AUTHOR=Guo Lulu , Mao Jian , Zhang Qidong , Fan Wu , Wang Dingzhong , Li Zhonghao , Huang Jiaqiang , Xie Jianping 

TITLE=Pharmacokinetic and pharmacodynamic studies of nicotine in rat brain: a simultaneous investigation of nicotine metabolites and the release of neurotransmitters in vivo

JOURNAL=Frontiers in Chemistry

VOLUME=Volume 11 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2023.1275478

DOI=10.3389/fchem.2023.1275478

ISSN=2296-2646

ABSTRACT=Little knowledge about the real-time changes of neurochemicals during brain nicotine (Nic) metabolic process hinders the recognition of its multiple neuropharmacological effects. The biggest challenge lies in the insufficiency in synchronous investigation of brain Nic pharmacokinetics and the characteristics of local neurotransmitter release. Here, a precolumn "one-step" derivatization-based online microdialysis coupled with UHPLC-HRMS/MS system was developed for the in vivo sampling and direct, dynamic multi-analysis of Nic metabolites and several neurochemicals from rat brains. The dynamic profiles of more than 10 Nic metabolites and neurotransmitters were simultaneously obtained after Nic single injection (2 mg• kg -1 , i.p.), which confirmed the feasibility and reliability of the method. Good linearity (R 2 > 0.994), precision (RSD from 1.68% to 8.44%) and accuracy (RE from -2.56% to 6.47%) passed the criteria for all target analytes, respectively. Compared to the saline-pretreated group, proadifen pretreatment (50 mg• kg -1 • d -1 , i.p., 4 days) caused significant inhibition of brain CYP2B1 activity to decrease by 36.9% averagely. When exposed to Nic, the brain Cmax of Nic was 1.26 times higher and the levels of Nic metabolites, nornicotine, and nicotine-N-oxide, were decreased by 85.3% and 34.4% in proadifen-pretreated rats. Meanwhile, the higher level of brain Nic induced more release of dopamine, serotonin, glutamate, and γ-amino-butyric acid in the nucleus accumbens. The concentrations of Nic and dopamine were positive correlated, and the average levels of γ-amino-butyric acid and serotonin were 2.7 and 1.2 times higher under the inhibition of Nic metabolism. These results demonstrated that the novel and effective method pave the way for synchronously monitoring the longtime minor changes of extracellular transmitters during the brain Nic metabolic process, and the metabolic activity of Nic under different physiological conditions could regulate the residence of brain Nic and its pharmacological effects.