Masahiro Imoto

Pharmacological characterization of nicotinic receptor-mediated acetylcholine release in rat brain : an in vivo microdialysis study

In vivo microdialysis was used to investigate nicotinic receptor-mediated acetylcholine release in the hippocampus, frontal cortex, and striatum of freely moving rats. Intraperitoneal administration of (-)-nicotine increased the release of acetylcholine in the hippocampus and frontal cortex but not in the striatum. (-)-Nicotine exhibited a bell-shaped dose-response relationship, and showed attenuation of response at the highest dose (5.0 mg/kg i.p.) in both the hippocampus and frontal cortex. In the hippocampus, (-)-nicotine (1.0 mg/kg i.p.)-induced increase of acetylcholine release was blocked by pretreatment with the centrally acting nicotinic receptor channel blocker, mecamylamine (1.0 mg/kg i.p.), but not by hexamethonium (5.0 mg/kg i.p.), suggesting that the effects of (-)-nicotine were mediated by the central nicotinic receptor. (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT-418, 1.0 and 5.0 mg/kg i.p.), reported to be a selective agonist for alpha4beta2 nicotinic receptor subunits, also enhanced the release of acetylcholine in the hippocampus, while 3-(2,4-dimethoxybenzlidene)-anabaseine (GTS-21, 1.0 and 5.0 mg/kg i.p.), which has high affinity for the alpha7 nicotinic receptor subunit, was without effect. The natural alkaloids isolated from plants, (-)-cytisine and (-)-lobeline, had little effect on acetylcholine release from the hippocampus. A competitive antagonist for alpha4beta2 subunits of the nicotinic receptor, dihydro-beta-erythroidine, and a partial agonist for the beta2 subunit-containing nicotinic receptor, (-)-cytisine, inhibited (-)-nicotine-induced increase of acetylcholine release from the hippocampus, whereas a selective antagonist for the alpha7 subunit, methyllycaconitine, and a partial agonist for the alpha3 subunit-containing nicotinic receptor, (-)-lobeline, did not. These results indicate that there are certain differences among brain regions in the response of nicotinic receptor-mediated acetylcholine release and that (-)-nicotine-induced acetylcholine release in the rat hippocampus may be attributed to activation of the alpha4beta2 nicotinic receptor subunits.

Nicotinic acetylcholine receptor (nACh-R) agonist-induced changes in brain monoamine turnover in mice

The aim of the present study was to evaluate the effects of nicotinic acetylcholine receptor (nACh-R) agonists such as (−)-nicotine and related compounds on brain monoamine turnover. A single administration of (−)-nicotine (0.04, 0.2, 1.0, and 5.0 mg/kg SC) increased both noradrenaline (NA) and dopamine (DA) turnover in a dose-dependent manner, and the maximum effects were achieved 30 min after treatment with (−)-nicotine (1.0 mg/kg). The effect of (−)-nicotine on serotonin (5-HT) turnover was complicated; 5-HT turnover was increased at a low dose of (−)-nicotine (0.04 mg/kg) but decreased at a high dose (1.0 mg/kg). The (−)-nicotine (1.0mg/kg)-induced changes in monoamine turnover were blocked by pretreatment with the centrally acting nACh-R channel blocker mecamylamine (2.0 mg/kg IP) but not by hexamethonium (2.0 mg/kg IP). These findings indicate that systemically administered (−)-nicotine can enhance brain NA and DA turnover and affect 5-HT turnover, both of which are mediated by central nACh-R. The changes in the monoamine turnover induced by (±)-anabasine were similar to those induced by (−)-nicotine, while (−)-lobeline and (−)-cytisine had little effect, and l,l-dimethyl-4-phenyl-piperazinium (DMPP) increased NA and 5-HT turnover but not DA turnover at all doses tested. (S)-3-Methyl-5-(l-methyl-2-pyrrolidinyl)isoxazole (ABT-418), a selective neuronal nACh-R agonist, increased NA, DA and 5-HT turnover, but had a weaker effect on DA turnover than NA and 5-HT turnover. In addition, 9-amino-l,2,3,4-tetrahydroacridine (THA), an acetylcholine esterase inhibitor, also increased monoamine turnover in the brain. Pretreatment with mecamylamine completely blocked the THA-induced increase in NA and 5-HT turnover, but not in DA turnover, suggesting that the nACh-R system is involved in the THA-induced increase in brain NA and 5-HT turnover. On the other hand, (−)-cytisine, a partial agonist for the β2 subunit containing nACh-R, completely inhibited the nACh-R agonist-and THA-induced increases in NA turnover, but not in DA turnover, and normalized the changes in 5-HT turnover. In conclusion, the subtypes of nACh-Rs mediating DA turnover may be different from those mediating NA and 5-HT turnover in the CNS.