Jpn. J. Pharmacol. 74 (2), 139-146 (1997)

Nicotinic Agonist Modulation of Neurotransmitter Levels in the Rat Frontoparietal Cortex

Kathleen L. Summers (1), William R. Kem (2,*) and Ezio Giacobini (1,#)

(1) Department of Pharmacology, Southern Illinois University, Springfield, IL 62794-9230, USA
(2) Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610-0267, USA
(*) To whom correspondence should be addressed.
Present address: Dept. of Geriatrics, University of Geneva, Medical School, Route de Mon-Idee, CH-1226 Thonex-Geneva, Switzerland

Abstract: Anabaseine is a naturally occurring toxin that stimulates a variety of neuronal and muscleÅ@nicotinic receptors. GTS-21 [3-(2,4-dimethoxybenzylidene)anabaseine], an anabaseine derivative, selectively stimulates alpha7-containing nicotinic receptors. Here we report the first in vivo study of the effects of these two nicotinic agonists on cortical extracellular acetylcholine (ACh), dopamine (DA), norepinephrine (NE) and serotonin (5-HT) levels, measured with a microdialysis probe placed within the frontoparietal cortex inÅ@the absence of a cholinesterase inhibitor. At 3.6 micromol/kg, s.c., anabaseine increased cortical ACh and NEÅ@above baseline values without significantly affecting DA and 5-HT. The ACh and NE elevations were inhibited by i.p. pre-administration (4.9 micromol/kg) of the nicotinic antagonist mecamylamine (Mec). In contrast, GTS-21 (3.6 micromol/kg, s.c.) significantly increased NE and DA without affecting ACh and 5-HT levels. Following Mec injection, GTS-21 increased ACh 25-fold and 5-HT 13-fold, while NE and DA levels were slightly decreased in comparison with GTS-21 alone. We suggest that at the dose used, Mec may preferentially block high affinity nicotinic receptors which normally provide an inhibitory influence uponÅ@ACh release, thereby permitting expression of the complete stimulatory effect of GTS-21 on neuronal alpha7-receptors. GTS-21 and other receptor subtype-selective nicotinic agonists should be helpful in clarifying theÅ@roles of particular nicotinic receptors in modulating cortical neurotransmitter levels.

Keywords: Acetylcholine, Alzheimer's therapy, Mecamylamine, Microdialysis, Nicotinic agonist