Cellular and sub-cellular localization of GABAB receptor subtype(s) in the cortex, thalamus and spinal cord.
Physiological function(s) of GABAB receptor subtype(s) investigated by biochemical, ion imaging, and in vitro and in vivo electrophysiological techniques in the cortex, thalamus and spinal cord.
Genetic, morphological, biochemical and electrophysiological analysis of GABAB receptor subtype(s) in experimental models of absence epilepsy and chronic pain.
In order to determine the physiological functions of GABAB receptor subtype(s) and their role in epilepsy and chronic pain the following experiments will be carried out in control animals and in experimental models of these diseases.
Linkage analysis of aberrant genes and homology screening for GABAB receptors will be performed in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS).
Using selective antibodies, the cellular and subcellular localisation of GABAB receptors in the brain will be investigated in developing (P1 - P40) and adult Wistar rats, in GAERS and in two models of chronic pain (Freund's adjuvant monoarthritis and carrageenan-induced inflammation). Autoradiographic and binding techniques will be used to detect the presence of GABAB receptor subtype(s) with different interactions with GTP-binding sites in Wistar and GAERS rats. The brain areas involved in convulsive seizures following injection of GABAB receptor antagonists will be localized by means of c-Fos induction and metabolic rate of glucose, while amino acid levels will be monitored in vivo using microdialysis probes.
The mechanism underlying modulation of transmitter release by GABAB receptors will be studied by combined in vitro electrophysiology and Ca2+ imaging. In vitro and in vivo electrophysiological techniques should allow to assess the role of GABAB receptors in GAERS rats and in the gamma-hydroxybutyric acid and penicillin models of absence epilepsy, while the cellular mechanisms underlying tolerance to baclofen will be investigated by in vitro electrophysiological experiments.
The role of GABAB receptors in nociception will be investigated in experimental models of chronic pain by monitoring changes in amino acid and peptide levels using microdialysis probes in the spinal cord, and by analysing the electrophysiological effect of GABAB receptor modulations on spinal reflexes and cellular responses of spinal cord sensory cells to noxious and innocuous stimuli.
Funding SchemeCSC - Cost-sharing contracts
B15 2TT Birmingham