The study of α4β2 nicotinic receptors has provided new indications in the treatment of pain. Efforts have been made to explore new α4β2 nicotinic receptor agonists, including TC-2559, as antinociceptive drugs. In ...The study of α4β2 nicotinic receptors has provided new indications in the treatment of pain. Efforts have been made to explore new α4β2 nicotinic receptor agonists, including TC-2559, as antinociceptive drugs. In this study, we discovered a set of novel epibatidine analogs with strong binding affinities to the α4β2 nicotinic receptors. Among these compounds, C-159, C-163, and C-9515 attenuated formalin-induced nociceptive responses in mice; C-9515 caused the most potent analgesic effect, which was blocked by mecamylamine, a non-selective nicotinic receptor antagonist. Furthermore, C-9515 potently inhibited chronic constriction injury(CCI)-induced neuropathic pain in rats, which was sensitive to DHβE, a selective α4β2 subtype antagonist,indicating that its analgesic effect was mediated by the activation of the α4β2 nicotinic receptors. In conclusion, the epibatidine analog C-9515 was found to be a potent α4β2 nicotinic receptor agonist with potent analgesic function, which demonstrated potential for the further exploration of its druggability.展开更多
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 nic...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.展开更多
Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4...Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4β2 nicotinic acetylcholine receptor(nAChR)on corticosterone(CORT)injured mice and cellular models.Fluoxetine was applied as a positive control,and the effects of VMY-2-95 were investigated with three different doses or concentrations(1,3,10 mg/kg in mice,and 0.003,0.03,0.1μmol/L in cells).As a result,VMY-2-95 showed significant antidepressant-like effects in the CORT injured mice by improving neuromorphic function,promoting hippocampal nerve proliferation,and regulating the contents of monoamine transmitters.Meanwhile,VMY-2-95 exhibited protective effects on cell viability,cell oxidant,cell apoptosis,and mitochondrial energy metabolism on corticosterone-impaired SH-SY5 Y cells.Also,the PKA-CREB-BDNF signaling pathway was up-regulated by VMY-2-95 both in vitro and in vivo,and pathway blockers were also combined with VMY-2-95 to verify the effects furtherly.Therefore,we preliminarily proved that VMY-2-95 had protective effects in depressed mice and SH-SY5 Y cells against injuries induced by corticosterone.This work indicated that the application of VMY-2-95 is a potential pharmacological solution for depression.This study also supported the development ofα4β2 nAChR antagonists towards neuropsychiatric dysfunctions.展开更多
基金supported by the National Natural Science Foundation of China(31471027,81400895 to Yun Wang and Weiwei Li)
文摘The study of α4β2 nicotinic receptors has provided new indications in the treatment of pain. Efforts have been made to explore new α4β2 nicotinic receptor agonists, including TC-2559, as antinociceptive drugs. In this study, we discovered a set of novel epibatidine analogs with strong binding affinities to the α4β2 nicotinic receptors. Among these compounds, C-159, C-163, and C-9515 attenuated formalin-induced nociceptive responses in mice; C-9515 caused the most potent analgesic effect, which was blocked by mecamylamine, a non-selective nicotinic receptor antagonist. Furthermore, C-9515 potently inhibited chronic constriction injury(CCI)-induced neuropathic pain in rats, which was sensitive to DHβE, a selective α4β2 subtype antagonist,indicating that its analgesic effect was mediated by the activation of the α4β2 nicotinic receptors. In conclusion, the epibatidine analog C-9515 was found to be a potent α4β2 nicotinic receptor agonist with potent analgesic function, which demonstrated potential for the further exploration of its druggability.
基金supported by Nebraska Cancer and Smoking Disease Research Programs LB506and LB595 to CS BOCKMAN and DJ STAIRS
文摘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.
基金supported by the National Natural Science Foundation of China(No.81603100)the Drug Innovation Major Project(2018ZX09711001-003-005,2018ZX09711001-012,China)+1 种基金CAMS Innovation Fund for Medical Sciences(2017-I2M1-010,China)Peking Union Medical College Graduate Innovation Fund Project(2017-1007-11,China)
文摘Nicotinicα4β2 receptor antagonists have drawn increasing attention in the development of new antidepressants.In this study,we aimed to investigate the protective effect of VMY-2-95,the new selective antagonist ofα4β2 nicotinic acetylcholine receptor(nAChR)on corticosterone(CORT)injured mice and cellular models.Fluoxetine was applied as a positive control,and the effects of VMY-2-95 were investigated with three different doses or concentrations(1,3,10 mg/kg in mice,and 0.003,0.03,0.1μmol/L in cells).As a result,VMY-2-95 showed significant antidepressant-like effects in the CORT injured mice by improving neuromorphic function,promoting hippocampal nerve proliferation,and regulating the contents of monoamine transmitters.Meanwhile,VMY-2-95 exhibited protective effects on cell viability,cell oxidant,cell apoptosis,and mitochondrial energy metabolism on corticosterone-impaired SH-SY5 Y cells.Also,the PKA-CREB-BDNF signaling pathway was up-regulated by VMY-2-95 both in vitro and in vivo,and pathway blockers were also combined with VMY-2-95 to verify the effects furtherly.Therefore,we preliminarily proved that VMY-2-95 had protective effects in depressed mice and SH-SY5 Y cells against injuries induced by corticosterone.This work indicated that the application of VMY-2-95 is a potential pharmacological solution for depression.This study also supported the development ofα4β2 nAChR antagonists towards neuropsychiatric dysfunctions.
