Neuromodulating effect of Pregabalin on neurotransmitter release at the mouse Calyx of Held

M.N. DI GUILMI, F.J. URBANO, C. GONZÁLEZ-INCHAUSPE & O.D. UCHITEL

Huerta Grande, Cordoba

Congreso; FIRST JOINT MEETING OF THE ARGENTINE SOCIETY FOR NEUROSCIENCES (SAN) AND THE ARGENTINE WORKSHOP IN NEUROSCIENCES (TAN); 2009

SAN-Taller

Pregabalin (PGB) is an anticonvulsant and analgesic medication. The mechanism of action of PGB has been only partially characterized; it is generally accepted that PGB subtly reduces calcium-dependent overflow of neurotransmitters in several tissues. The á2-ä type 1 auxiliary subunit of voltage-gated calcium channels is the primary high-affinity binding site for PGB. However, the cellular and molecular basis of its inhibitory action on neurotransmitter release is unknown. Here, we studied the effect of PGB on the Calyx of Held-Medial Nucleus of the Trapezoid Body (MNTB) synapse in brainstem slices using whole cell patch clamp. Excitatory postsynaptic currents (EPSCs) and presynaptic calcium currents were recorded. The amplitude of EPSCs was reduced by a 30% (500 ìM, 15 min). During high frequency stimulation PGB has no effect on short term depression but a faster rate of recovery from synaptic depression at 100 Hz was observed with PGB. We found a decrease in the frequency of minis in +PGB vs. -PGB conditions and an enhancement of pair pulse facilitation. These data suggest a presynaptic effect of PGB. On the other hand, P/Q-type calcium channels mediated currents decreased in the presence of PGB evoked by either action potential trains or long duration square pulses (I-V protocol). Calcium current activation curves, showed no differences. However, two pulses inactivation protocol shows a larger rescue of the inactivation mediated by PGB. These results suggest that PGB: 1) blocks presynaptic P/Q-type mediated calcium currents that would reduce synaptic transmission, and 2) accelerates the recovery of P/Q channels from inactivated states that would allow for shorter recovery times after high frequency synaptic stimulation.