Effect of differential rearing environments on nicotine-stimulated locomotor activity and nicotinic acetylcholine receptor subtypes

OBJECTIVE Individuals vary in sensitivity to the behavioral effects of nicotine,resulting in differences in their vulnerability to addiction.The role of rearing environment in determining individual sensitivity to nicotine is unclear.The neuropharmacological mechanisms mediating the effect of rearing environment on the actions of nicotine are also understood.Thus,the contribution of rearing environment in determining the sensitivity to the locomotor effects of nicotine and regulating α4β2*-and α7-nicotinic acetylcholine(n ACh) receptor expressionwas determined in rats reared in isolated(IC) or enriched(EC) conditions.METHODS To measure locomotor activity,adolescent rats(postnatal day 21-51)were injected with saline(1 mL·kg^(-1)) or nicotine(0.3 mg·kg^(-1)) subcutaneously,then placed in chamberswhere ambulatory activity was monitored for 30-min by computer for 14 daily sessions.α4β2*-andα7-n ACh receptor expression in the mesolimbic dopamine pathway was determined by quantitative autoradiography of [125 I]-epibatidine and [125 I]-bungarotoxinbinding,respectively,in 16 μmol·L^(-1) coronal sections.Values for receptor expression in fmol are ±s of 8 brains and compared by two-tailed,unpaired t-test with P<0.05 considered significant.RESULTS EC-rats are similarly sensitive as IC-rats to the locomotor effects of nicotine.[125 I]-epibatidine binding in the ventral tegmental area of EC-rats was reduced(2.8±0.3 fmo L) compared to IC-rats(4.0±0.4 fmo L);there was no difference in the nucleus accumbens.There was no difference between EC-and IC-rats in α7-n ACh receptor expression in the mesolimbic dopamine pathway.CONCLUSION Rearing environment differentially regulates n ACh receptor subtypes in EC and IC rats.These data suggest regulation of n ACh receptors by environmental factors may be a mechanism for the protective effect of enrichment against altered sensitivity to nicotine in genetically vulnerable individuals.The characterization of these mechanisms will aid in development of novel pharmacological tools mimicking the protection afforded by environmental enrichment in nicotine-sensitive individuals.

Nicotine-induced transcriptional changes and mitochondrial dysfunction in the ventral tegmental area revealed by single-nucleus transcriptomics

Nicotine is widely recognized as the primary contributor to tobacco dependence.Previous studies have indicated that molecular and behavioral responses to nicotine are primarily mediated by ventral tegmental area(VTA)neurons,and accumulating evidence suggests that glia play prominent roles in nicotine addiction.However,VTA neurons and glia have yet to be characterized at the transcriptional level during the progression of nicotine self-administration.Here,a male mouse model of nicotine self-administration is established and the timing of three critical phases(pre-addiction,addicting,and post-addiction phase)is characterized.Single-nucleus RNA sequencing in the VTA at each phase is performed to comprehensively classify specific cell subtypes.Adaptive changes occurred during the addicting and post-addiction phases,with the addicting phase displaying highly dynamic neuroplasticity that profoundly impacts the transcription in each cell subtype.Furthermore,significant transcriptional changes in energy metabolism-related genes are observed,accompanied by notable structural alterations in neuronal mitochondria during the progression of nicotine self-administration.The results provide insights into mechanisms underlying the progression of nicotine addiction,serving as an important resource for identifying potential molecular targets for nicotine cessation.

L-theanine inhibits nicotine-induced dependence via regulation of the nicotine acetylcholine receptor-dopamine reward pathway

In this study, the inhibitory effect of L-theanine, an amino acid derivative of tea, on the rewarding effects of nicotine and its underlying mechanisms of action were studied. We found that L-theanine inhibited the rewarding effects of nicotine in a con- ditioned place preference （CPP） model of the mouse and reduced the excitatory status induced by nicotine in SH-SY5Y cells to the same extent as the nicotine receptor inhibitor dihydro-beta-erythroidine （DHI3E）. Further studies using high performance liquid chromatography, western blotting and immunofluorescence staining analyses showed that L-theanine significantly in- hibited nicotine-induced tyrosine hydroxylase （TH） expression and dopamine production in the midbrain of mice. L-theanine treatment also reduced the upregulation of the ~4,132 and c^7 nicotine acetylcholine receptor （nAChR） subunits induced by nico- tine in mouse brain regions that related to the dopamine reward pathway, thus decreasing the number of cells that could react to nicotine. In addition, L-theanine treatment inhibited nicotine-induced c-Fos expression in the reward circuit related areas of the mouse brain. Knockdown of c-Fos by siRNA inhibited the excitatory status of cells but not the upregulation of TH induced by nicotine in SH-SY5Y cells. Overall, the present study showed that L-theanine reduced the nicotine-induced reward effects via inhibition of the nAChR-dopamine reward pathway. These results may offer new therapeutic strategies for treatment of to- bacco addiction.

Reanalysis of Cigarettes Confirms Increased Addictive Nicotine

吸烟对人健康的危害不言而喻,"戒烟"也早已成为关注公众健康的各国政府努力的方向。然而面对席卷全球的戒烟浪潮的烟草商们却在悄悄采取策略以保障他们的收益:他们增加每根香烟中尼古丁的含量,刻意延长人们吸一支烟的时间,或是增加吸烟时吞吐烟雾的次数。烟草商的目的只有一个,即千方百计诱使人们对香烟更加上瘾!针对这种现象,人们不得不呼吁司法层面的监控。