scholarly journals Acupuncture attenuates alcohol dependence through activation of endorphinergic input to the nucleus accumbens from the arcuate nucleus

2019 ◽  
Vol 5 (9) ◽  
pp. eaax1342 ◽  
Author(s):  
Suchan Chang ◽  
Dan Hyo Kim ◽  
Eun Young Jang ◽  
Seong Shoon Yoon ◽  
Young Seob Gwak ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Alcohol Dependence ◽  
Alcohol Use Disorder ◽  
Arcuate Nucleus ◽  
Ethanol Withdrawal ◽  
Potential Treatment ◽  
Self Administration ◽  
Behavioral Manifestation ◽  
Acupuncture Effects ◽  
The Brain

A withdrawal-associated impairment in β-endorphin neurotransmission in the arcuate nucleus (ARC) of the hypothalamus is associated with alcohol dependence characterized by a chronic relapsing disorder. Although acupuncture activates β-endorphin neurons in the ARC projecting to the nucleus accumbens (NAc), a role for ARC β-endorphin neurons in alcohol dependence and acupuncture effects has not been examined. Here, we show that acupuncture at Shenmen (HT7) points attenuates behavioral manifestation of alcohol dependence by activating endorphinergic input to the NAc from the ARC. Acupuncture attenuated ethanol withdrawal tremor, anxiety-like behaviors, and ethanol self-administration in ethanol-dependent rats, which are mimicked by local injection of β-endorphin into the NAc. Acupuncture also reversed the decreased β-endorphin levels in the NAc and a reduction of neuronal activity in the ARC during ethanol withdrawal. These results suggest that acupuncture may provide a novel, potential treatment strategy for alcohol use disorder by direct activation of the brain pathway.

scholarly journals Assessing the role of long-noncoding RNA in nucleus accumbens in subjects with alcohol dependence

2019 ◽  
Author(s):  
Gowon O. McMichael ◽  
John Drake ◽  
Eric Sean Vornholt ◽  
Kellen Cresswell ◽  
Vernell Williamson ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Alcohol Dependence ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Enrichment Analysis ◽  
Protein Coding ◽  
Network Analyses ◽  
Snp Data ◽  
The Brain

AbstractRecently, long noncoding RNA (lncRNA) were implicated in the etiology of alcohol dependence (AD). As lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the brain is the first critical step towards understanding lncRNA functions in AD. To that end, we profiled the expression of lncRNA and protein coding genes (PCG) in nucleus accumbens (NAc) from 41 subjects with AD and 41 controls. At false discovery rate (FDR) of 5%, we identified 69 and 309 differentially expressed lncRNA and PCG genes, respectively. Using co-expression network analyses, we identified three lncRNA and five PCG modules significantly correlated with AD at Bonferroni adj. p≤0.05. To better understand lncRNA functions, we integrated the lncRNA and PCG hubs from the significant AD modules; at FDR of 5%, we identified 3 151 positive and 2 255 negative correlations supporting the functional role of lncRNA in the development of AD. Gene enrichment analysis revealed that PCG significantly correlated with lncRNA are, among others, enriched for neuronal and immune related processes. To highlight the mechanisms, by which genetic variants contribute to AD, we integrated lncRNA and PCG hubs with genome-wide SNP data. At FDR≤0.3, we identified 276 expression quantitative trait loci (eQTL), affecting the expression of 20 and 256 lncRNA and PCG hubs, respectively. Our study is the first to profile lncRNA expression in nucleus accumbens in a large postmortem alcohol brain sample and our results may provide novel insights into the regulation of the brain transcriptome across disease.

scholarly journals Interaction of dopamine, nitric oxide and testosterone in the brain system of motivational reinforcement in rats with alcohol dependence and under nitric oxide donator impact

2018 ◽  
Keyword(s):  
Nitric Oxide ◽  
Nucleus Accumbens ◽  
Alcohol Consumption ◽  
Alcohol Dependence ◽  
Alcohol Withdrawal ◽  
Brain Structures ◽  
Male Rats ◽  
Dopamine Level ◽  
Testosterone Concentration ◽  
The Brain

