NEUROPSYCHOPHARMACOLOGY
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2021
·Vol. 47
·期 3
·652-663
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IF 7.855
Manz Kevin M.,Coleman Benjamin C.,Jameson Alexis N.,Ghose Dipanwita G.,Patel Sachin,Grueter Brad A.
Parvalbumin-expressing fast-spiking interneurons (PV-INs) within feedforward microcircuits in the nucleus accumbens (NAc) coordinate goal-directed motivational behavior. Feedforward inhibition of medium spiny projection neurons (MSNs) is initiated by glutamatergic input from corticolimbic brain structures. While corticolimbic synapses onto MSNs are targeted by the psychostimulant, cocaine, it remains unknown whether cocaine also exerts acute neuromodulatory actions at collateralizing synapses onto PV-INs. Using whole-cell patch-clamp electrophysiology, optogenetics, and pharmacological tools in transgenic reporter mice, we found that cocaine decreases thalamocortical glutamatergic drive onto PV-INs by engaging a monoamine-independent mechanism. This mechanism relies on postsynaptic sigma-1 (σ 1 ) activity, leading to the mobilization of intracellular Ca 2+ stores that trigger retrograde endocannabinoid signaling at presynaptic type-1 cannabinoid receptors (CB 1 R). Cocaine-evoked CB 1 R activity occludes the expression of CB 1 R-dependent long-term depression (LTD) at this synaptic locus. These findings provide evidence that acute cocaine exposure targets feedforward microcircuits in the NAc and extend existing models of cocaine action on mesolimbic reward circuits.
研究领域:
神经科学
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药理学
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DOI
PubMed
高影响因子
BEHAVIOURAL BRAIN RESEARCH
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2012
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IF 3.417
Haichen Niu,Yingwei Zheng,Joshua D. Rizak,Yaodong Fan,Wei Huang,Yuanye Ma,Hao Lei
Animals attain information about their environment through different sense organs. For example, the dominant external resource about the environment for rodents is obtained through olfaction. Many environmental conditions (stress or enriched environment) are known to affect an animal's susceptibility to drug addiction. However, it is not known how external information is integrated and paired with drug stimuli to develop into addictive behavior. Here, we investigated the effects of olfactory epithelium lesions induced with ZnSO4 effusion (ZnE) on morphine-induced sensitization and conditioned place preference in mice. We found that the lesion of the olfactory epithelium attenuated the repeated morphine (40 mg/kg)-induced behavioral sensitization and morphine-induced conditioned place preference (CPP) behaviors, such as hyper-locomotion during morphine (40 mg/kg) conditioned training. Additionally, the expression of FosB-like proteins, transcription factors associated with behavioral alterations, in the nucleus accumbens of the brain was attenuated in morphine administered mice treated by ZnE. Taken together, these results indicated that lesion of the olfactory epithelium lead to a decrease in morphine sensitization and CPP behavior in mice as well as modulate specific molecular markers of neuroadaption to drugs of abuse. These findings also suggest that olfaction plays an important role in the development of addictive behaviors that can be modulated by external actions.
研究领域:
神经科学
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药理学
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行为学
✓ 已验证
DOI
PubMed
高影响因子
Andrology
·
2022
·Vol. 10
·期 4
·808-817
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IF 4.456
Guotao Chen,Deshui Yu,Yunhong Wu,Jian Dong,Lei Hu,Ninghan Feng
Background The central molecular mechanisms of nonorganic erectile dysfunction remains unknown. Objective This study aimed to investigate the association of dopaminergic neurons projecting to the nucleus accumbens of male rats with nonorganic erectile dysfunction. Materials/methods Nonorganic erectile dysfunction was induced by chronic mild stress. The sucrose consumption test, sexual behavior test, and apomorphine test were carried out to select depression-like rats with erectile dysfunction. These rats were considered as nonorganic erectile dysfunction model rats. Dopamine D1/D2 receptor agonist/antagonist was infused into the nucleus accumbens to observe the effect on sexual behavior. Dopaminergic projections to the nucleus accumbens were labeled with both the retrograde tracer FluoroGold injected into the nucleus accumbens and tyrosine hydroxylase. The expression level of tyrosine hydroxylase in dopaminergic neurons projecting to the nucleus accumbens in the ventral tegmental area was measured. The expression levels of dopamine D1/D2 receptors and tyrosine hydroxylase in the nucleus accumbens were also measured. Results Nonorganic erectile dysfunction was proved by the sucrose consumption test, sexual behavior test, and apomorphine test in model rats. After central infusion of the dopamine D2 receptor agonist into the nucleus accumbens, the recovery of erectile function, sexual arousal, and motivation were indicated by increased intromission ratio and decreased mount latency. Decreased expression levels of dopamine D2 receptors and tyrosine hydroxylase in the nucleus accumbens and decreased expression level of tyrosine hydroxylase in the dopaminergic neurons projecting to the nucleus accumbens were observed in model rats. Discussion These results suggest the impairment of dopaminergic neurons projecting to the nucleus accumbens and dopamine D2 signaling in the nucleus accumbens, causing the suppression of erectile function, sexual arousal, and motivation. Conclusion These results suggest that the impaired dopamine D2 receptor pathway in the nucleus accumbens may be one of the main pathway involved in the development of nonorganic erectile dysfunction in the present model.
