Lack of localization of 5‐HT 6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5‐HT 6 receptor‐mediated acetylcholine release

The involvement of the cholinergic system in learning and memory together with the cognitive enhancing properties of 5‐HT 6 receptor antagonists led us to study the relationship between 5‐HT 6 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‐HT 6 receptor mRNA or protein expression in the deafferentated frontal cortex, suggesting that 5‐HT 6 receptors are not located on cholinergic neurons. The 5‐HT 6 receptor antagonist SB‐357134 (0.001–1 µ m ) induced a concentration‐dependant K + ‐evoked [ 3 H]acetylcholine (ACh) release in vitro in rat cortical and striatal slices, which was blocked by tetrodotoxin. SB‐357134, up to 1 µ m , stimulated glutamate release in cortical and striatal slices. In the cortex, riluzole (1 µ m ) blocked the SB‐357134‐induced K + ‐stimulated [ 3 H]ACh release, and simultaneous administration of MK‐801 (1 µ m ) and SB‐357134 (0.05 µ m ) elicited an increase in K + ‐evoked ACh release. In the striatum, SB‐357134, 1 µ m , decreased dopamine release, and the increase in K + ‐evoked [ 3 H]ACh release induced by 5‐HT 6 receptor blockade was reversed by the D 1 receptor antagonist, SCH23390 (1 µ m ). In both the frontal cortex and striatum, bicuculline, 1 µ m , showed no effect on SB‐357134‐evoked [ 3 H]ACh. These results are discussed in terms of neurochemical mechanisms involved in 5‐HT 6 receptor functions.