The complex of neurophysiological methods (stereotaxic implantation of electrodes into brain structures, recording of electrical activity of the neocortex, hippocampus, hypothalamus, and nucleus accumbens) was applied to 65 laboratory male rats with models of chronic alcoholization (during 40 days of alcohol consumption in dose 1.25 g/kg body mass) and alcohol withdrawal during 2 days. The leading role of functional changes of electrogenesis in hippocampus, hypothalamus and nucleus accumbens has been revealed in rats being in states of alcohol dependence. The highest absolute spectral powers of oscillations of the β and Ѳ rhythms in the hippocampus and manifestations of generalized hypersynchronous activity with initiation in the hippocampus and hypothalamus were noted in rats under alcohol dependence. The paroxysmal pattern of activity on EEG of the structures of the limbico-neocortical system acquired an “explosive” character after alcohol withdrawal. The complex of neurochemical methods (detection of dopamine and testosterone concentration with enzymoimmunoassay and nitric oxide concentration with spectrophotometric analysis in the brain structures and serum) was carried out after 40 days of alcoholization as well as after 2 days of alcohol withdrawal. Decreased levels of testosterone and nitric oxide were identified in hypothalamus and hippocampus as well as testosterone in nucleus accumbens and serum. There were observed increased dopamine release in nucleus accumbens in response to latest dose of alcohol consumption and recovery of dopamine level after alcohol withdrawal. To the contrary, the dopamine content decreased in hypothalamus in the state of alcohol withdrawal. The five-time (twice a day) intranasal introduction of sodium nitroprusside repaired nitric oxide and testosterone levels in the brain structures of motivational reinforcement and suppressed seizure pattern on EEG but didn’t change testosterone concentration in serum. Obtained data are considered as one of the important aspects of interactions in the system of hormonal-neurotransmitter-metabolic regulatory mechanisms of motivational reinforcement under formation and suppression of alcohol dependence.

scholarly journals Central orexin (hypocretin) 2 receptor antagonism reduces ethanol self-administration, but not cue-conditioned ethanol-seeking, in ethanol-preferring rats

2013 ◽  
Vol 16 (9) ◽  
pp. 2067-2079 ◽  
Author(s):  
Robyn Mary Brown ◽  
Shaun Yon-Seng Khoo ◽  
Andrew John Lawrence
Keyword(s):  
Nucleus Accumbens ◽  
G Protein Coupled Receptors ◽  
Self Administration ◽  
Potential Therapeutic Target ◽  
Guide Cannulae ◽  
Hypothalamic Neuropeptides ◽  
Reinforcing Effects ◽  
G Protein Coupled ◽  
The Brain

Abstract Orexins are hypothalamic neuropeptides which bind to two G-protein-coupled receptors, orexin-1 (OX1R) and orexin-2 (OX2R) receptor. While a role for OX1R has been established in both ethanol reinforcement and ethanol-seeking behaviour, the role of OX2R in these behaviours is relatively less-studied. The aim of this study was to determine the role of central OX2R in ethanol-taking and ethanol-seeking behaviour. Indiana ethanol-preferring rats were trained to self-administer ethanol (10% w/v) or sucrose (0.7–1% w/v) in the presence of reward-associated cues before being implanted with indwelling guide cannulae. The selective OX2R antagonist TCS-OX2-29 was administered i.c.v. to assess its effect on operant self-administration and cue-induced reinstatement following extinction. Following i.c.v. injection TCS-OX2-29 reduced self-administration of ethanol, but not sucrose. Despite reducing ethanol self-administration, TCS-OX2-29 had no impact on cue-induced reinstatement of ethanol seeking. To determine where in the brain OX2R were acting to modulate ethanol self-administration, TCS-OX2-29 was microinjected into either the shell or core of the nucleus accumbens (NAc). Intra-NAc core, but not shell, infusions of TCS-OX2-29 decreased responding for ethanol. Importantly, the doses of TCS-OX2-029 used were non-sedating. Collectively, these findings implicate OX2R in the NAc in mediating the reinforcing effects of ethanol. This effect appears to be drug-specific as antagonism of central OX2R had no impact on sucrose self-administration. Thus, OX2R in addition to OX1R may represent a potential therapeutic target for the treatment of ethanol-use disorders. However, unlike OX1R, no impact of OX2R antagonism was observed on cue-induced reinstatement, suggesting a more prominent role for OX2R in ethanol self-administration compared to cue-conditioned ethanol-seeking.