研究领域:
神经科学
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药理学
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行为科学
✓ 已验证
DOI
PubMed
高影响因子
NEURON
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2023
·
IF 16.2
Xiao-Na Zhu,Jie Li,Gao-Lin Qiu,Lin Wang,Chen Lu,Yi-Ge Guo,Ke-Xin Yang,Fang Cai,Tao Xu,Ti-Fei Yuan,Ji Hu
Summary Lasker’s award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia . Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT. Fiber photometry recording on awake freely moving mice and [ 18 F] FP-CIT-PET scanning further establishes that propofol administration evokes rapid and lasting dopamine accumulation in nucleus accumbens (NAc). The enhanced dopaminergic tone drives biased activation of dopamine-receptor-1-expressing medium spiny neurons (D1-MSNs) in NAc and reverses anhedonia in chronically stressed animals. Collectively, these findings suggest the therapeutic potential of propofol against anhedonia, which warrants future clinical investigations.
研究领域:
药理学
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神经科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2023
·
IF 14.5
Yue Zhang,Jingwen Gao,Na Li,Peng Xu,Shimeng Qu,Jinqian Cheng,Mingrui Wang,Xueru Li,Yaheng Song,Fan Xiao,Xinyu Yang,Jihong Liu,Hao Hong,Ronghao Mu,Xiaotian Li,Youmei Wang,Hui Xu,Yuan Xie,Tianming Gao,Guangji Wang,Jiye Aa
Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.
研究领域:
神经科学
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药理学
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精神病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NEUROSCIENCE
·
2025
·
IF 4
Tianyi Yang,Yan Chen,Maolin Wang,Ren Ren,Fang Yan,Peng Xu,Bin Di
Nitrous oxide use Disorder（NUD）has recently received increasing social concern for its sharp rise among young people. However, the underlying mechanisms of NUD remain largely unexplored, which obstructs treatment strategy development and may exacerbate the epidemic of N2O abuse. Thus, specifying the essential mechanisms and targets in NUD are desperately needed. Here we unveiled a series of molecular adaptations regarding N2O reward memory in Nucleus accumbens (NAc) of mice through multi-omics approaches comprising transcriptomics, proteomics, metabolomics approaches. Our miRNA transcriptomics and pull-down proteomics analyzes uncovered that miR-7220-5p regulated N2O-induced conditioned-place preference (CPP) and associated increase of dendritic spine density in NAc of male mice. Our pull-down proteomics and metabolomics analyzes revealed that miR-7220-5p modulated ERK signaling pathway by directly binding with NR2B receptor. In summary, our work confirmed that restoring miR-7220-5p expression in NAc protected against synaptic abnormality via the NR2B/ERK/CREB signaling, thereby attenuating CPP behaviors in NUD. Selective inhibition of NR2B or ERK signaling blocked the reward memory of N2O-CPP via NAc microinjection. Our study proposed a potential therapeutic strategy for NUD and provided comprehensive resources of biological data to support future investigations of NUD treatment.Significance Statement Nitrous oxide Use Disorder (NUD) has recently received tremendously increasing social concern for its sharp rise among young people. Although the neurological consequences and their etiologies of consuming N2O have been well elucidated, the underlying mechanisms of NUD remain largely unexplored, which obstructs the development of clinical treatment strategies and may exacerbate the epidemic of N2O abuse. Our work uncovered the role of miR-7220-5p/NR2B/ERK/CREB signaling against synaptic abnormality/CPP behaviors. Selective inhibition of NR2B or ERK signaling blocked the reward memory of N2O-CPP via NAc microinjection. Our study proposed therapeutic targets for overcoming NUD behaviors and the omics data provided comprehensive biological resources to support future investigations of NUD.
