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Antianxiety Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
5-HT1A is heteroreceptor and expressed widely in the amygdala, hippocampus, and the prefrontal cortex of brain (Albert et al., 1990) and modulates anxiety and the related behavior (Savitz et al., 2009; Meltzer et al., 2012; Donaldson et al., 2013). 5-HT1A receptor is an autoreceptor coupled with Gi and Go proteins and the related pathways (Lanfumey and Hamon, 2004; Barnes and Sharp, 1999) and the stimulation of these receptors inhibit the activity of these neurons (Celada et al., 2004). Buspirone shows partial agonism at the 5-HT1A receptors and is used in the treatment of behavioral disturbances in dementia including agitation (Salzman, 2001; Apter and Allen, 1997; Holzer et al., 1995; Stanislav et al., 1994). Adverse effects include headache, dizziness, nervousness, and lightheadedness (Jann, 1988).
Epilepsy
Published in Divya Vohora, The Third Histamine Receptor, 2008
Divya Vohora, Krishna K. Pillai
Presynaptic H3 receptors occur both on histaminergic neurons of the CNS (autoreceptors) and on nonhistaminergic neurons of the CNS and autonomic nervous system [72]. Thus, they regulate the release of not only histamine but also other important transmitters such as norepinephrine (NE) [73], dopamine (DA) [74], 5-hydroxytryptamine (5-HT)[75], acetylcholine (Ach)[76] and gamma amino butyric acid (GABA) [47] through heteroreceptors in the CNS. Such effects of H3 heteroreceptors have been most thoroughly investigated in the mouse brain cortex where they cause inhibition of NE release [77] and in the guinea pig small intestine causing inhibition of ACh release [78]. H3 receptor antagonists have been demonstrated to enhance whereas histamine and H3 receptor agonists have been shown to reduce the release of these transmitters in in vitro studies. All these transmitters are related in some or the other way to epilepsy and epileptic seizures [57]. Although THP, an H3 receptor antagonist, was found to increase the release of GABA from the rat hypothalamus [47], RAMH, a selective agonist, inhibited the release [79]. It is needless to emphasize the importance of GABA in seizures and epilepsy. The effect of these ligands on GABA release correlates well with their effects on modulation of seizure activity. A study by Arrang et al. [80], however, demonstrated no inhibition of ACh release from rat entorhinal cortex synaptosomes following H3 receptor activation. H3 receptor antagonists also provided protection against amygdala kindling in rats [22]. A reduction in DA and NE content occurs following amygdala kindling [13]. Thus, it is possible that the protection afforded by these agents involve an indirect action through the enhancement of release of these neurotransmitters in brain. However, the dose of THP employed in the study provided protection but did not affect the brain levels of DA, 3,4-dihydroxyphenylacetic acid, 5-HT, and 5-hydoxyindoleacetic acid [23]; thus, ruling out the possibility of involvement of these neurotransmitters in the protective effect. The role for NE, however, may not be overlooked, as H3 receptors regulating the release of NE are located in the catecholaminergic nerve terminals. However, the modulation of even catecholaminergic tone was also not confirmed by in vivo studies [61]. In view of all these observations, the heteroreceptor function seems to play a minor role in contrast with the modulation of histamine release by these receptors [81].
Neuroprotection by trans-resveratrol against collagenase-induced neurological and neurobehavioural deficits in rats involves adenosine A1 receptors
Published in Neurological Research, 2020
Noor Azliza Wani Abd. Aziz, Igor Iezhitsa, Renu Agarwal, Roqiah Fatmawati Abdul Kadir, Azian Abd. Latiff, Nafeeza Mohd Ismail
Clinically, intrastriatal ICH causes long-term sensorimotor deficits among patients. Current evidence suggests that the adenosine receptors may play an important role in the modulation of striatal pathways [66]. The receptor–receptor interactions between adenosine and dopamine based on their antagonistic actions were shown beneficial in Parkinson’s Disease model [67]. This heteromer involving adenosine 2A receptor (A2AR) and dopamine D2 receptor (D2R) targets the indirect pathway of basal ganglia to reduce the symptomatic movements. In stroke model, on the other hand, heteroreceptor of A1R with dopamine D1 receptor (D1R) may produce a beneficial approach by targeting the direct pathway to improve movements. Furthermore, in the striatum, interactions between A1R and A2AR and between A1R and D1R were reported previously [68]. Interestingly, previous studies have shown that A1R is inhibited in response to A2AR stimulation by glutamate-mediated excitotoxicity [69]. Hence, it is likely that conversely, A1R activation suppresses excitotoxic neurotransmission resulting in neuroprotective effect.
Design, synthesis, and anticonvulsant effects evaluation of nonimidazole histamine H3 receptor antagonists/inverse agonists containing triazole moiety
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mingxia Song, Rui Yan, Yanhui Zhang, Dongfu Guo, Naiming Zhou, XianQing Deng
Histamine H3 receptors (H3R) as a G-protein coupled receptor (GPCR) binding to histamine like other histamine receptors, is expressed mainly in the central nervous system, where it acts as an auto-receptor in histaminergic neurons, and negatively regulates the synthesis and release of histamine11. What is more, as a inhibitory heteroreceptor, H3R also regulates the release of other neurotransmitters including dopamine, acetylcholine, serotonin, norepinephrine, γ-aminobutyric acid, and glutamate. These neurotransmitters, especially γ-aminobutyric acid and glutamate, are related to epilepsy inextricably12,13. Therefore, more attention has been focussed on H3R as an attractive therapeutic target for epilepsy treatment14.
Targeting the receptor-based interactome of the dopamine D1 receptor: looking for heteromer-selective drugs
Published in Expert Opinion on Drug Discovery, 2019
Verònica Casadó-Anguera, Antoni Cortés, Vicent Casadó, Estefanía Moreno
A heteromer with D2R has also been reported [62,80,82,86]. This heteromer is located predominantly in subsets of dynorphin/enkephalin spiny projection neurons (SPNs) of the nucleus accumbens [87]. It is coupled to Gαq/11 proteins and requires the co-activation of both receptors for activating intracellular calcium release [81,82]. In addition, Hasbi et al. [62] reported that disrupting the D1R-D2R heteromer with a peptide targeting an interaction interface caused a blockade of the signaling both in vitro and in vivo. This heteroreceptor complex may contribute to synaptic plasticity [82] and has been related to drug addiction, schizophrenia and depression [88]. However, in 2015, Frederick et al. [89] reported that D1R and D2R are segregated at the subcellular level, even in SPNs of the nucleus accumbens, which co-express both DRs; this fact suggested that they may not be able to heteromerize in vivo.