Ro 15-4513: Partial inverse agonism at the BZR and interaction with ethanol

Bonetti, E. P.; Burkard, W. P.; Gabl, Michael; Hunkeler, Walter; Lorez, H.P.; Martin, James R.; Moehler, H; Osterrieder, Wolfgang; Pieri, L.; Polc, P.

doi:10.1016/0091-3057(88)90259-6

Cited by 88 publications

(27 citation statements)

References 34 publications

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“…In fact, in our hands, benzodiazepine receptor antagonists and most inverse agonists actually blocked the anti-alcohol actions of Ro15-4513 (11). However, it was also clear from these early studies that Ro15-4513 blocks only some of the behavioral effects of low to moderate doses of ethanol (8)(9)(10)(11)(12) and that its intrinsic inverse agonist properties could confound the interpretation of the behavioral data (11,12). Consequently, these findings were met with considerable skepticism, and at least two controversies emerged.…”

Section: Alcohol and Gabamentioning

confidence: 97%

Alcohol-sensitive GABA receptors and alcohol antagonists

Paul

2006

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

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Section: Alcohol and Gabamentioning

confidence: 97%

Alcohol-sensitive GABA receptors and alcohol antagonists

Paul

2006

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

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“…This view is based upon the inverse agonist, RO15-4513, which binds to the furosemide-sensitive receptor Mhatre et al, 1988), antagonizing the deficit in righting reflex induced by ethanol (Bonetti et al, 1989;Suzdak et al, 1986a; see review by Ticku and Kulkarni, 1988). Additionally, in vivo, the BZD-inverse agonists, RO15-4513 and FG7142, blocked the ethanol-induced depression of Purkinje neurons in the cerebellum (Palmer et al, 1988; see review by Palmer and Hoffer, 1990).…”

Section: Argument For An Action Of Ethanol On Bzd-insensitive Gaba a mentioning

confidence: 99%

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Neuropsychopharmacol

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Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.

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“…A number of detailed studies by different groups showed that Ro15-4513 prevented the increased exploration and locomotion at very low EtOH doses (0.25, 0.5 and 0.75 g/kg in rats) (June & Lewis, 1994), the anxiolytic effects at low doses (1 g/kg in rats) (Suzdak et al, 1986a;Glowa et al, 1988;Becker & Hale, 1991) the sedative, motor impairing, as well as amnestic effects at moderate EtOH doses (2 g/kg rats or mice) (Suzdak et al, 1986a;Bonetti et al, 1988;Nabeshima et al, 1988;Dar, 1995), as well as the anticonvulsant (seizure protective) effects of EtOH (2 g/kg) against bicuculline and picrotoxin-induced convulsions (Kulkarni & Ticku, 1989). In addition, the observation that Ro15-4513 reduces EtOH self-administration (June et al, 1991;Rassnick et al, 1993;Petry, 1995) suggests that the rewarding effects of EtOH might be mediated by EtOH/Ro15-4513-sensitive GABA A R. However, Ro15-4513 does not prevent all EtOH effects: at higher EtOH doses (≥2 g/kg in rats), Ro15-4513 significantly reduces, but does not prevent the anesthetic ("sleep"-inducing) effects of EtOH (Marrosu et al, 1989), and Ro15-4513 does not prevent the hypothermic effects of EtOH (Hoffman et al, 1987;Syapin et al, 1987), consistent with the notion that part of the hypothermic (and analgesic) EtOH actions are mediated by other targets, possibly GIRK K + channels (Blednov et al, 2003;Costa et al, 2005).…”

Section: A Gaba a Receptor Ligand The Benzodiazepine Ro15-4513 Is Amentioning

confidence: 99%

Low dose acute alcohol effects on GABAA receptor subtypes

Wallner

Hanchar

Olsen

2006

Pharmacology & Therapeutics

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GABA A receptors (GABA A Rs) are the main inhibitory neurotransmitter receptors and have long been implicated in mediating at least part of the acute actions of ethanol. For example, ethanol and GABAergic drugs including barbiturates and benzodiazepines share many pharmacological properties. Besides the prototypical synaptic GABA A R subtypes, nonsynaptic GABA A Rs have recently emerged as important regulators of neuronal excitability. While high doses (≥100 mM) of ethanol have been reported to enhance activity of most GABA A R subtypes, most abundant synaptic GABA A Rs are essentially insensitive to ethanol concentrations that occur during social ethanol consumption (<30 mM). However, extrasynaptic δ and β3 subunit-containing GABA A Rs, associated in the brain with α4or α6 subunits, are sensitive to low millimolar ethanol concentrations, as produced by drinking half a glass of wine. Additionally, we found that a mutation in the cerebellar α6 subunit (α6R100Q), initially reported in rats selectively bred for increased alcohol sensitivity, is sufficient to produce increased alcohol-induced motor impairment and further increases of alcohol sensitivity in recombinant α6β3δ receptors. Furthermore, the behavioral alcohol antagonist Ro15-4513 blocks the low dose alcohol enhancement on α4/6/β3δ receptors, without reducing GABA-induced currents. In binding assays α4β3δ GABA A Rs bind [ 3 H] Ro15-4513 with high affinity, and this binding is inhibited, in an apparently competitive fashion, by low ethanol concentrations, as well as analogs of Ro15-4513 that are active to antagonize ethanol or Ro15-4513's block of ethanol. We conclude that most low to moderate dose alcohol effects are mediated by alcohol actions on alcohol/Ro15-4513 binding sites on GABA A R subtypes.

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Ro 15-4513: Partial inverse agonism at the BZR and interaction with ethanol

Cited by 88 publications

References 34 publications

Alcohol-sensitive GABA receptors and alcohol antagonists

Alcohol-sensitive GABA receptors and alcohol antagonists

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Low dose acute alcohol effects on GABAA receptor subtypes

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