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 rela ted compounds on brain monoamine turnover. A single administration of (-)-nicotine (0.04, 0.2, 1.0, and 5.0 mg/kg SC) increased both noradre naline (NA) and dopamine (DA) turnover in a dose-dependent manner, and the maximum effects were achieved 30 min after treatment with (-)-nic otine (1.0 mg/kg). The effect of (-)-nicotine on serotonin (5-HT) turn over 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 (1.0 mg/kg)induced changes in monoamine turnover were bloc ked by pretreatment with the centrally acting nACh-R channel blocker m ecamylamine (2.0 mg/kg IP) but not by hexamethonium (2.0 mg/kg IP). Th ese findings indicate that systemically administered (-)-nicotine can enhance brain NA and DA turnover and affect 5-HT turnover, both of whi ch are mediated by central nACh-R. The changes in the monoamine turnov er induced by (+/-)-anabasine were similar to those induced by (-)-nic otine, while (-)-lobeline and (-)-cytisine had little effect, and 1,1- dimethyl-4-phenyl-piperazinium (DMPP) increased NA and 5-HT turnover b ut not DA turnover at all doses tested. (S)-3-Methyl-5-(1-methyl-2-pyr rolidinyl)isoxazole (ABT-418), a selective neuronal nACh-R agonist, in creased NA, DA and 5-HT turnover, but had a weaker effect on DA turnov er than NA and 5-HT turnover. In addition, 9-amino-1,2,3,4-tetrahydroa cridine (THA), an acetylcholine esterase inhibitor, also increased mon oamine turnover in the brain. Pretreatment with mecamylamine completel y 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 beta 2 subunit containing nACh-R , completely inhibited the nACh-R agonist- and THA-induced increases i n NA turnover, but not in DA turnover, and normalized the changes in 5 -HT turnover. In conclusion, the subtypes of nACh-Rs mediating DA turn over may be different from those mediating NA and 5-HT turnover in the CNS.