ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
GABA site agonist gaboxadol induces addiction-predicting persistent changes in ventral tegmental area dopamine neurons but is not rewarding in mice or baboons.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 39 citations in OpenAlex.
- Article
- Sleep Modulates Alcohol Toxicity inInternational journal of molecular sciences · 2022Article
- GABAJournal, genetic engineering & biotechnology · 2021Review
- Tonic GABAergic inhibition, via GABAThe European journal of neuroscience · 2021Article
- Mice Lacking GABAFrontiers in pharmacology · 2021Article
- Excitatory/inhibitory balance across ontogeny contributes to age-specific behavioral outcomes of ethanol-like challenge in conditioned taste aversion.Developmental psychobiology · 2019Article
- Female-specific decreases in alcohol binge-like drinking resulting from GABAScientific reports · 2019Article
- Conditioned Aversion and Neuroplasticity Induced by a Superagonist of Extrasynaptic GABAFrontiers in molecular neuroscience · 2019Article
- Examining the effects of alcohol on GABAAlcohol (Fayetteville, N.Y.) · 2018Article
- Valium without dependence? Individual GABANeuropsychiatric disease and treatment · 2018Review
- Ventral Tegmental Area GABA Neurons Are Resistant to GABA(A) Receptor-Mediated Inhibition During Ethanol Withdrawal.Frontiers in neuroscience · 2018Article
- Activation of extrasynaptic δ-GABAHormones and behavior · 2017Article
- Rodent models and mechanisms of voluntary binge-like ethanol consumption: Examples, opportunities, and strategies for preclinical research.Progress in neuro-psychopharmacology & biological psychiatry · 2016Review
- GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response.Frontiers in neuroendocrinology · 2015Review
- Neural basis of benzodiazepine reward: requirement for α2 containing GABAA receptors in the nucleus accumbens.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2014Article
- Neurosteroid Agonist at GABAA receptor induces persistent neuroplasticity in VTA dopamine neurons.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2014Article
- Tonic inhibition of accumbal spiny neurons by extrasynaptic α4βδ GABAA receptors modulates the actions of psychostimulants.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2014Article
- GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area.Frontiers in pharmacology · 2014Article
- GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics.Frontiers in cellular neuroscience · 2014Article
- Chronic treatment with mood-stabilizers attenuates abnormal hyperlocomotion of GluA1-subunit deficient mice.PloS one · 2014Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dopamine neurons of the ventral tegmental area (VTA) are involved at early phases of drug addiction. Even the first in vivo dose of various abused drugs induces glutamate receptor plasticity at the excitatory synapses of these neurons. Benzodiazepines that suppress the inhibitory GABAergic interneurons in the VTA via facilitation of synaptic GABA(A) receptors have induced neuroplasticity in dopamine neurons due to this disinhibitory mechanism. Here, we have tested a non-benzodiazepine direct GABA site agonist 4,5,6,7-tetrahydroisoxazolol[4,5-c]pyridine-3-ol (THIP) (also known as gaboxadol) that acts preferentially via high-affinity extrasynaptic GABA(A) receptors. A single sedative dose of THIP (6 mg/kg) to mice induced glutamate receptor plasticity for at least 6 d after administration. Increased AMPA/NMDA receptor current ratio and increased frequency, amplitude, and rectification of AMPA receptor responses suggested persistent targeting of GluA2-lacking AMPA receptors in excitatory synapses of VTA dopamine neurons ex vivo after THIP administration. This effect was abolished in GABA(A) receptor δ(-/-) mice, which have a loss of extrasynaptic GABA(A) receptors. In behavioral experiments, we found neither acute reinforcement in intravenous self-administration sessions with THIP at relevant doses using a yoked control paradigm in mice nor in baboons using a standard paradigm for assessing drug abuse liability; nor was any place preference found after conditioning sessions with various doses of THIP but rather a persistent aversion in 6 mg/kg THIP-conditioned mice. In summary, we found that activation of extrasynaptic δ-subunit-containing GABA(A) receptors leads to glutamate receptor plasticity of VTA dopamine neurons, but is not rewarding, and, instead, induces aversion.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.