusoidal rotation were evaluated. The most evident vestibulo-oculomotor symptom immediately after a unilateral vestibular loss was a spontaneous nystagmus, which gradually abated during the following days. Further, an asymmetry between ipsi- and contra-lesional gains was evident during sinusoidal vestibular stimulation. Single systemic doses of the GABAB receptor antagonist [3-[1-(S)-[[3-(cyclohexylmethyl)-hydroxyphosphinoyl]-2-(S)-hydroxypropyl]amino]ethyl]-benzoic acid (CGP 56433A), the agonist baclofen, or the GABAA receptor agonist (4,5,6,7-tetrahydroisoxazolo-[5,4-c]-pyridin-3-ol (THIP) were given at different intervals after unilateral vestibular deafferentation. CGP 56433A highly aggravated the vestibulo-oculomotor symptoms, observed as an increase in spontaneous nystagmus and slow phase velocity gain asymmetry. This effect was most pronounced during the first 2 days after unilateral vestibular loss, when CGP 56433A even decompensated the vestibular system to the extent that all vestibular responses were abolished. Baclofen caused no effect during the first days after unilateral vestibular loss, but in parallel with the abatement of spontaneous nystagmus, the drug equilibrated or even reversed the remaining spontaneous nystagmus with corresponding effects on the slow-phase velocity gain asymmetry. The effects of baclofen were very similar after both chemical and surgical deafferentation. THIP caused a slight depression of all vestibular responses. All single dose effects of the drugs were transient.

Altogether these results reveal that endogenous stimulation of GABAB receptors in GABA-ergic vestibulo-oculomotor circuits are important for reducing the vestibular asymmetry during the early period after unilateral vestibular deafferentation. A possible role for GABAB receptors in the reciprocal inhibitory commissural pathways in the vestibular nuclei is suggested.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25264 (URN)10.1016/S0306-4522(01)00618-2 (DOI)9704 (Local ID)9704 (Archive number)9704 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
4. Vestibulo-oculomotor behaviour in rats following a transient unilateral vestibular loss induced by lidocaine
Open this publication in new window or tab >>Vestibulo-oculomotor behaviour in rats following a transient unilateral vestibular loss induced by lidocaine
2003 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 120, no 4, 1105-1114 p.Article in journal (Refereed) Published
Abstract [en]

The effects of a transient vestibular nerve blockade, achieved by intra-tympanic instillation of lidocaine, were studied in rats by recording horizontal eye movements in darkness. Evaluation of the dose-response relationship showed that a maximal effect was attained with a concentration of 4% lidocaine. Within 15 min of lidocaine instillation, a vigorous spontaneous nystagmus was observed which reached maximal frequency and velocity of the slow phase after about 20 min. Subsequently, the nystagmus failed for approximately half an hour before it reappeared. This could be avoided by providing visual feedback in between the recordings in darkness or by a contralateral instillation of 2.5% lidocaine. It is suggested that the failure reflects an overload of the vestibulo-oculomotor circuits.

After recovery from the nerve blockade, when the gaze was stable, dynamic vestibular tests were performed. They revealed that a decrease of the slow phase velocity gain and the dominant time constant during, respectively, sinusoidal- and step stimulation toward the unanaesthetised side, had developed with the nerve blockade. These modulations were impaired by a nodulo-uvulectomy but not by bilateral flocculectomy, which is consistent with the concept of vestibular habituation.

A GABAB receptor antagonist, CGP 56433A, given systemically during the nerve blockade, aggravated the vestibular asymmetry. The same effect has previously been demonstrated in both short- (days) and long-term (months) compensated rats, by antagonising the GABAB receptor.

In summary, this study provides the first observations of vestibulo-oculomotor disturbances during the first hour after a rapid and transient unilateral vestibular loss in the rat. By using this method, it is possible to study immediate behavioural consequences and possible neural changes that might outlast the nerve blockade.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25265 (URN)10.1016/S0306-4522(03)00407-X (DOI)9705 (Local ID)9705 (Archive number)9705 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved

Open Access in DiVA

No full text

Authority records BETA

Magnusson, Anna

Search in DiVA

By author/editor
Magnusson, Anna
By organisation
Cell biologyFaculty of Health Sciences
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 82 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf