Possible role of adenosine in the CNS effects of ethanol

Dar, M. Saeed; Mustafa, S. Jamal; Wooles, W. R.

doi:10.1016/0024-3205(83)90819-6

Cited by 120 publications

(58 citation statements)

References 11 publications

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“…Other potential alcohol targets that might contribute to Ro15-4513-insensitive acute alcohol actions are NMDA (1), glycine (2), and adenosine receptors (65), and voltage-and Ca 2ϩ -activated (BK) potassium channels (66,67). In addition, we show here that the Ro15-4513-insensitive alcohol action on ␣4␤3␦ GABA A R is abolished by a mutation (␤3N265M) in the ␤3 subunit.…”

Section: Discussion Extrasynaptic ␦ Subunit-containing Receptors As Tmentioning

confidence: 63%

Low-dose alcohol actions on α4β3δ GABA _A receptors are reversed by the behavioral alcohol antagonist Ro15-4513

Wallner

Hanchar

Olsen

2006

Proc. Natl. Acad. Sci. U.S.A.

110

114

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Although it is now more than two decades since it was first reported that the imidazobenzodiazepine Ro15-4513 reverses behavioral alcohol effects, the molecular target(s) of Ro15-4513 and the mechanism of alcohol antagonism remain elusive. Here, we show that Ro15-4513 blocks the alcohol enhancement on recombinant ''extrasynaptic'' ␣4͞6␤3␦ GABAA receptors at doses that do not reduce the GABA-induced Cl ؊ current. At low ethanol concentrations (<30 mM), the Ro15-4513 antagonism is complete. However, at higher ethanol concentrations (>100 mM), there is a Ro15-4513-insensitive ethanol enhancement that is abolished in receptors containing a point mutation in the second transmembrane region of the ␤3 subunit (␤3N265M). Therefore, ␣4͞6␤3␦ GABA receptors have two distinct alcohol modulation sites: (i) a low-dose ethanol site present in ␣4͞6␤3␦ receptors that is antagonized by the behavioral alcohol antagonist Ro15-4513 and (ii) a site activated at high (anesthetic) alcohol doses, defined by mutations in membrane-spanning regions. Receptors composed of ␣4␤3N265M␦ subunits that lack the high-dose alcohol site show a saturable ethanol dose-response curve with a half-maximal enhancement at 16 mM, close to the legal blood alcohol driving limit in most U.S. states (17.4 mM). Like in behavioral experiments, the alcohol antagonist effect of Ro15-4513 on recombinant ␣4␤3␦ receptors is blocked by flumazenil and ␤-carboline-ethyl ester (␤-CCE). Our findings suggest that ethanol͞Ro15-4513-sensitive GABA A receptors are important mediators of behavioral alcohol effects.alcohol intoxication ͉ alcohol receptor ͉ anesthetics A lthough alcohol is one of the most widely used and abused drugs, the molecular targets that mediate alcohol effects at concentrations relevant for mild social intoxication are only beginning to be revealed. Neurotransmitter receptors for GABA, NMDA and glycine, and G protein-gated K ϩ channels have been identified as potential alcohol targets that are sensitive to intoxicating alcohol concentrations (1-4). GABA A receptors (GABA A Rs) have long been suspected to be important mediators of alcohol effects (5, 6) because benzodiazepines (BZs) and barbiturates, classic GABA A R agonists, share common pharmacological properties with ethanol, such as sedativehypnotic, anti-anxiety, and motor in-coordinating and anticonvulsant effects and have additive, possibly even synergistic effects, when taken together with ethanol (7). In addition, BZs, barbiturates, and ethanol produce tolerance and cross-tolerance to each other (8), consistent with GABA A Rs as targets of action.We have recently identified subtypes of GABA A Rs, those containing the ␦ and the ␤3 subunit, that are uniquely sensitive to low alcohol concentrations (9). Consistent with the view that ␦ subunit-containing receptors are important mediators of alcohol actions is the finding that GABA A R ␦-subunit knockout mice show multiple defects in behavioral responses to ethanol (10). Receptors containing the ␦ subunit have an exclusively nonsynaptic distribution, ...

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Section: Discussion Extrasynaptic ␦ Subunit-containing Receptors As Tmentioning

confidence: 63%

Low-dose alcohol actions on α4β3δ GABA _A receptors are reversed by the behavioral alcohol antagonist Ro15-4513

Wallner

Hanchar

Olsen

2006

Proc. Natl. Acad. Sci. U.S.A.

110

114

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“…luction in the We found no significant effect of PhiPrAdo on cAMP accu- (17,18) from each individual alcoholic or control subject studied (data not shown). DISCUSSION Adenosine is an inhibitory neuromodulator (19) that may play a role in mediating the effects of ethanol in the central nervous system (5,20). We have found (6) that adenosine receptor-stimulated cAMP levels in NG108-15 neural cells are increased by ethanol added acutely and that these levels become depressed after chronic exposure to ethanol.…”

Section: Resultsmentioning

confidence: 94%

Basal and adenosine receptor-stimulated levels of cAMP are reduced in lymphocytes from alcoholic patients.

