Abstract
Menthol is a widely-used cooling and flavoring agent derived from mint leaves. In the peripheral nervous system, menthol regulates sensory transduction by activating TRPM8 channels residing specifically in primary sensory neurons. Although behavioral studies have implicated menthol actions in the brain, no direct central target of menthol has been identified. Here we show that menthol reduces the excitation of rat hippocampal neurons in culture and suppresses the epileptic activity induced by pentylenetetrazole injection and electrical kindling in vivo. We found menthol not only enhanced the currents induced by low concentrations of GABA but also directly activated GABAA receptor (GABAAR) in hippocampal neurons in culture. Furthermore, in the CA1 region of rat hippocampal slices, menthol enhanced tonic GABAergic inhibition although phasic GABAergic inhibition was unaffected. Finally, the structure-effect relationship of menthol indicated that hydroxyl plays a critical role in menthol enhancement of tonic GABAAR. Our results thus reveal a novel cellular mechanism that may underlie the ambivalent perception and psychophysical effects of menthol and underscore the importance of tonic inhibition by GABAARs in regulating neuronal activity.
Highlights
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain
In the presence of a cocktail of transmitter receptor antagonists, including CNQX (10 mM), D-AP5 (20 mM, for NMDA receptors), bicuculline (BMI, 10 mM, for GABAA receptor (GABAAR)) and strychnine (STR, 1 mM, for glycine receptors), we found that the firing frequencies of cultured hippocampal neurons induced by the same set of step-depolarization currents were identical before and after addition of menthol (300 mM, Fig. S1)
Based on the finding that menthol potentiates the response of recombinant GABAARs expressed in Xenopus oocytes [22], we examined the effect of menthol on the activation of GABAARs in hippocampal neurons
Summary
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. Its principal action is to activate ionotropic A-type GABA receptors (GABAARs), leading to an inward flow of Cl2 and a hyperpolarizing postsynaptic response. The GABAergic transmission shapes neural activity via two spatially and temporally unique modes of inhibition [1]. Previous studies in brain slices [2,4] and neuronal cultures [5,6], and in vivo [7] have shown that different GABAAR subtypes are responsible for mediating tonic inhibition, depending on brain regions and cell types [1,8]. Recent studies suggest that tonic inhibition may regulate neural network excitability [2] and information processing [7]. The enhancement of GABAergic tonic inhibition is a promising therapeutic approach for diseases involving network hyper-excitability
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