β 2-adrenoceptor-mediated facilitation of glutamatergic transmission in rat ventromedial hypothalamic neurons

Abstract

Adrenergic modulation of glutamatergic spontaneous miniature excitatory postsynaptic currents (mEPSCs) was investigated in mechanically dissociated rat ventromedial hypothalamic (VMH) neurons using a conventional whole-cell patch clamp technique. Noradrenaline (NA) reversibly increased mEPSC frequency without affecting the current amplitude in a concentration-dependent manner, indicating that NA acts presynaptically to facilitate the probability of spontaneous glutamate release. NA (10 μM) action on glutamatergic mEPSC frequency was completely blocked by 1 μM ICI-188551 [(±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methyl-ethyl)amino]-2-butanol], a selective β 2-adrenoceptor antagonist, and mimicked by 1 μM formoterol, a selective β 2-adrenoceptor agonist. Neither α-adrenoceptor nor β 1-adrenoceptor blockers affected the NA-induced increase in mEPSC frequency. NA action on glutamatergic mEPSC frequency was completely occluded in the presence of either 10 μM forskolin, an adenylyl cyclase (AC) activator, or blocked by 1 μM SQ22536 [9-(tetrahydro-2-furanyl)-9H-purin-6-amine], a selective AC inhibitor. Furthermore, the NA-induced increase in mEPSC frequency was completely attenuated by either 1 μM KT5720 or 1 μM H-89 ( N-[2-( p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide), specific PKA inhibitors. However, NA still could increase mEPSC frequency either in the Ca 2+-free external solution or in the presence of 1 μM thapsigargin. The results suggest that activation of presynaptic β 2-adrenoceptors facilitates spontaneous glutamate release to VMH neurons via cAMP/PKA signal transduction pathway. β 2-Adrenoceptor-mediated presynaptic modulation of excitatory glutamatergic transmission would therefore be expected to play a pivotal role in the regulation of a variety of behavioral functions, which are mediated by the VMH.