The adenosinergic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) was investigated in mechanically dissociated rat tuberomammillary nucleus (TMN) neurons using a conventional whole‐cell patch clamp technique. Adenosine (100 μM) reversibly decreased mIPSC frequency without affecting the current amplitude, indicating that adenosine acts presynaptically to decrease the probability of spontaneous GABA release. The adenosine action on GABAergic mIPSC frequency was completely blocked by 1 μM DPCPX, a selective A1 receptor antagonist, and mimicked by 1 μM CPA, a selective A1 receptor agonist. This suggests that presynaptic A1 receptors were responsible for the adenosine‐mediated inhibition of GABAergic mIPSC frequency. CPA still decreased GABAergic mIPSC frequency even either in the presence of 200 μM Cd2+, a general voltage‐dependent Ca2+ channel blocker, or in the Ca2+‐free external solution. However, the inhibitory effect of CPA on GABAergic mIPSC frequency was completely occluded by 1 mM Ba2+, a G‐protein coupled inwardly rectifying K+ (GIRK) channel blocker. In addition, the CPA‐induced decrease in mIPSC frequency was completely occluded by either 100 μM SQ22536, an adenylyl cyclase (AC) inhibitor, or 1 μM KT5720, a specific protein kinase A (PKA) inhibitor. The results suggest that the activation of presynaptic A1 receptors decreases spontaneous GABAergic transmission onto TMN neurons via the modulation of GIRK channels as well as the AC/cAMP/PKA signal transduction pathway. This adenosine A1 receptor‐mediated modulation of GABAergic transmission onto TMN neurons may play an important role in the fine modulation of the excitability of TMN histaminergic neurons as well as the regulation of sleep‐wakefulness.
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