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Interaction of the benzodiazepines with the GABAA receptor
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
These pyrazolopyridines possess anxiolytic activity and are thought to act at the GABAA receptor, since they induce a number of allosteric changes in the binding properties of this receptor. Pyrazolopyridines increase the affinity of [3H]-diazepam and of [3H]-flunitrazepam to their binding site, and this effect is strongly synergistic with that of GABA (Beer et al, 1978; Supavilai and Karobath, 1979, 1981). This increase in benzodiazepine affinity can be blocked by the channel-directed GABAA receptor antagonist picrotoxin (Supavilai and Karobath, 1979; Leeb-Lundberg et al, 1981). Etazolate and cartazolate also increase the apparent binding capacity of the GABA binding site (Placheta and Karobath, 1980) in a similar manner to that seen for the barbiturates and potentiate GABA-evoked chloride currents (Barnes et al, 1983). Direct binding of radiolabelled pyrazolopyridines has not been demonstrated.
Preclinical Antidepressant-Like Effects of Terpenes, Polyphenolics, and Other Non-Flavonoid Phytochemicals
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
Ellagic acid also showed anxiolytic-like effects in mice. It increased time spent in the open arms of the elevated plus maze in a manner similar to diazepam. Moreover, that effect was blocked by pretreatment with the GABA-A receptor antagonist, picrotoxin, and the benzodiazepine antagonist, flumazenil.69
Neuropsychology of Cognitive Aging in Rodents
Published in David R. Riddle, Brain Aging, 2007
Joshua S. Rodefer, Mark G. Baxter
Administration of the 5-HT(6) receptor antagonist SB-271046 improved acquisition and consolidation in a water maze task in aged rats. Treatment with SB-271046 improved swim strategy, escape latencies, and task recall, suggesting that the drug may enhance cognitive processes as well as ameliorate age-related cognitive deficits observed in older animals [78]. In addition, Froestl et al. [79] examined the effects of the novel GABA(B) receptor antagonist SGS742. Chronic administration of SGS742 was reported to upregulate GABA(B) receptors in the frontal cortex of rats and produce cognitive enhancing effects in aged rats in both radial and water maze tasks.
Calcium, magnesium, potassium, and sodium oxybates oral solution for cataplexy or excessive daytime sleepiness associated with narcolepsy
Published in Expert Opinion on Pharmacotherapy, 2023
Orexin agonist therapies that are showing promise include JZP 441 (DSP-1087) [25], TAK 925 [26], and TAK 861 [27]. TAK 994 [27] completed Phase 2 studies but was withdrawn due to safety signals. H3 receptor antagonists/inverse agonists under investigation for EDS include TS 091 (Enerisant) [33], SUVN-G 3031 (Samelisant) [34], and JNJ 17216498 [35]. A GABAA receptor antagonist (pentetrazol) completed Phase 2, but results are not available [36]. Reboxetine, a norepinephrine reuptake inhibitor [29], ulotaront (SEP 363856), a trace amine associated receptor 1, and serotonin 5-H1A agonist [28], and mazindol, a sympathomimetic amine that blocks dopamine and norepinephrine reuptake [32], are also undergoing clinical investigation. Both THN 102 (a combination of modafinil and flecainide) [37] and clarithromycin [38] underwent phase 2 trials for treatment of EDS.
Morphine ameliorates pentylenetetrazole-induced locomotor pattern in zebrafish embryos; mechanism involving regulation of opioid receptors, suppression of oxidative stress, and inflammation in epileptogenesis
Published in Toxicology Mechanisms and Methods, 2023
Fümet Duygu Üstündağ, İsmail Ünal, Ünsal Veli Üstündağ, Derya Cansız, Merih Beler, A. Ata Alturfan, Pınar Mega Tiber, Ebru Emekli-Alturfan
As a GABA receptor antagonist, PTZ has been widely utilized in animal models to cause seizures. The principal effect of a PTZ-induced seizure is to lower GABA levels (Erdtmann-Vourliotis et al. 1998). PTZ-induced epilepsy model is characterized by progressive excitability changes and a significant imbalance in excitatory-inhibitory neurotransmission (Zhu et al. 2016). High increases in Ca++ and K+ intracellular currents, as well as glutamate release in post-synaptic terminals, are triggered by each chemical or electrical stimulus (Bymaster et al. 2003). Together, these activities cause a significant bioenergetics malfunction, resulting in free radical overproduction and activation of caspase-mediated cell death pathways (Agarwal et al. 2011; de Souza et al. 2019). In the present study, PTZ exposure led to increased NO levels. NO interacts with ROS to produce peroxynitrite which is a powerful cell death inducer (Borutaite et al. 2000). Similar to our results, De Souza et al. (2019), reported that PTZ-kindling increased nitrite levels in all of the brain locations in mice. The oxidative damage to membrane lipids causes LPO. LPO was found to be higher in rats subjected to PTZ in previous investigations (Mazhar et al. 2017; de Souza et al. 2019). Our data support these findings since the PTZ-exposed zebrafish embryos had higher MDA levels. The reduction in MDA levels was maintained by both morphine and VPA pretreatments.
C-Fos mapping and EEG characteristics of multiple mice brain regions in pentylenetetrazol-induced seizure mice model
Published in Neurological Research, 2019
Huajun Yang, Wei Shan, Fei Zhu, Tingting Yu, Jingjing Fan, Anchen Guo, Fei Li, Xiaofeng Yang, Qun Wang
One of the most important brain structures for the generation and spread of epileptic discharges is the piriform cortex. This structure is also important for the induction and propagation of epileptic activity [24]. Piriform cortex is typically the first region that is disinhibited during seizure induction [25,26]. Administration of a GABA(A) receptor antagonist directly into the piriform cortex resulted in generalized seizure [27]. Projections from the piriform cortex contribute to the formation of epileptic pathological network [24,28]. In our study, robust c-Fos expression was observed in the piriform cortex, which validates its significant involvement in PTZ-induced seizures.