3-[2,4-dimethoxybenzylidene]anabaseine (DMXB) selectively activates rat alpha 7 receptors and improves memory-related behaviors in a mecamylamine-sensitive manner

The alpha 7 nicotinic receptor agonist 3-[2,4-dimethoxybenzylidene]anabaseine (DMXB; GTS-21) was investigated for its ability to: (1) activate a variety of nicotinic receptor subtypes in Xenopus oocytes; (2) improve passive avoidance and spatial Morris water task performances in mecamylamine-sensitive manners in bilaterally nucleus basalis lesioned rats; and (3) elevate high-affinity [H-3]acetylcholine (ACh) and high-affinity alpha-[I-125]bungarotoxin binding in rat neocortex following 2 weeks of daily injections. DMXB (100 mu M) activated alpha 7 homo-oligomeric receptors, without significant activity at alpha 2-, alpha 3-and alpha 4-containing subtypes. Mecamylamine blocked rat alpha 7 receptors weakly if co-administered with agonist, but much more potently when pre-applied. Bilateral ibotenic acid lesions of the nucleus basalis interfered with passive avoidance and spatial memory-related behaviors. DMXB (0.5 mg/kg, i.p.) improved passive avoidance behavior in lesioned animals in a mecamylamine-sensitive manner. DMXB (0.5 mg/kg 15 min before each session) also improved performance in the training and probe components of the Morris water task. DMXB-induced improvement in the probe component but not the training phase was mecamylamine-sensitive. [H-3]ACh binding was elevated after 14 days of daily i.p. injections with 0.2 mg/kg nicotine but not after 1 mg/kg DMXB. Neither drug elevated high-affinity alpha-[I-125]bungarorotoxin binding over this interval. (C) 1997 Elsevier Science B.V.