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Benzodiazepine drugs in sleep disorders
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
As with the anxiety disorders (see Chapter 9) there is interest in using new GABAA receptor acting drugs in the treatment of sleep disorders. The partial agonist, pagoclone has been evaluated in a small trial and shown to have a profile as predicted from its pharmacology—it improved some aspects of sleep but to a lesser extent than that produced by the full agonist zopiclone (Wilson et al, 1997). Other GABAA receptor modulating drugs, such as the direct GABAAagonist, THIP (also called gaboxadol), are in clinical trials for insomnia.
Licit and illicit drugs
Published in Jason Payne-James, Richard Jones, Simpson's Forensic Medicine, 2019
Jason Payne-James, Richard Jones
In the absence of drugs, the GABAA receptor (GABAAR) binds to GABA, which is the major inhibitory neurotransmitter within the CNS. When it is activated, the GABAA receptor selectively conducts chloride ion through its central pore into the cell. As a consequence, the neuron becomes hyperpolarised. When a cell is hyperpolarised, action potentials are less likely to occur and neurotransmission is slowed. The active site on the GABAA receptor is, of course, GABA. However, the receptor also contains a number of other different binding sites, including areas where BZs, non-BZs, barbiturates, ethanol and even inhaled anaesthetics can bind.
Overview of Neurotransmission: Relationship to the Action of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Benzodiazepines have been shown to decrease 5-HT turnover, but again this is not believed to be the mechanism by which they exert anticonvulsant effects.35 Instead, the interaction of the benzodiazepines with the high affinity binding site on the GABAA receptor complex is believed to play a primary role in their mechanism of action.
Moringa oleifera seed ethanol extract and its active component kaempferol potentiate pentobarbital-induced sleeping behaviours in mice via a GABAergic mechanism
Published in Pharmaceutical Biology, 2022
Wei-Liang Liu, Bai-Fen Wu, Jian-Hua Shang, Xue-Feng Wang, Yun-Li Zhao, Ai-Xiang Huang
To evaluate whether or not EEMOS and KA improved sleeping behaviours through the biosynthesis of GABA, the mice were given corresponding samples for 14 d to examine the activation of GAD65/67. Moreover, GABAA receptor subunits were also assessed. As depicted in Figure 8, compared with CG, these findings indicated that EEMOS (2 g/kg) and KA (2 mg/kg) treatment increased the expression of GAD65 and α1-subunit (p < 0.05) (Figure 8(A,C)), but did not affect the amounts of GAD67, γ2-subunits in the hypothalamus (p > 0.05; Figure 8(B,D)). Additionally, EST (2 mg/kg) significantly enhanced the amounts of GAD65 and α1-subunit (p < 0.01), but did not influence the abundance of GAD67 and γ2-subunits.
Therapeutic potential of GABAA receptor subunit expression abnormalities in fragile X syndrome
Published in Expert Review of Precision Medicine and Drug Development, 2022
Mathijs B. van der Lei, R. Frank Kooy
To overcome the sedative and addictive limitations of classical benzodiazepines, novel compounds needed to be developed that avoid the subunits of the GABAA receptor that are responsible for the side effects of classical benzodiazepines. Therefore, the main focus of the industry switched to the development of compounds targeting only specific subunits of the GABAA receptor. Studies with α-subunit point mutated mice provided insights into the specific contribution of each subunit to the (un)wanted effects of benzodiazepines. Results showed that in α1 subunit point mutated mice the sedative effect of diazepam was absent and the desired anxiolytic effects were still present [50]. Moreover, mice with a point mutation in the α2 subunit showed nearly completely abolished anxiolytic and sedative myorelaxant effects after treatment with diazepam [51,52]. In α3 subunit point mutated mice the myorelaxant effects of diazepam were still present and only abolished at high concentrations [52]. At last, mice with a point mutation in the α5 subunit showed no impairments in the sedative, anticonvulsant, or anxiolytic effects of diazepam, but impaired associative learning in the trace conditioning task was noted [53].
Pharmacotherapeutic management of co-morbid alcohol and opioid use
Published in Expert Opinion on Pharmacotherapy, 2020
Lauren E. Hood, Jonna M. Leyrer-Jackson, M. Foster Olive
In addition to glutamatergic alterations, alcohol also alters GABAergic neurotransmission, specifically through actions at the GABAA receptor. Specifically, alcohol induces transient changes in GABAA receptor levels, composition, and cellular localization [177], and in vitro studies have repeatedly shown that ethanol down-regulates GABAA–mediated phasic and inhibitory currents, which is consistent with changes in receptor surface expression [178]. Further, binge-like drinking decreases GABAA receptor levels within the dorsal raphe nucleus [179], decreases c-fos immunoreactivity within the nucleus accumbens (suggesting the reward circuitry activity to be dampened) [180]. Lastly, GABAA receptor antagonists reduce alcohol effects in vivo while GABAergic positive allosteric modulators (PAMs) mimic alcohol effects, further supporting the role of direct activation and alterations of GABAergic circuitry within the reward pathway [177,181].