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The effects of the potential glycine receptor antagonist, AMBD, in thalamic ventrobasal nuclei McCarthy, Sarah Monica

Abstract

This thesis describes the effects of 6-aminomethyl-3-methyl-4H,1,2,4-benzothiadiazine-1,1-dioxide (AMBD) on membrane properties and synaptic inhibition in neurons of the ventrobasal (VB) nuclei in the thalamus. Although gamma-aminobutyric acid (GABA) has a well-established role as a neurotransmitter in the VB nuclei, recent evidence demonstrates that this area exhibits glycinergic inhibition that is sensitive to blockade by strychnine. AMBD has pharmacological properties that are consistent with glycine receptor antagonism, but its actions in the thalamus are unknown. The major objective was to determine the effects of AMBD on inhibitory postsynaptic currents (IPSCs) in the VB nuclei evoked by electrical stimulation of the medial lemniscus (ML), the major sensory input. AMBD significantly reduced the peak amplitude of glycinergic and GABAaergic mixed IPSCs, pharmacologically isolated glycinergic and GABAaergic IPSCs, and purely glycinergic IPSCs. AMBD had no effects on most of the purely GABAaergic IPSCs. AMBD eliminated the slow and intermediate, not the fast, decay components of mixed glycinergic and GABAaergic IPSCs. AMBD decreased the apparent frequency but not the amplitude of spontaneous IPSCs (sIPSCs), implicating a possible presynaptic action. We propose that AMBD has both presynaptic and postsynaptic sites of action. According to this proposal, AMBD antagonized the effects of glycine-like amino acids at the postsynaptic fast and slow glycine receptors, as well as at a presynaptic site that attenuates the effects of GABA. Blockade of the presynaptic site resulted in reduced GABA release by nerve terminals. In summary, AMBD has actions expected from a specific antagonist of glycine-like amino acids at thalamic receptors.

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