| In the central nervous system, gamma-aminobutyric acid (GABA) has been the predominant neurotransmitter that mediates inhibitory synaptic transmission. It has long been suspected that a disruption of the GABAergic system is likely the cause of epilepsy. GABAB receptors have been implicated to play a role in this disorder, but to what extent are largely unknown. To this end, the goal of the present thesis is to investigate whether GABAB receptors contribute to seizure genesis and modulation in rat strains that are either seizure prone (Fast) or resistant (Slow). In experiment #1, chronic daily microinfusion of a potent GABAB antagonist, SCH 50911, into the amygdala along with other GABAergic pharmacological agents including baclofen were administered, through infusion or systemic injection, at various time periods during kindling. SCH 50911 and baclofen, administered via microinfusion, alone did not significantly alter afterdischarge thresholds and durations. However, a single systemic injection of baclofen completely abolished behavioural seizures in all Fast rats, and half of Slow rats. This same treatment in conjunction with infusion of SCH 50911 delivered the next day resulted in a substantial increase in the number of convulsive seizures, especially among Fast rats, compared to systemic baclofen administration alone. Distinct patterns of electroencephalographic recordings from administration of various GABAergic agents provide further evidence of seizure susceptibility and propagation. In experiment #2, the distribution of GABAB receptors, GAT1, and their co-localization at inhibitory terminals were explored using immunocytochemical techniques. No strain differences were evident. There was a slight tendency for increased GAT1 expression following kindling with no observable change in GABA B immunoreactivity. Assessment of in vitro measurements from experiment #3 revealed that kindling of the amygdala resulted in (1) lower membrane resistance in Fast and Slow rats compared to sham controls; (2) greater and lower GABAB IPSP amplitudes in Fast and Slow rats, respectively; (3) increase and decrease of total charge transfer of the kindled (stimulated) amygdala and contralateral (non-stimulated) amygdala of Slow rats, respectively; (4) no changes in baclofen-induced slope conductance and reversal potential. The implications of these results suggest that GABAB receptor-mediated inhibition in the amygdala plays a modulatory role in kindling-induced epileptogenesis. An interplay between GABAA and GABAB receptors is critical for the regulation and dampening of neural network excitability, which differs between the Fast and Slow rats. Further elucidation of pre- and postsynaptic mechanisms that contribute to inhibition will ultimately be vital towards the development of more efficacious treatment protocols for epileptic patients. |
