A high affinity ligand for GABA A -receptor containing a 5 subunit antagonizes ethanol?s neurobehavioral effects in Long-Evans rats

McKay, Peter F.; Foster, Katrina L.; Mason, Dynesha; Cummings, Rancia; García, Marín; Williams, Larry J.; Grey, Collette; McCane, Shannan; He, Xiaohui; Cook, James M.; June, Harry L.

doi:10.1007/s00213-003-1671-z

Cited by 43 publications

(34 citation statements)

References 21 publications

(28 reference statements)

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“…Immediately after each mouse had completed its session, the entire activity chamber was cleaned to eliminate odors and related stimuli to prevent the next subject from following the path of the prior mouse. Other specific details of these procedures and apparatus have previously and recently been reported (June et al, 1998a, b;McKay et al, 2004).…”

Section: Drugsmentioning

confidence: 97%

“…The two BDZ antagonists were also selected since their in vitro efficacy profile has recently been characterized at the a1-a5 receptor subunits June et al, 2003). The efficacy profile of BDZ receptor ligands has been suggested to be important in determining the precise neuromechanism of action in which ligands antagonize alcohol neurobehavioral properties (for a review, see Jackson and Nutt, 1995;June et al, 2003;McKay et al, 2004).…”

Section: Drugsmentioning

confidence: 99%

“…Procedures: To habituate the mice to the activity monitor prior to any drug treatment, mice were given 3-daily 10 min sessions (June et al, 1998a, b;McKay et al, 2004). These sessions thoroughly habituated the animals to the openfield arena.…”

Section: Drugsmentioning

confidence: 99%

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Dopamine and Benzodiazepine-Dependent Mechanisms Regulate the EtOH-Enhanced Locomotor Stimulation in the GABAA α1 Subunit Null Mutant Mice

June

Foster

Eiler

et al. 2006

Neuropsychopharmacol

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The present study investigated the role of the a1-containing GABA A receptors in the neurobehavioral actions of alcohol. In Experiment 1, mice lacking the a1 subunit (a1 (À/À)) were tested for their capacity to initiate operant-lever press responding for alcohol or sucrose. Alcohol intake in the home cage was also measured. In Experiment 2, the a1 (À/À) mice were injected with a range of alcohol doses (0.875-4.0 g/kg; i.p.) to evaluate the significance of the a1 subunit in alcohol's stimulant actions. In Experiment 3, we determined if the alcohol-induced stimulant effects were regulated via dopaminergic (DA) or benzodiazepine (BDZ)-dependent mechanisms. To accomplish this, we investigated the capacity of DA (eticlopride, SCH 23390) and BDZ (flumazenil, bCCt) receptor antagonists to attenuate the alcohol-induced stimulant actions. Compared with wild-type mice (a1 ( + / + )), the null mutants showed marked reductions in both EtOH and sucrose-maintained responding, and home-cage alcohol drinking. The null mutants also showed significant increases in locomotor behaviors after injections of low-moderate alcohol doses (1.75-3.0 g/kg). bCCt, flumazenil, eticlopride, and SCH 23390 were able to attenuate the alcohol-induced stimulation in mutant mice, in the absence of intrinsic effects. These data suggest the a1 receptor plays an important role in alcohol-motivated behaviors; however, it also appears crucial in regulating the reinforcing properties associated with normal ingestive behaviors. Deleting the a1 subunit of the GABA A receptor appears to unmask alcohol's stimulatory effects; these effects appear to be regulated via an interaction of both DA-and GABA A BDZ-dependent mechanisms. Neuropsychopharmacology (2007) 32, 137-152.

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Section: Drugsmentioning

confidence: 97%

Section: Drugsmentioning

confidence: 99%

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Dopamine and Benzodiazepine-Dependent Mechanisms Regulate the EtOH-Enhanced Locomotor Stimulation in the GABAA α1 Subunit Null Mutant Mice

June

Foster

Eiler

et al. 2006

Neuropsychopharmacol

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“…However, it is possible that other brain regions implicated in anxiety, and/ or alcohol-withdrawal-induced anxiety, including the BNST, for example (McKay et al, 2004;Funk et al, 2006), could also have an altered response to NPS after chronic drinking.…”

Section: Discussionmentioning

confidence: 99%

Chronic Ethanol Potentiates the Effect of Neuropeptide S in the Basolateral Amygdala and Shows Increased Anxiolytic and Anti-Depressive Effects

Enquist

Ferwerda

Madhavan

et al. 2012

Neuropsychopharmacol

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Alleviating anxiety and depression is pivotal for reducing the risk of relapse in alcoholics. Currently available anxiolytic treatments are limited by side effects, including reduced efficacy in alcoholics, addiction, and sedation. We examined whether the neuropeptide S receptor (NPSR) was effective at controlling ethanol consumption and the anxiety and depression produced by forced abstinence from ethanol. We found that the anxiolytic and anti-depressant effects of NPS are enhanced in acute ethanol abstinent mice. In addition, we found that NPS reduced ethanol consumption and is not in and of itself rewarding. We also provide evidence that ethanol consumption increases the ability of NPS to modulate neuronal activity in the basolateral amygdala. Finally, we found that local injection of NPS in the basolateral amygdala promotes anxiolysis after chronic ethanol consumption, thereby providing insight into the molecular mechanism underlying the changes in behavioral response to NPS. In light of the improved anxiolytic efficacy and benign side effects of NPS in ethanol-withdrawn animals, the NPSR may prove a suitable target for reducing relapse in alcoholism.

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“…However, almost all other negative modulators of GABA receptors (a.k.a., inverse agonists) do not act as alcohol antagonists (for recent review see (Wallner et al, 2006a)). Two exceptions of inverse agonists that do show alcohol antagonist actions are the Ro15-4513 structural analogs, RY080 and RY024, that also have been reported to show behavioral alcohol antagonism (McKay et al, 2004;Cook et al, 2005); these compounds also bind with high affinity to the [ 3 H] Ro15-4513/alcohol site on α4β3δ receptors .…”

Section: Interactions Of Alcohol and The Benzodiazepine Behavioral Almentioning

confidence: 99%

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

Olsen

Hanchar

Meera

et al. 2007

Alcohol

128

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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A high affinity ligand for GABA A -receptor containing a 5 subunit antagonizes ethanol?s neurobehavioral effects in Long-Evans rats

Abstract: The results suggest the GABA(A)receptor containing alpha(5)subtype plays an important role in regulating the reinforcing, motor-impairing, and sedative effects of alcohol in outbred rats.

Cited by 43 publications

References 21 publications

Dopamine and Benzodiazepine-Dependent Mechanisms Regulate the EtOH-Enhanced Locomotor Stimulation in the GABAA α1 Subunit Null Mutant Mice

Dopamine and Benzodiazepine-Dependent Mechanisms Regulate the EtOH-Enhanced Locomotor Stimulation in the GABAA α1 Subunit Null Mutant Mice

Chronic Ethanol Potentiates the Effect of Neuropeptide S in the Basolateral Amygdala and Shows Increased Anxiolytic and Anti-Depressive Effects

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

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