Nicotinic receptors mediate increased GABA release in brain through a tetrodotoxin-insensitive mechanism during prolonged exposure to nicotine.
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.
Zhu
P J
PJ
Department of Pharmacology, The George Washington University Medical Center, Washington, DC 20037, USA. pzhu@mail.nih.gov
Chiappinelli
V A
VA
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*
D011978:Receptors, Nicotinic; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D009538:Nicotine