A novel neuromodulating effect of Pregabalin on neurotransmitter release at the mouse calyx of Held

M.N. DI GUILMI; F.J. URBANO,; C. GONZALEZ INCHAUSPE,; O.D. UCHITEL,

Chicago

Congreso; Society for Neuroscience, 2009.; 2009

Pregabalin [S-[+]-3-isobutylGABA, Lyrica] is an anticonvulsant and analgesicmedication which was originally synthesized with the intention of modulatingbrain GABA receptors, resulting ineffective. The mechanism of action ofpregabalin (PGB) has been only partially characterized; it is generally acceptedthat PBG subtly reduce calcium-dependent overflow of neurotransmitters inseveral tissues. However, the cellular and molecular basis of its inhibitoryaction on neurotransmitter release is unknown. The α2-δ type 1 auxiliarysubunit of voltage-gated calcium channels is the primary high-affinity bindingsite for PGB (Gee et al., 1996). The exact action of PGB on presynapticcalcium channels function is still a matter of controversy.Here, we studied the effect of PGB on the Calyx of Held-Medial Nucleus ofthe Trapezoid Body (MNTB) synapse in brainstem slices using whole cell patchclamp recordings. Excitatory postsynaptic currents (EPSCs) and presynapticcalcium currents were recorded at Calyx of Held-MNTB complex at both lowand high frequency stimulation.The amplitude of EPSCs at the Calyx - MNTB was reduced by a 30%. Nodifferences were observed in the depression rate from high frequency trains buta faster rate of recovery from synaptic depression at 100 Hz was observed inthe presence of PGB (500 μM)(p=0.043). We found no differences in the meanamplitude of miniature EPSCs (39± 2pA in -PGB (n =11) and 38± 2pA in+PGB (n =10), while observing greater minis frequencies -PGB versus +PGBconditions (1.71±0.35 Hz and 0.49±0.06 Hz, respectively (p=0.0044)). Therelease probability (Pr) was 0.45 ± 0.024 (n =6) for -PGB and 0.35 ± 0.015 (n=6) for +PGB (p = 0.00014) indicating a decrement of the Pr after PGBapplication. On the other hand, P/Q-type calcium channels mediated currentsdecreased in presence of PGB (500 μM) after high frequency trainsAbstract Print View http://www.abstractsonline.com/Plan/AbstractPrintView.aspx?mID=2...1 de 2 10/9/2009 9:48 AM(100-300Hz). The calcium current was partially recovered by isoleucine (1.5mM), suggesting specific PGB-mediated effects. Calcium currents activationcurves, obtained from plotting tail currents versus command voltage showed nodifferences. However, two pulses inactivation protocol shows a larger rescue ofthe inactivation.These results suggest that PGB effects on Calyx of Held-MNTB synapse is twofold: 1) blocking presynaptic P/Q-type mediated calcium currents that wouldreduce synaptic transmission, and 2) accelerating the recovery of P/Q channelsfrom inactivated states that would allow for lower recovery times after highfrequency synaptic stimulation.