研究领域:
神经科学
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分子生物学
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药理学
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生物信息学
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精神病学
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细胞信号传导
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成瘾研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
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2021
·
IF 5.251
Mengwen Shi,Jiaxin Tang,Chengmei Yang,Guanlong Guo,Huaxing Ou,Weihai Chen
Prepulse inhibition (PPI) is disrupted in many neuropsychiatric diseases. Although the inverse agonist of the 5-hydroxytryptamine 2A (5-HT 2A ) receptors, pimavanserin , alleviates PPI deficits in rodents, the precise mechanisms and critical brain areas in the reversal effect of 5-HT 2A receptor inverse agonists remain unclear. The present study aimed to investigate the critical brain areas responsible for the reversal effect of the 5-HT 2A receptor inverse agonist on PPI deficits in male mice. The results showed that intraperitoneal administration of pimavanserin was found to improve normal PPI behavior and reverse PPI deficits elicited by the dopamine D 1 /D 2 receptor nonselective agonist, pergolide . Further, local infusion of pimavanserin into the nucleus accumbens and ventral hippocampus reversed PPI deficits, whereas the same manipulation in the medial prefrontal cortex or ventral tegmental area did not reverse PPI deficits. Overall, the nucleus accumbens and ventral hippocampus are the critical brain areas responsible for the reversal effect of 5-HT 2A inverse agonists on PPI deficits. Such findings contribute to the extensive exploration of the accurate molecular and neural mechanisms underlying the antipsychotic effects of 5-HT 2A receptor inverse agonists, especially the neural circuits modulated by 5-HT 2A receptor activity.
研究领域:
神经科学
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药理学
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精神病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2021
·Vol. 178
·期 24
·4808-4825
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IF 8.74
Yan-Fei Yang,Hui Dong,Yan Shen,Lei Li,Michael Lazarus,Wei-Min Qu,Zhi-Li Huang
Background and Purpose Modafinil is a potent eugeroic (wakefulness-promoting) drug that is prescribed to treat narcolepsy and has a low incidence of abuse. Although previous studies have shown that modafinil-induced arousal depends on the dopamine receptors and transporters, the specific part/s of the dopamine transmitter system underlying this mechanism remained unclear. Here, we investigated the role of mesencephalic dopamine neurons in modafinil-evoked arousal. Experimental Approach A dopamine indicator (dLight1.1) was employed to detect dopamine changes in the nucleus accumbens (NAc) and dorsal striatum. We specifically lesioned mesencephalic dopamine neurons via diphtheria toxin (DTA) in the dopamine transporter (DAT)-Cre mice. Then, the sleep–wake states were recorded to evaluate the effect of modafinil on arousal. Finally, the extent of DTA-induced lesions was determined by immunohistochemistry. Key Results Modafinil promptly increased dopamine levels in the NAc and dorsal striatum in a dose-dependent manner. Lesioning of dopamine neurons in the substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) had no significant effects on physiological sleep–wake cycles. Modafinil at 90 mg·kg −1 increased continuous wakefulness for 355 min in control mice. However, these effects were slightly decreased by 6.7% in the SNc-lesioned mice and were prominently diminished by 32.8% in VTA-lesioned mice. Furthermore, the modafinil-induced arousal was completely blocked in the SNc-VTA-lesioned mice, whereas lesions of the dorsal raphé nucleus had no effect. Conclusion and Implications Taken together, our findings indicate that mesencephalic dopamine neurons are essential for modafinil-induced arousal. Graphical
研究领域:
神经科学
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药理学
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睡眠医学
✓ 已验证
DOI
PubMed
高影响因子
NEUROSCIENCE LETTERS
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2022
·
IF 3.197
Tianyi Yang,Guang Yue,Yu Ge,Yue Zhang,Peng Xu,Youmei Wang,Bo Li,Bin Di
Nitrous oxide (N 2 O) has a long history of abuse, but its abuse mechanism has not been clear yet. This research aimed at the possibility of mesolimbic dopaminergic system (MLDS) involved in the rewarding effect of N 2 O. In this work, the rewarding behavior of N 2 O in mice was evaluated using a typical gas-administered conditioned place preference (CPP) procedure. SCH 23390, a Dopamine D1 receptor (D1R) antagonist, and Haloperidol, a Dopamine D2 receptor (D2R) antagonist were administered during CPP to evaluate the role of dopamine receptors in the N 2 O-induced CPP. The accompanying changes in phosphorylation of extracellular signal-regulated kinase (ERK) in MLDS related brain regions, including the ventral tegmental area (VTA), caudate putamen (CPu), prefrontal cortex (PFC), and nucleus accumbens (NAc) were measured to assess the neural plasticity changes in the CPP mice by Western blot analysis. Results revealed that 60% N 2 O induced CPP in the gas-administered mice and promoted the ERK phosphorylation (p-ERK) in the NAc and CPu during the test session of the CPP test. Pretreatment of SCH 23390 (0.5 mg/kg) inhibited the acquisition of N 2 O-induced CPP and the enhanced p-ERK in NAc. It suggested that Dopamine D1 receptor may play an important role in the acquisition of N 2 O-induced CPP and the accompanied ERK activation in the NAc, which provide insight into the molecular mechanism in the rewarding properties of nitrous oxide.
研究领域:
神经科学
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药理学
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行为科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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