Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility

Exposure to addictive substances impairs flexible decision-making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 d) reduction of excitatory thalamic inputs onto CINs and reduced pause response of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder.

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Fluoxetine improves behavioural deficits induced by chronic alcohol addiction by alleviating RNA editing of 5-HT2C receptors in astrocytes

10.1101/751065 ◽

2019 ◽

Author(s):

Zexiong Li ◽

Shanshan Liang ◽

Shuai Li ◽

Beina Chen ◽

Manman Zhang ◽

...

Keyword(s):

Alcohol Consumption ◽

Rna Editing ◽

Alcohol Intake ◽

Motor Coordination ◽

Alcohol Addiction ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

Adenosine Deaminases ◽

Underlying Pathology

AbstractThe alcoholism and major depressive disorder are common comorbidity, with alcohol-induced depressive symptoms being eased by selective serotonin re-uptake inhibitors (SSRIs), although the mechanisms underlying pathology and therapy are poorly understood. Chronic alcohol consumption affects the activity of serotonin 2C receptors (5-HT2CR) by regulating adenosine deaminases acting on RNA (ADARs) in neurones. Astrogliopathic changes contribute to alcohol addiction, while decreased release of ATP from astrocytes can trigger depressive-like behaviours in mice. In this study, we discovered that chronic alcohol addiction increased editing of RNA of 5-HT2CR via up-regulating the expression of ADAR2, consequnetly reducing the release of ATP from astrocytes induced by 5-HT2CR agonist, MK212. At the same time SSRI antidepressant fluoxetine decreased the expression of ADAR2 through the transactivation of EGFR/PI3K/AKT/cFos signalling pathway. Reduction in ADAR2 activity eliminated the RNA editing of 5-HT2CR in vivo and increased release of astroglial ATP which was suppressed by chronic alcohol consumption. Meanwhile, fluoxetine improved the behavioural and motor symptoms induced by alcohol addiction and decreased the alcohol intake. Our study suggests that the astrocytic 5-HT2CR contribute to alcohol addiction; fluoxetine thus can be used to alleviate depression, treat alcohol addiction and improve motor coordination.

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Effect of chronic alcohol consumption by rats on tumor necrosis factor-α and interleukin-6 clearance in vivo and by the isolated, perfused liver

Biochemical Pharmacology ◽

10.1016/0006-2952(96)00416-9 ◽

1996 ◽

Vol 52 (6) ◽

pp. 891-899 ◽

Cited By ~ 22

Author(s):

Ion V. Deaciuc ◽

Julie M. Alappat ◽

Kathleen H. McDonough ◽

Nympha B. D'Souza

Keyword(s):

Alcohol Consumption ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Perfused Liver ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

Factor Α ◽

Necrosis Factor

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Inhibition of cholinergic interneurons potentiates corticostriatal transmission in D1 receptor-expressing medium-sized spiny neurons and restores motor learning in parkinsonian condition

10.1101/2021.07.07.451477 ◽

2021 ◽

Author(s):

Gwenaelle Laverne ◽

Jonathan Pesce ◽

Ana Reynders ◽

Christophe Melon ◽

Lydia Kerkerian-Le Goff ◽

...

Keyword(s):

Motor Learning ◽

Long Term Potentiation ◽

D1 Receptor ◽

Skill Learning ◽

D1 Receptors ◽

Projection Neurons ◽

Cholinergic Interneurons ◽

Term Potentiation ◽

The Impact

Striatal cholinergic interneurons (CINs) respond to salient or reward prediction-related stimuli after conditioning with brief pauses in their activity, implicating them in learning and action selection. This pause is lost in animal models of Parkinson′s disease. How this signal regulates the functioning of the striatum remains an open question. To address this issue, we examined the impact of CIN firing inhibition on glutamatergic transmission between the cortex and the medium-sized spiny projection neurons expressing dopamine D1 receptors (D1 MSNs). Brief interruption of CIN activity had no effect in control condition whereas it increased glutamatergic responses in D1 MSNs after nigrostriatal dopamine denervation. This potentiation was dependent upon M4 muscarinic receptor and protein kinase A. Decreasing CIN firing by opto/chemogenetic strategies in vivo rescued long-term potentiation in some MSNs and alleviated motor learning deficits in parkinsonian mice. Taken together, our findings demonstrate that the control exerted by CINs on corticostriatal transmission and striatal-dependent motor-skill learning depends on the integrity of dopaminergic inputs.

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Effects of Chronic Alcohol Consumption on the Broad Phospholipid Signal in Human Brain: An In Vivo 31P MRS Study

Alcoholism Clinical and Experimental Research ◽

10.1111/j.1530-0277.2001.tb02131.x ◽

2001 ◽

Vol 25 (1) ◽

pp. 89-97 ◽

Cited By ~ 21

Author(s):

M. R. Estilaei ◽

G. B. Matson ◽

G. S. Payne ◽

M. O. Leach ◽

G. Fein ◽

...

Keyword(s):

Alcohol Consumption ◽

Human Brain ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

31P Mrs

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Tetrahydrobiopterin, a cofactor for NOS, improves endothelial dysfunction during chronic alcohol consumption

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.281.5.h1863 ◽

2001 ◽

Vol 281 (5) ◽

pp. H1863-H1869 ◽

Cited By ~ 23

Author(s):

Hong Sun ◽

Kaushik P. Patel ◽

William G. Mayhan

Keyword(s):

Alcohol Consumption ◽

Chronic Alcohol ◽

Sprague Dawley ◽

Chronic Alcohol Consumption ◽

Sprague Dawley Rats ◽

Pial Arterioles ◽

Cerebral Arterioles ◽

Oxide Synthase ◽

Enos Protein

We sought to investigate mechanisms that may account for impaired nitric oxide synthase (NOS)-dependent dilatation of cerebral arterioles during alcohol consumption. Our goals were to examine 1) the effect of exogenous application of a cofactor for NOS, i.e., tetrahydrobiopterin (BH4) on the reactivity of pial arterioles during alcohol consumption; and 2) endothelial NOS (eNOS) protein in nonalcohol-fed and alcohol-fed rats. Sprague-Dawley rats were fed liquid diets with or without alcohol for 2–3 mo. We measured in vivo diameter of pial arterioles in response to NOS-dependent agonists (ACh and ADP) and a NOS-independent agonist (nitroglycerin) before and during application of BH4. Blood vessels were then harvested for Western blot analysis of eNOS protein. In nonalcohol-fed rats, ACh and ADP produced vasodilatation, which was impaired in alcohol-fed rats. Vasodilatation to nitroglycerin was similar in both groups of rats. Application of BH4 did not alter vasodilatation in nonalcohol-fed rats but improved impaired vasodilatation in alcohol-fed rats. Also, eNOS protein in cerebral cortex microvessels, the basilar artery, and aorta was not different between nonalcohol-fed and alcohol-fed rats. Thus impaired NOS-dependent vasodilatation during alcohol consumption does not appear to be related to an alteration in eNOS protein but may be related to a deficiency and/or alteration in the utilization of BH4.

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