Diamond¹,

Wrubel²,

Estrin³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

140

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Alcoholism causes serious neurologic disease that may be due, in part, to the ability of ethanol to interact with neural cell membranes and change neuronal function. Adenosine receptors are membrane-bound proteins that appear to mediate some of the effects of ethanol in the brain. Human lymphocytes also have adenosine receptors, and their activation causes increases in cAMP levels. To test the hypothesis that basal and adenosine receptor-stimulated cAMP levels in lymphocytes might be abnormal in alcoholism, we studied lymphocytes from 10 alcoholic subjects, 10 age-and sexmatched normal individuals, and 10 patients with nonalcoholic liver disease. Basal and adenosine receptor-stimulated cAMP levels were reduced 75% in lymphocytes from alcoholic subjects. Also, there was a 76% reduction in ethanol stimulation of cAMP accumulation in lymphocytes from alcoholics. Similar results were demonstrable in isolated T cells. Unlike other laboratory tests examined, these measurements appeared to distinguish alcoholics from normal subjects and from patients with nonalcoholic liver disease. Reduced basal and adenosine receptor-stimulated levels of cAMP in lymphocytes from alcoholics may reflect a change in cell membranes due either to chronic alcohol abuse or to a genetic predisposition unique to alcoholic subjects.Despite the widespread incidence of alcoholism, the molecular events accounting for intoxication, tolerance, and physical dependence after alcohol abuse are poorly understood. Ethanol is believed to intercalate into cell membranes, producing acute and adaptive changes in membrane fluidity (1, 2) or membrane constituents (3,4). Adenosine receptors are membrane-bound proteins that appear to mediate some of the effects of ethanol in the central nervous system (5). We recently reported (6) that ethanol acutely increases adenosine receptor-stimulated cAMP levels in a clonal neural cell line (neuroblastoma-glioma hybrid and that with time these cells adapt to the presence of ethanol, showing a reduction in adenosine receptor-stimulated cAMP levels. After chronic exposure to ethanol, the NG108-15 cells require ethanol to achieve normal levels of adenosine receptorstimulated cAMP, which may indicate a form of cellular "dependence." This process is completely reversible upon ethanol withdrawal.These observations suggest that intact single cells adapt to the presence of ethanol. Moreover, depressed adenosine receptor-stimulated cAMP levels in cells might be a biochemical change of pathophysiologic significance in chronic alcoholism. Since human lymphocytes have the same A2 adenosine receptors as the neuroblastoma cells (7), we could test directly whether alcoholics have altered cAMP levels. We undertook a controlled study of basal and adenosine receptor-stimulated cAMP levels in lymphocytes of chronic alcoholics, normal subjects, and patients with nonalcoholic liver disease. Mixed lymphocytes and T cells from chronic alcoholics showed a striking reduction in basal and adenosine receptor-stimulated cAMP levels. Moreov...

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“…Изучению отрезвляющих свойств антагонистов аденозиновых рецепторов посвящено значительное число исследований [42, 71,72,[74][75][76]. Чаще оценивалась способность антагонистов модифицировать развитие утраты рефлекса переворачивания на фоне алкоголя [42, 71,74,75].…”

Section: отрезвляющие средства модулирующие систему аденозинаunclassified

Amethystic agents influencing toxicodynamics of ethanol

Golovko¹

2013

BIOMED KHIM

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The pathogenetic mechanisms of acute alcoholic intoxications are examined and is based the expediency of the search for the amethystic agents, which influence neurotransmitter systems. Promising should be considered the agents, which modulate GABA-systems (partial reverse agonists of benzodiazepine receptors), glutamate (antagonists of metabotropic receptors mGluR2/3), opioid neuropeptides (antagonists of opioid receptors), acetylcholine (reversible inhibitors of acetylcholinesterase and M-cholinoagonists), adenosine (selective antagonists of A -receptors). The amethystic effect manifest also the substances, which modify the second messengers systems (calcium, nitrergic and cascade of arachidonic acid). The most of the means examined possesses the moderate amethystic potential, and effectiveness is manifested predominantly during the preventive application.

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Possible role of adenosine in the CNS effects of ethanol

Cited by 120 publications

References 11 publications

Low-dose alcohol actions on α4β3δ GABA _A receptors are reversed by the behavioral alcohol antagonist Ro15-4513

Low-dose alcohol actions on α4β3δ GABA _A receptors are reversed by the behavioral alcohol antagonist Ro15-4513

Basal and adenosine receptor-stimulated levels of cAMP are reduced in lymphocytes from alcoholic patients.

Amethystic agents influencing toxicodynamics of ethanol

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Possible role of adenosine in the CNS effects of ethanol

Cited by 120 publications

References 11 publications

Low-dose alcohol actions on α4β3δ GABA A receptors are reversed by the behavioral alcohol antagonist Ro15-4513

Low-dose alcohol actions on α4β3δ GABA A receptors are reversed by the behavioral alcohol antagonist Ro15-4513

Basal and adenosine receptor-stimulated levels of cAMP are reduced in lymphocytes from alcoholic patients.

Amethystic agents influencing toxicodynamics of ethanol

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Product

Resources

About

Low-dose alcohol actions on α4β3δ GABA _A receptors are reversed by the behavioral alcohol antagonist Ro15-4513

Low-dose alcohol actions on α4β3δ GABA _A receptors are reversed by the behavioral alcohol antagonist Ro15-4513