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Gene Targeting Models of Epilepsy: Technical and Analytical Considerations
Published in Steven L. Peterson, Timothy E. Albertson, Neuropharmacology Methods in Epilepsy Research, 2019
The observation of an epilepsy syndrome in 5-HT2C receptor mutant mice is consistent with several lines of evidence indicating that serotonin system activity produces anticonvulsant effects in a variety of epilepsy models, including AGSs.39-42 Despite these findings, the identity of the receptors that contribute to these actions of serotonin has been unclear. Interestingly, several commonly used psychiatric drugs with convulsant side effects have potent 5-HT2C receptor antagonist properties.43 The above findings indicate that the 5-HT2C receptor may play a significant role in the serotoninergic inhibition of neuronal network excitability, and indicate its potential as a target for anticonvulsant drug development. 5-HT2C receptor null mutant mice provide a useful tool for exploring mechanisms through which serotonin systems regulate brain excitability.
Neurobiology of Mood Disorders
Published in Dr. Ather Muneer, Mood Disorders, 2018
The modern era of psychopharmacology was ushered in the 1950s with the discovery of medications that possessed a tricyclic structure, e.g., chlorpromazine, imipramine and amitriptyline. Soon afterwards it was found that these compounds effected monoamine transmission in the brain by a variety of mechanisms, for example by blocking the synaptic transporters or antagonizing the postsynaptic receptors, and this was their initial pharmacodynamic action. Even after the passage of several decades, the modern psychotherapeutic agents are still based on the same principle and all current medications act by manipulating the monoamine neurotransmitters. For example, the major class of antidepressant drugs used now are selective serotonin reuptake inhibitors (SSRIs). Multiple human functional imaging studies using PET, SPECT and fMRI have also found alterations in these systems in subjects with mood disorders.13 Administration of the antidepressant, agomelatine (a melatonin receptor agonist and weak 5-HT2C receptor antagonist), leads to increases in monoaminergic neuronal activity which can be blocked with the melatonergic antagonist S22153. These results point to a modulatory role for the pineal hormone, melatonin, in monoaminergic activity, linking the circadian and monoamine systems.14
Serotonin receptors and valvular heart disease
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Javier G. Castillo, David H. Adams
Among the seven families of 5-HT receptors, the 5-HT2 family has been traditionally linked to secondary cardiovascular disease, especially 5-HT2A and 5-HT2B [19]. This family consists of three different GPCRs (5-HT2A, 5-HT2B, and 5-HT2C) that induce a sudden increase in the intracellular concentration of IP3, thus generating the production of DAG and calcium. Parallel to these reactions, 5-HT2 receptors also generate secondary organ-specific responses, among which the brain is the most prevalent target [20]. In the brain, 5-HT2C receptors are uniformly distributed in all brain areas and represent an important target for psychoactive agents (i.e., atypical antipsychotics and anorectics), whereas the presence of 5-HT2A receptors is only important in cortical regions and the concentration of 5-HT2B receptors is very low (minor involvement) [21]. However, a very characteristic trait of 5-HT2 receptors is the lack of selectivity. This is due to an approximate 50% homology among receptors, and as a consequence, drugs intended to target 5-HT2A or 5-HT2C receptors located in the brain may interact with peripheral 5-HT2B receptors and vice versa [22].
Sexual dysfunction with major depressive disorder and antidepressant treatments: impact, assessment, and management
Published in Expert Opinion on Drug Safety, 2022
Joan Winter, Kimberly Curtis, Bo Hu, Anita H. Clayton
Serotonin binding at the post-synaptic 5-HT1A receptor produces antidepressant and anxiolytic effects, while increased binding at the 5-HT2A and 5-HT2C receptors leads to increased anxiety, insomnia, and sexual dysfunction. Multiple antidepressants (eg. mirtazapine, trazodone, several TCAs, and norquetiapine – the active metabolite of quetiapine) with fewer sexual side effects exhibit antagonism at 5-HT2. The release of dopamine and norepinephrine in the cortex is inhibited by stimulation of 5-HT2A and 5-HT2C receptors [9–10]. Norepinephrine and nitric oxide promote tumescence of sexual organs and lubrication. Dopamine is a key neurotransmitter of the reward system, which includes the nucleus accumbens/ventral striatum, ventral tegmental area (VTA), pre-frontal cortex, orbitofrontal cortex, anterior cingulate cortex, and amygdala. Dopamine promotes sexual function at varying concentrations at progressive stages of sexual engagement: from sexual desire to increased parasympathetic activation required for erections, and finally climax. Dopamine may also be involved in the medial preoptic area of the hypothalamus (mPOA) in the initial disinhibition of genital reflexes[12]. In addition to central effects, serotonin acts in the peripheral nervous system by directly suppressing spinal ejaculatory centers [10–11]. Thus, the increase of serotonin at the synaptic cleft as a result of antidepressant action can impact many levels of sexual functioning: decreased interest and arousal, inhibited/delayed orgasm, and diminished intensity and frequency of orgasm[13].
Has the bloom gone out of lorcaserin following the CAMELLIA-TIMI61 trial?
Published in Expert Opinion on Pharmacotherapy, 2021
Many drugs that influence appetite have stimulated neurotransmitter pathways that influence the signaling of appetite and satiety by the central nervous system. Unfortunately, most have had to be withdrawn or had severe restrictions on their use due to a range of side-effects that include life-threatening psychological and cardiovascular events. Earlier drugs such as fenfluramine increased the release of serotonin and activated a range of receptors such as the 5-HT2c receptor, which has a key role in stimulating hypothalamic signaling of satiety. However, the use of fenfluramine by itself and in combination with other drugs was found to cause heart valve damage, cardiac fibrosis and pulmonary hypertension, which resulted in the banning and withdrawal of drugs of this class. These undesirable side-effects are thought to be mediated by serotonin 5-HT2a and 2b receptors. Subsequent pharmaceutical refinement focused on discovering molecules that selectively bind to the 5-HT2c receptor, and lorcaserin, a full 5-HT2c agonist, (with low activity at 5-HT2a and 2b receptors) was shown to have consistent effects on weight loss, without inducing significant side-effects on the cardiovascular system. Through a series of multi-center trials involving about 5 thousand patients, lorcaserin received approval for marketing and use in the USA in 2012, while continuing post-market evaluation of safety [6].
The preclinical discovery and development of agomelatine for the treatment of depression
Published in Expert Opinion on Drug Discovery, 2020
George Konstantakopoulos, Stefanos Dimitrakopoulos, Panayiota G. Michalopoulou
In the present review, we briefly described the preclinical development and clinical applications of agomelatine, the first antidepressant with a mechanism of action extending beyond monoaminergic neurotransmission. Agomelatine activates melatonin MT1 and MT2 receptors, facilitating the resynchronization of altered circadian rhythms. It is also an antagonist at the serotonin 5-HT2C receptors, increasing the release of both noradrenaline and dopamine at the fronto-cortical dopaminergic and noradrenergic pathways. The interplay between melatonergic agonism and 5-HT2C antagonism may explain molecular and cellular actions of agomelatine responsible for its antidepressant and anxiolytic properties. The preclinical research reviewed indicates the potential therapeutic effect in several animal models of depression and anxiety.