title: Muscarinic M4 receptors regulate GABAergic transmission in rat tuberomammillary nucleus neurons.
abstract: Histaminergic neurons within the tuberomammillary nucleus (TMN) play an important role in sleep-wakefulness regulation. Here, we report the muscarinic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in mechanically dissociated rat histaminergic neurons using a conventional whole-cell patch clamp technique. Muscarine, a nonselective muscarinic acetylcholine (mACh) receptor agonist, reversibly decreased mIPSC frequency without affecting the current amplitude, indicating that muscarine acts presynaptically to decrease the probability of spontaneous GABA release. The muscarine action on GABAergic mIPSC frequency was completely blocked by atropine, a nonselective mACh receptor antagonist, and tropicamide, an M(4) receptor antagonist. The muscarine-induced decrease in mIPSC frequency was completely occluded in the presence of Cd(2+), a general voltage-dependent Ca(2+) channel blocker, or in a Ca(2+)-free external solution. However, pharmacological agents affecting adenylyl cyclase or G-protein coupled inwardly rectifying K(+) channel activity did not prevent the inhibitory action of muscarine on GABAergic mIPSCs. These results suggest that muscarine acts on M(4) receptors on GABAergic nerve terminals projecting to histaminergic neurons to inhibit spontaneous GABA release via the inhibition of Ca(2+) influx from the extracellular space. Muscarine also inhibited action potential-dependent GABA release by activating presynaptic M(4) receptors in more physiological conditions. The M(4) receptor-mediated modulation of GABAergic transmission onto TMN neurons may contribute to the regulation of sleep-wakefulness.
authors: Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu 700-412, Republic of Korea.
authors: Michiko
authors: M
authors: Nakamura
authors: Il-Sung
authors: IS
authors: Jang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003627:Data Interpretation, Statistical; D055724:Electrophysiological Phenomena / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006632:Histamine / Q000502:physiology; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D009116:Muscarine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043588:Receptor, Muscarinic M4 / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
chemical_list: D018721:Muscarinic Agonists; D043588:Receptor, Muscarinic M4; D005680:gamma-Aminobutyric Acid; D009116:Muscarine; D006632:Histamine