The role of different serotonin receptor subtypes in seizure susceptibility

Gharedaghi, Mohammad Hadi; Seyedabadi, Mohammad; Ghia, Jean–Eric; Dehpour, Ahmad Reza; Rahimian, Reza

doi:10.1007/s00221-013-3757-0

Cited by 49 publications

(63 citation statements)

References 166 publications

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“…Alternatively, 5-HT 2 receptors, and more specifically the 5-HT 2A and the 5-HT 2C receptors, are G q/11 -coupled membrane receptors that increase intracellular Ca 21 levels and increase interneuronal excitability (Jiang et al, 2009;Bonn et al, 2012). The 5-HT 3A receptor is a ligand-gated sodium, potassium, and calcium channel that also increases interneuronal excitability but leads to a rapidly desensitizing depolarization (Rainnie, 1999;Mascagni and McDonald, 2007;Gharedaghi et al, 2014).…”

Section: Serotonergic Afferentsmentioning

confidence: 99%

The basolateral amygdala γ‐aminobutyric acidergic system in health and disease

Prager

Bergstrom

Wynn

et al. 2015

J of Neuroscience Research

152

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The brain comprises an excitatory/inhibitory neuronal network that maintains a finely tuned balance of activity critical for normal functioning. Excitatory activity in the basolateral amygdala (BLA), a brain region that plays a central role in emotion and motivational processing, is tightly regulated by a relatively small population of gamma-aminobutyric acid (GABA) inhibitory neurons. Disruption in GABAergic inhibition in the BLA can occur when there is a loss of local GABAergic interneurons, alterations in GABAA receptor activation, or dysregulation of mechanisms that modulate BLA GABAergic inhibition. Disruptions in GABAergic control of the BLA emerge during development, in aging populations, or after a trauma, ultimately resulting in hyperexcitability. BLA hyperexcitability manifests behaviorally as an increase in anxiety, emotional dysregulation, or the development of seizure activity. This article reviews the anatomy, development, and physiology of the GABAergic system in the BLA, and circuits that modulate GABAergic inhibition, including the dopaminergic, serotonergic, noradrenergic, and cholinergic systems. We highlight how alterations in various neurotransmitter receptors, including the acid sensing ion channel 1a (ASIC1a), cannabinoid receptor 1 (CB1), and glutamate receptor subtypes, expressed on BLA interneurons, modulate GABAergic transmission and how defects of these systems affects inhibitory tonus within the BLA. Finally, we discuss alterations in the BLA GABAergic system in neurodevelopmental (autism/Fragile X syndrome) and neurodegenerative (Alzheimer’s disease) diseases, and after the development of epilepsy, anxiety, and traumatic brain injury. A more complete understanding of the intrinsic excitatory/inhibitory circuit balance of the amygdala and how imbalances in inhibitory control contribute to excessive BLA excitability will guide the development of novel therapeutic approaches in neuropsychiatric diseases.

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Section: Serotonergic Afferentsmentioning

confidence: 99%

The basolateral amygdala γ‐aminobutyric acidergic system in health and disease

Prager

Bergstrom

Wynn

et al. 2015

J of Neuroscience Research

152

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“…Notably, some interesting progress has been made in the understanding of the mechanisms underlying epilepsy, revealing novel targets for future AEDs (Löscher et al, 2013). For instance, current evidence underscores the role of SER (5-HT) in epilepsy and it has been suggested that serotonergic drugs have great potential in the treatment of various epilepsy conditions (Gharedaghi et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

