Lack of localization of 5-HT6 receptors on cholinergic neurons:: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release

The involvement of the cholinergic system in learning and memory together with the cognitive enhancing properties of 5-HT6 receptor antagonists led us to study the relationship between 5-HT6 receptors and cholinergic neurotransmission. A selective cholinergic lesion, induced by injection of the immunotoxin 192-IgG-Saporin into the nucleus basalis magnocellularis, failed to alter the density of 5-HT6 receptor mRNA or protein expression in the deafferentated frontal cortex, suggesting that 5-HT6 receptors are not located on cholinergic neurons. The 5-HT6 receptor antagonist SB-357134 (0.001-1 mu M) induced a concentration-dependant K+-evoked [H-3]acetylcholine (ACh) release in vitro in rat cortical and striatal slices, which was blocked by tetrodotoxin. SB-357134, up to 1 mu M, stimulated glutamate release in cortical and striatal slices. In the cortex, riluzole (1 mu M) blocked the SB-357134-induced K+-stimulated [H-3]ACh release, and simultaneous administration of MK-801 (1 mu M) and SB-357134 (0.05 mu M) elicited an increase in K+-evoked ACh release. In the striatum, SB-357134, 1 mu M, decreased dopamine release, and the increase in K+-evoked [H-3]ACh release induced by 5-HT6 receptor blockade was reversed by the D-1 receptor antagonist, SCH23390 (1 mu M). In both the frontal cortex and striatum, bicuculline, 1 mu M, showed no effect on SB-357134-evoked [H-3]ACh. These results are discussed in terms of neurochemical mechanisms involved in 5-HT6 receptor functions.