Nicotinic agonist modulation of neurotransmitter levels in the rat frontoparietal cortex.

Abstract

Anabaseine is a naturally occurring toxin that stimulates a variety of neuronal and muscle nicotinic receptors. GTS-21 [3-(2,4-dimethoxybenzylidene)anabaseine], an anabaseine derivative, selectively stimulates alpha 7-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 in the absence of a cholinesterase inhibitor. At 3.6 mumol/kg, s.c., anabaseine increased cortical ACh and NE above baseline values without significantly affecting DA and 5-HT. The ACh and NE elevations were inhibited by i.p. pre-administration (4.9 mumol/kg) of the nicotinic antagonist mecamylamine (Mec). In contrast, GTS-21 (3.6 mumol/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 upon ACh release, thereby permitting expression of the complete stimulatory effect of GTS-21 on neuronal alpha 7-receptors. GTS-21 and other receptor subtype-selective nicotinic agonists should be helpful in clarifying the roles of particular nicotinic receptors in modulating cortical neurotransmitter levels.