Benzodiazepines in the Treatment of Alcoholism

Nutt, David; Adinoff, Bryon; Linnoila, Markku

doi:10.1007/978-1-4899-1678-5_15

Cited by 44 publications

(15 citation statements)

References 202 publications

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“…Behavioral evidence shows that alcohol shares many pharmacological effects with prototypical GABA A R agonists like barbiturates and benzodiazepines (Liljequist and Engel, 1982;Dar and Wooles, 1985;Harris, 1990). Furthermore, benzodiazepines and barbiturates show cross-tolerance with alcohol (Le et al, 1986), consistent with action on similar receptor subtypes, and benzodiazepines are widely used to treat the potential life-threatening effects of abrupt alcohol withdrawal in alcoholics (Nutt et al, 1989).…”

Section: Gaba a Receptors As Plausible Alcohol Targetsmentioning

confidence: 99%

GABAA receptor subtypes: the “one glass of wine” receptors

Olsen

Hanchar

Meera

et al. 2007

Alcohol

129

121

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This review discusses evidence for and apparent controversy about, GABA A receptor subtypes that mediate alcohol effects experienced during social drinking. GABA A receptors that contain the β3 and δ subunits were shown to be enhanced by alcohol concentrations that mirror the concentrationdependence of alcohol responses in humans. A mutation (α6R100Q) previously found in alcohol non-tolerant (ANT) rats in the cerebellar GABA A receptor α6 subunit is sufficient for increased alcohol-induced ataxia in rats homozygous for this mutation (α6-100QQ) and further increases alcohol-sensitivity of tonic GABA currents (mediated by α6βδ receptors) in cerebellar granule cells of α6-100QQ rats and in recombinant α6R100Qβ3δ receptors. This provided the first direct evidence that these types of receptors mediate behavioral effects of ethanol. Furthermore the behavioral alcohol antagonist Ro15-4513 specifically reverses ethanol enhancement on α4/6β3δ receptors. Unexpectedly, native and recombinant α4/6β3δ receptors bind the behavioral alcohol antagonist Ro15-4513 with high affinity and this binding is competitive with EtOH, suggesting a specific and mutually exclusive (competitive) ethanol/Ro15-4513 site which explains the puzzling activity of Ro15-4513 as a behavioral alcohol antagonist.Our conclusion from these findings is that alcohol/Ro15-4513-sensitive GABA A receptor subtypes are important alcohol targets and that alcohol at relevant concentrations is more specific than previously thought. In this review we discuss technical difficulties in expressing recombinant δ subunit-containing receptors in oocytes and mammalian cells, that may have contributed to negative results and confusion. Not only because we have reproduced detailed positive results numerous times, and we and many others have built extensively on basic findings, but also because we explain and combine many previously puzzling results into a coherent and highly plausible paradigm on how alcohol exerts an important part of its action in the brain, we are confident about our findings and conclusions. However, many important open questions remain to be answered.

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Section: Gaba a Receptors As Plausible Alcohol Targetsmentioning

confidence: 99%

GABAA receptor subtypes: the “one glass of wine” receptors

Olsen

Hanchar

Meera

et al. 2007

Alcohol

129

121

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“…Over stimulation of noradrenergic neurons during periods of lowered blood alcohol is the cause of well-recognised symptoms such as tremor, diaphoresis, anxiety and agitation, as well as signs such as tachycardia and hypertension. It is further enhanced by both the state of increased glutamate function and the loss of noradrenergic autoinhibition caused by reduced presynaptic a 2 adrenoceptor function (Nutt et al, 1988). Thyroid hormones T 3 and T 4 may also be increased during the withdrawal period (Heinz et al, 1996) and may further contribute to this adrenergic effect.…”

Section: Alcohol Withdrawal Syndromementioning

confidence: 99%

Adverse physical effects of alcohol misuse

Barclay¹,

Barbour²,

Stewart³

et al. 2008

Adv. psychiatr. treat

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This article outlines the majority of the adverse physical effects that have been described secondary to the consumption of alcohol at levels above recommended sensible limits. These conditions are cited according to the organ system they belong to. Only brief descriptions are provided because of the vastness of this topic. The underlying pathophysiology of tolerance and withdrawal is touched upon as this is of relevance to the psychiatrist. Definitions of the terms used describing alcohol misuse, and sensible upper limits of alcohol consumption are also mentioned.

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“…A childhood history of attention deficit hyperactivity disorder or conduct disorder, or both, apparently increases a child's risk of becoming alcoholic (Goodwin, 1989). Panic attacks are also more common among alcoholics than among the rest of the population (Nutt et al, 1989). On the other hand, the prevalence of depression in alcoholic patients has long been considered to be higher than in the general population; alcoholic patients have more pre-alcoholic symptoms such as fighting and problems at school than patients with primary depression (Woodruff, 1973).…”

Section: -Ht Alcoholism and Other Psychiatric Disordersmentioning

confidence: 99%

5-Hydroxytryptamine and alcoholism

Ferreira

Soares‐da‐Silva

1991

Hum. Psychopharmacol. Clin. Exp.

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Ethanol interferes with several brain functions, namely with specific neurotransmission processes. Depletion of brain 5-hydroxytryptamine (5-HT) impairs the acquisition of tolerance to ethanol or facilitates its loss, while activation of 5-HT brain transmission facilitates tolerance development and decreases ethanol consumption. One hypothesis which has been put towards is that genetically determined low 5-HT brain levels may be related to a predisposition to alcoholism. Acute ethanol intake transiently increases brain 5-HT turnover; therefore, ethanol consumption might be hypothesized as an attempt to correct a deficit of 5-HT brain transmission. The findings that administration of selective 5-HT neuronal uptake blockers (zimelidine, citalopram, fluvoxamine and fluoxetine) decrease ethanol intake has given further support to this hypothesis. However, the time course of this effect is different from the antidepressant action described for these compounds. Also, there is evidence to suggest that lower doses of the 5-HT uptake blockers are needed in order to reduce ethanol intake in alcoholic patients; this, however, requires further investigation. Interestingly, other clinical entities which have been found to be associated with a hypothetical dysfunction in 5-HT brain transmission, such as obsessive compulsive disorder, panic disorder and some forms of depression, have also been associated with alcoholism, and seem to respond as well to 5-HT neuronal uptake blockers.

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Benzodiazepines in the Treatment of Alcoholism

Cited by 44 publications

References 202 publications

GABAA receptor subtypes: the “one glass of wine” receptors

GABAA receptor subtypes: the “one glass of wine” receptors

Adverse physical effects of alcohol misuse

5-Hydroxytryptamine and alcoholism

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