Animal models of alcohol use disorder and the brain: From casual drinking to dependence.

2019 ◽  
Vol 5 (3) ◽  
pp. 222-242 ◽  
Author(s):  
Nicole A. Crowley ◽  
Nigel C. Dao ◽  
Sarah N. Magee ◽  
Alexandre J. Bourcier ◽  
Emily G. Lowery-Gionta
Keyword(s):  
Alcohol Use ◽  
Animal Models ◽  
Alcohol Use Disorder ◽  
The Brain

Alcohol Use Disorder

2018 ◽  
Author(s):  
Igor Ponomarev
Keyword(s):  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
Critical Discussion ◽  
Epigenetic Mechanisms ◽  
Future Directions ◽  
Clinically Significant ◽  
Early Life Exposures ◽  
The Brain ◽  
Epigenetic Research

Alcohol use disorder (AUD) is characterized by clinically significant impairments in health and social function. Epigenetic mechanisms of gene regulation may provide an attractive explanation for how early life exposures to alcohol contribute to the development of AUD and exert lifelong effects on the brain. This chapter provides a critical discussion of the role of epigenetic mechanisms in AUD etiology and the potential of epigenetic research to improve diagnosis, evaluate risks for alcohol-induced pathologies, and promote development of novel therapies for the prevention and treatment of AUD. Challenges of the current epigenetic approaches and future directions are also discussed.

scholarly journals The Role of Neuropeptide Y in the Nucleus Accumbens

2021 ◽  
Vol 22 (14) ◽  
pp. 7287
Author(s):  
Masaki Tanaka ◽  
Shunji Yamada ◽  
Yoshihisa Watanabe
Keyword(s):  
Nervous System ◽  
Nucleus Accumbens ◽  
Neuropeptide Y ◽  
Emotional Behavior ◽  
Characteristic Functions ◽  
Receptor Subtypes ◽  
Neuroendocrine Mechanisms ◽  
Fear And Anxiety ◽  
The Brain

Neuropeptide Y (NPY), an abundant peptide in the central nervous system, is expressed in neurons of various regions throughout the brain. The physiological and behavioral effects of NPY are mainly mediated through Y1, Y2, and Y5 receptor subtypes, which are expressed in regions regulating food intake, fear and anxiety, learning and memory, depression, and posttraumatic stress. In particular, the nucleus accumbens (NAc) has one of the highest NPY concentrations in the brain. In this review, we summarize the role of NPY in the NAc. NPY is expressed principally in medium-sized aspiny neurons, and numerous NPY immunoreactive fibers are observed in the NAc. Alterations in NPY expression under certain conditions through intra-NAc injections of NPY or receptor agonists/antagonists revealed NPY to be involved in the characteristic functions of the NAc, such as alcohol intake and drug addiction. In addition, control of mesolimbic dopaminergic release via NPY receptors may take part in these functions. NPY in the NAc also participates in fat intake and emotional behavior. Accumbal NPY neurons and fibers may exert physiological and pathophysiological actions partly through neuroendocrine mechanisms and the autonomic nervous system.

scholarly journals The Adenosine A2A Receptor Activation in Nucleus Accumbens Suppress Cue-Induced Reinstatement of Propofol Self-administration in Rats

2021 ◽  
Author(s):  
Zhanglei Dong ◽  
Bingwu Huang ◽  
Chenchen Jiang ◽  
Jiangfan Chen ◽  
Han Lin ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
D2 Receptor ◽  
Fixed Ratio ◽  
Receptor Activation ◽  
Addictive Behaviors ◽  
Self Administration ◽  
A2a Receptors ◽  
Mediated Effects ◽  
Seeking Behavior ◽  
Adenosine A2a

