Abstract : Previous work by the principal investigators and others has shown that the major type of synaptic receptor for the major inhibitory neurotransmitter, the GABA-A receptor/chloride channel complex, is the target of numerous drugs and toxins. The GABA-A receptor function is directly potentiated by several categories of central nervous system depressants including benzodiazepines, barbiturates, steroid anesthetics, avermectin pesticides, and possibly ethanol. GABA-A receptor function is directly blocked by the GABA antagonist bicuculline, benzodiazepine inverse agonists, convulsant barbiturates, and a series of cyclic convulsant molecules like picrotoxin. These neuroexcitatory GABA blockers include pentylenetetrazol, chlorinated hydrocarbon insecticides like dieldrin and lindane, and the synthetic cage convulsants of Casida, such as t-butyl bicyclophosphorothionate (TBPS), one of the most toxic substances to mammals ever encountered. We demonstrated that these convulsant drugs acted potently on GABA-A receptors in mammals and invertebrates, using a combination of electrophysiology and biochemistry. Structural and pharmacological comparisons of the different subtypes of GABA-A receptors in various species and in various regions of human brain are underway. This will help to define to define the specificity of the neurotransmitter and drug binding sites in the various receptors and should lead to the development of new useful drugs.
GABAergic inhibitory transmission is involved in the acute and chronic effects of ethanol on the brain and behavior. One-dose ethanol exposure induces transient plastic changes in GABAA receptor subunit levels, composition, and regional and subcellular localization. Rapid down-regulation of early responder δ subunit-containing GABAA receptor subtypes mediating ethanol-sensitive tonic inhibitory currents in critical neuronal circuits corresponds to rapid tolerance to ethanol's behavioral responses. Slightly slower, α1 subunit-containing GABAA receptor subtypes mediating ethanol-insensitive synaptic inhibition are down-regulated, corresponding to tolerance to additional ethanol behaviors plus cross-tolerance to other GABAergic drugs including benzodiazepines, anesthetics, and neurosteroids, especially sedative-hypnotic effects. Compensatory up-regulation of synaptically localized α4 and α2 subunit-containing GABAA receptor subtypes, mediating ethanol-sensitive synaptic inhibitory currents follow, but exhibit altered physio-pharmacology, seizure susceptibility, hyperexcitability, anxiety, and tolerance to GABAergic positive allosteric modulators, corresponding to heightened alcohol withdrawal syndrome. All these changes (behavioral, physiological, and biochemical) induced by ethanol administration are transient and return to normal in a few days. After chronic intermittent ethanol (CIE) treatment the same changes are observed but they become persistent after 30 or more doses, lasting for at least 120 days in the rat, and probably for life. We conclude that the ethanol-induced changes in GABAA receptors represent aberrant plasticity contributing critically to ethanol dependence and increased voluntary consumption. We suggest that the craving, drug-seeking, and increased consumption in the rat model are tied to ethanol-induced plastic changes in GABAA receptors, importantly the development of ethanol-sensitive synaptic GABAA receptor-mediating inhibitory currents that participate in maintained positive reward actions of ethanol on critical neuronal circuits. These probably disinhibit nerve endings of inhibitory GABAergic neurons on dopamine reward circuit cells, and limbic system circuits mediating anxiolysis in hippocampus and amygdala. We further suggest that the GABAA receptors contributing to alcohol dependence in the rat and presumably in human alcohol use disorders (AUD) are the ethanol-induced up-regulated subtypes containing α4 and most importantly α2 subunits. These mediate critical aspects of the positive reinforcement of ethanol in the dependent chronic user while alleviating heightened withdrawal symptoms experienced whenever ethanol is absent. The speculative conclusions based on firm observations are readily testable.
Research Article| December 01 1976 Custom Laboratory Equipment Made from Acrylic Plastic Richard W. Olsen, Richard W. Olsen Search for other works by this author on: This Site PubMed Google Scholar Douglas E. Petry Douglas E. Petry Search for other works by this author on: This Site PubMed Google Scholar The American Biology Teacher (1976) 38 (9): 554–555. https://doi.org/10.2307/4445745 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Richard W. Olsen, Douglas E. Petry; Custom Laboratory Equipment Made from Acrylic Plastic. The American Biology Teacher 1 December 1976; 38 (9): 554–555. doi: https://doi.org/10.2307/4445745 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentThe American Biology Teacher Search This content is only available via PDF. Copyright 1976 National Association of Biology Teachers Article PDF first page preview Close Modal You do not currently have access to this content.
Alcohol (EtOH) intoxication causes changes in the rodent brain γ-aminobutyric acid receptor (GABAAR) subunit composition and function, playing a crucial role in EtOH withdrawal symptoms and dependence. Building evidence indicates that withdrawal from acute EtOH and chronic intermittent EtOH (CIE) results in decreased EtOH-enhanced GABAAR δ subunit-containing extrasynaptic and EtOH-insensitive α1βγ2 subtype synaptic GABAARs but increased synaptic α4βγ2 subtype, and increased EtOH sensitivity of GABAAR miniature postsynaptic currents (mIPSCs) correlated with EtOH dependence. Here we demonstrate that after acute EtOH intoxication and CIE, upregulation of hippocampal α4βγ2 subtypes, as well as increased cell-surface levels of GABAAR α2 and γ1 subunits, along with increased α2β1γ1 GABAAR pentamers in hippocampal slices using cell-surface cross-linking, followed by Western blot and coimmunoprecipitation. One-dose and two-dose acute EtOH treatments produced temporal plastic changes in EtOH-induced anxiolysis or withdrawal anxiety, and the presence or absence of EtOH-sensitive synaptic currents correlated with cell surface peptide levels of both α4 and γ1(new α2) subunits. CIE increased the abundance of novel mIPSC patterns differing in activation/deactivation kinetics, charge transfer, and sensitivity to EtOH. The different mIPSC patterns in CIE could be correlated with upregulated highly EtOH-sensitive α2βγ subtypes and EtOH-sensitive α4βγ2 subtypes. Naïve α4 subunit knockout mice express EtOH-sensitive mIPSCs in hippocampal slices, correlating with upregulated GABAAR α2 (and not α4) subunits. Consistent with α2, β1, and γ1 subunits genetically linked to alcoholism in humans, our findings indicate that these new α2-containing synaptic GABAARs could mediate the maintained anxiolytic response to EtOH in dependent individuals, rat or human, contributing to elevated EtOH consumption.
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