Abstract
Glucocorticoids influence vagal parasympathetic output to the viscera via mechanisms that include modulation of neural circuitry in the dorsal vagal complex, a principal autonomic regulatory center. Glucocorticoids can modulate synaptic neurotransmitter release elsewhere in the brain by inducing release of retrograde signalling molecules. We tested the hypothesis that the glucocorticoid agonist dexamethasone (DEX) modulates GABA release in the rat dorsal motor nucleus of the vagus (DMV). Whole-cell patch-clamp recordings revealed that DEX (1-10 µM) rapidly (i.e. within three minutes) increased the frequency of tetrodotoxin-resistant, miniature IPSCs (mIPSCs) in 67% of DMV neurons recorded in acutely prepared slices. Glutamate-mediated mEPSCs were also enhanced by DEX (10 µM), and blockade of ionotropic glutamate receptors reduced the DEX effect on mIPSC frequency. Antagonists of type I or II corticosteroid receptors blocked the effect of DEX on mIPSCs. The effect was mimicked by application of the membrane-impermeant BSA-conjugated DEX, and intracellular blockade of G protein function with GDP βS in the recorded cell prevented the effect of DEX. The enhancement of GABA release was blocked by the TRPV1 antagonists, 5’-iodoresiniferatoxin or capsazepine, but was not altered by the cannabinoid type 1 receptor antagonist AM251. The DEX effect was prevented by blocking fatty acid amide hydrolysis or by inhibiting anandamide transport, implicating involvement of the endocannabinoid system in the response. These findings indicate that DEX induces an enhancement of GABA release in the DMV, which is mediated by activation of TRPV1 receptors on afferent terminals. The effect is likely induced by anandamide or other ‘endovanilloid’, suggesting activation of a local retrograde signal originating from DMV neurons to enhance synaptic inhibition locally in response to glucocorticoids.
Highlights
Parasympathetic autonomic control of most thoracic and abdominal viscera is accomplished by neurons in the medullary dorsal vagal complex
The effect of DEX on miniature IPSCs (mIPSCs) was examined in dorsal motor nucleus of the vagus (DMV) neurons in the presence of TTX (1 μM)
All neurons were tested by the intra-assay K–S test to determine if DEX induced a significant change in mIPSC frequency within a recording, and neurons with a significant response were combined for further analysis
Summary
Parasympathetic autonomic control of most thoracic and abdominal viscera is accomplished by neurons in the medullary dorsal vagal complex. The dorsal vagal complex consists of area postrema, the nucleus tractus solitarius (NTS), and the dorsal motor nucleus of the vagus (DMV). Axons of preganglionic motor neurons in the DMV project throughout most of the gastrointestinal (GI) tract and other subdiaphragmatic viscera [1], as well as contributing to innervation of thoracic organs. Neurons of the DMV exhibit regular action potential firing [2,3]. This makes the neurons susceptible to small changes in membrane potential induced by synaptic currents.
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