title: Nicotinic receptors mediate increased GABA release in brain through a tetrodotoxin-insensitive mechanism during prolonged exposure to nicotine.
abstract: The effects of nicotine on the spontaneous release of GABA from nerve terminals in the chick lateral spiriform nucleus were examined using whole cell patch-clamp recording in brain slices. Exposure to 1 microM nicotine produced an early immediate increase in the frequency of spontaneous postsynaptic GABAergic currents. This effect was blocked in the presence of 0.5 microM tetrodotoxin. However, a prolonged application of 0.1-1 microM nicotine (>3 min) caused a tetrodotoxin-insensitive increase in the frequency of spontaneous GABAergic currents. This late tetrodotoxin-insensitive effect was blocked by the nicotinic antagonists dihydro-beta-erythroidine (30 microM) and mecamylamine (10 microM), but not by methyllycaconitine (50-100 nM), indicating that activation of high affinity nicotine receptors was mainly responsible for this effect. This enhancement was inhibited by the high threshold Ca(2+) channel blocker Cd(2+) (100 microM), but not by dantrolene or ryanodine. The tetrodotoxin-insensitive enhancement of the frequency of GABA currents by nicotine was reduced by inhibition of cAMP-dependent protein kinase with HA1004 (30 microM), but not by inhibition of protein kinase C with staurosporine (1 microM), and was facilitated by forskolin (10 microM) or bromo-cAMP (50 microM). The results indicate that nicotine-enhanced GABA release can operate through both tetrodotoxin-sensitive and -insensitive mechanisms in a single brain region and that a second messenger cascade may be involved in the tetrodotoxin-insensitive enhancement by nicotine.
authors.affiliation: Department of Pharmacology, The George Washington University Medical Center, Washington, DC 20037, USA. pzhu@mail.nih.gov
authors.forename: P J
authors.initials: PJ
authors.lastname: Zhu
authors.forename: V A
authors.initials: VA
authors.lastname: Chiappinelli
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002642:Chick Embryo; D066298:In Vitro Techniques; D009538:Nicotine / Q000633:toxicity*; D011978:Receptors, Nicotinic / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D011978:Receptors, Nicotinic; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D009538:Nicotine