Smolders²,

et al. 2017

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Dravet syndrome (DS) is a genetic encephalopathy that is characterized by severe seizures and prominent co-morbidities (e.g., physical, intellectual disabilities). More than 85% of the DS patients carry an SCN1A mutation (sodium channel, voltage gated, type I alpha subunit). Although numerous anti-epileptic drugs have entered the market since 1990, these drugs often fail to adequately control seizures in DS patients. Nonetheless, current clinical data shows significant seizure reduction in DS patients treated with the serotonergic (5-hydroxytryptamine, 5-HT) drug fenfluramine (FA). Recent preclinical research confirmed the anti-epileptiform activity of FA in homozygous scn1a mutant zebrafish larvae that mimic DS well. Here we explored the anti-epileptiform mechanisms of FA by investigating whether selective agonists/antagonists of specific receptor subtypes were able to counteract the FA-induced inhibition of seizures and abnormal brain discharges observed in the scn1a mutants. We show that antagonists of 5-HT1D and 5-HT2C receptor subtypes were able to do so (LY 310762 and SB 242084, respectively), but notably, a 5-HT2A-antagonist (ketanserin) was not. In addition, exploring further the mechanism of action of FA beyond its serotonergic profile, we found that the anti-epileptiform brain activity of FA was significantly abolished when it was administered in combination with a σ1-agonist (PRE 084). Our study therefore provides the first evidence of an involvement of the σ1 receptor in the mechanism of FA. We further show that the level of some neurotransmitters [i.e., dopamine and noradrenaline (NAD)] in head homogenates was altered after FA treatment, whereas γ-aminobutyric acid (GABA) and glutamate levels were not. Of interest, NAD-decreasing drugs have been employed successfully in the treatment of neurological diseases; including epilepsy and this effect could contribute to the therapeutic effect of the compound. In summary, we hypothesize that the anti-epileptiform activity of FA not only originates from its 5-HT1D- and 5-HT2C-agonism, but likely also from its ability to block σ1 receptors. These findings will help in better understanding the pharmacological profile of compounds that is critical for their applicability in the treatment of DS and possibly also other drug-resistant epilepsies.

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“…Specific subtypes of 5-HT receptors are thought to be selectively relevant to control of respiration, arousal and epilepsy [21–23]. At least seven subtypes of 5-HT receptors are expressed in the brainstem [24, 25], and the absence of 5-HT 2C receptors in transgenic mice is associated with seizure susceptibility that can result in seizure-induced death [26, 27], similar to that seen in DBA mice.…”

Section: Introductionmentioning

confidence: 99%

Serotonergic agents act on 5-HT 3 receptors in the brain to block seizure-induced respiratory arrest in the DBA/1 mouse model of SUDEP

Faingold

Randall

Zeng

et al. 2016

Epilepsy & Behavior

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Drugs that enhance the action of serotonin (5-hydroxytrypamine, 5-HT), including several selective serotonin reuptake inhibitors (SSRIs), reduce susceptibility to seizureinduced respiratory arrest (S-IRA) that leads to death in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP). However, it is not clear if specific 5-HT receptors are important in the action of these drugs and whether the brain is the major site of action of these agents in this SUDEP model. The current study examined the actions of agents that affect the 5-HT3 receptor subtype on S-IRA and whether intracerebroventricular (ICV) microinjection of an SSRI would reduce S-IRA susceptibility in DBA/1 mice. The data indicate that systemic administration of SR 57227, a 5-HT3 agonist, was effective in blocking S-IRA in doses that did not block seizures, and the S-IRA blocking effect of the SSRI, fluoxetine, was abolished by co-administration of a 5-HT3 antagonist, ondansetron. Intracerebroventricular administration of fluoxetine in the present study was also able to block S-IRA without blocking seizures. These findings suggest that 5-HT3 receptors play an important role in the block of S-IRA by serotonergic agents, such as SSRIs, which is consistent with the abnormal expression of 5-HT3 receptors in the brainstem of DBA mice observed previously. Taken together, these data indicate that systemically administered serotonergic agents act, at least in part in the brain, to reduce S-IRA susceptibility in DBA/1 mice and that 5-HT3 receptors may be important to this effect.

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The role of different serotonin receptor subtypes in seizure susceptibility

Cited by 49 publications

References 166 publications

The basolateral amygdala γ‐aminobutyric acidergic system in health and disease

The basolateral amygdala γ‐aminobutyric acidergic system in health and disease

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

Serotonergic agents act on 5-HT 3 receptors in the brain to block seizure-induced respiratory arrest in the DBA/1 mouse model of SUDEP

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