AbstractPropofol has shown strong addictive properties in rats and humans. Adenosine A2A receptors (A2AR) in the nucleus accumbens (NAc) modulate dopamine signal and addictive behaviors such as cocaine- and amphetamine-induced self-administration. However, whether A2AR can modulate propofol addiction remains unknown. AAV-shA2AR was intra-NAc injected 3 weeks before the propofol self-administration training to test the impacts of NAc A2AR on establishing the self-administration model with fixed ratio 1 (FR1) schedule. Thereafter, the rats were withdrawal from propofol for 14 days and tested cue-induced reinstatement of propofol seeking behavior on day 15. The propofol withdrawal rats received one of the doses of CGS21680 (A2AR agonist, 2.5–10.0 ng/site), MSX-3 (A2AR antagonist, 5.0–20.0 μg/site) or eticlopride (D2 receptor (D2R) antagonist, 0.75–3.0 μg/site) or vehicle via intra-NAc injection before relapse behavior test. The numbers of active and inactive nose-poke response were recorded. Focal knockdown A2AR by shA2AR did not affect the acquisition of propofol self-administration behavior, but enhance cue-induced reinstatement of propofol self-administration compared with the AAV-shCTRLgroup. Pharmacological activation of the A2AR by CGS21680 (≥ 5.0 ng/site) attenuated cue-induced reinstatement of propofol self-administration behavior. Similarly, pharmacological blockade of D2R by eticlopride (0.75–3.0 μg/site) attenuated propofol seeking behavior. These effects were reversed by the administration of MSX-3 (5.0–20.0 μg/site). The A2AR- and D2R-mediated effects on propofol relapse were not confounded by the learning process, and motor activity as the sucrose self-administration and locomotor activity were not affected by all the treatments. This study provides genetic and pharmacological evidence that NAc A2AR activation suppresses cue-induced propofol relapse in rats, possibly by interacting with D2R.

scholarly journals Ibudilast, a neuroimmune modulator, reduces heavy drinking and alcohol cue-elicited neural activation: a randomized trial

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Erica N. Grodin ◽  
Spencer Bujarski ◽  
Brandon Towns ◽  
Elizabeth Burnette ◽  
Steven Nieto ◽  
...  
Keyword(s):  
Macrophage Migration Inhibitory Factor ◽  
Alcohol Use Disorder ◽  
Cue Reactivity ◽  
Negative Mood ◽  
Heavy Drinking ◽  
Neural Activation ◽  
Daily Diary Study ◽  
Alcohol Cues ◽  
To Receive ◽  
The Brain

AbstractIbudilast, a neuroimmune modulator which selectively inhibits phosphodiesterases (PDE)-3, -4, -10, and -11, and macrophage migration inhibitory factor (MIF), shows promise as a novel pharmacotherapy for alcohol use disorder (AUD). However, the mechanisms of action underlying ibudilast’s effects on the human brain remain largely unknown. Thus, the current study examined the efficacy of ibudilast to improve negative mood, reduce heavy drinking, and attenuate neural reward signals in individuals with AUD. Fifty-two nontreatment-seeking individuals with AUD were randomized to receive ibudilast (n = 24) or placebo (n = 28). Participants completed a 2-week daily diary study during which they filled out daily reports of their past day drinking, mood, and craving. Participants completed an functional magnetic resonance imaging (fMRI) alcohol cue-reactivity paradigm half-way through the study. Ibudilast did not have a significant effect on negative mood (β = −0.34, p = 0.62). However, ibudilast, relative to placebo, reduced the odds of heavy drinking across time by 45% (OR = 0.55, (95% CI: 0.30, 0.98)). Ibudilast also attenuated alcohol cue-elicited activation in the ventral striatum (VS) compared to placebo (F(1,44) = 7.36, p = 0.01). Alcohol cue-elicited activation in the VS predicted subsequent drinking in the ibudilast group (F(1,44) = 6.39, p = 0.02), such that individuals who had attenuated ventral striatal activation and took ibudilast had the fewest number of drinks per drinking day in the week following the scan. These findings extend preclinical and human laboratory studies of the utility of ibudilast to treat AUD and suggest a biobehavioral mechanism through which ibudilast acts, namely, by reducing the rewarding response to alcohol cues in the brain leading to a reduction in heavy drinking.

scholarly journals Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking

2019 ◽  
Vol 22 (11) ◽  
pp. 710-723 ◽  
Author(s):  
Atul P Daiwile ◽  
Subramaniam Jayanthi ◽  
Bruce Ladenheim ◽  
Michael T McCoy ◽  
Christie Brannock ◽  
...  
Keyword(s):  
Sex Differences ◽  
Nucleus Accumbens ◽  
Fixed Ratio ◽  
Female Rats ◽  
Male Rats ◽  
Mrna Levels ◽  
Self Administration ◽  
Male And Female ◽  
Orexin Receptors ◽  
Male And Female Rats

Abstract Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

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