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Effects of 5-HT receptor antagonists on seizure susceptibility and locomotor activity in DBA/2 mice
1Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284-7764.
Abstract:
The effect of antagonists of serotonin (5-HT) receptor subtypes and alpha 2-adrenoceptors was investigated on audiogenic seizures and locomotor activity in DBA/2 mice. 5HT1c receptor antagonists (mianserin and cyproheptadine), 5-HT3 receptor antagonist (zacopride) and 5-HT4 receptor antagonist (ICS 205-930) increased the latency of audiogenic seizures and decreased the severity of convulsions in young (20-27 days old) DBA/2 mice. However, the effect of these antagonists varied in older (30-37 days old) mice. Ketanserin, 5-HT2 receptor antagonist, was devoid of any activity on audiogenic seizures. Yohimbine (0.5 mg/kg, i.p.), an alpha 2-adrenoceptor antagonist, increased the severity of audiogenic seizures, and the anti-convulsant effect of 5-HT receptor subtypes antagonists became more pronounced in the presence of yohimbine. 5-HT3 and 5-HT4 receptor antagonists produced hypolocomotor activity in young mice whereas 5-HT1c and 5-HT2 receptor antagonists were devoid of any effect on locomotor activity. Yohimbine did not induce any effect on locomotor activity but the mice exhibited more pronounced hypolocomotor activity following the administration of 5-HT3, 5-HT4 and 5HT1c receptor antagonists in the presence of yohimbine. However, the results varied with these agents in the older mice. These observations implicate a role of 5-HT1c, 5-HT3, 5-HT4 and alpha 2-adrenoceptors in audiogenic seizures in young DBA/2 mice, and 5-HT3 and 5-HT4 receptors in locomotor activity in these mice. Furthermore, these results also suggest an interaction between 5-HT receptors and alpha 2-adrenoceptors, and differential development patterns of various 5-HT receptor subtypes in the CNS.
Insights
Antagonists targeting serotonin (5-HT) 1c, 3, and 4 receptors, alongside alpha 2-adrenoceptors, show anticonvulsant effects against audiogenic seizures in young DBA/2 mice. These agents also influence locomotor activity, suggesting complex receptor interactions.
Area of Science:
- Neuropharmacology
- Behavioral Neuroscience
Background:
- Audiogenic seizures are a model for studying epilepsy and neuronal excitability.
- Serotonin (5-HT) and alpha 2-adrenoceptors are implicated in modulating seizure activity and motor function.
- DBA/2 mice are a standard genetic model for audiogenic seizures.
Purpose of the Study:
- To investigate the role of specific serotonin (5-HT) receptor subtypes and alpha 2-adrenoceptor antagonists in audiogenic seizures and locomotor activity.
- To explore potential interactions between these receptor systems in the central nervous system (CNS).
Main Methods:
- Administration of various 5-HT receptor antagonists (5-HT1c, 5-HT2, 5-HT3, 5-HT4) and an alpha 2-adrenoceptor antagonist (yohimbine) to DBA/2 mice of different age groups.
- Assessment of seizure latency, severity, and locomotor activity following drug administration.
Main Results:
- 5-HT1c, 5-HT3, and 5-HT4 receptor antagonists increased seizure latency and decreased seizure severity in young DBA/2 mice.
- Yohimbine exacerbated seizures but potentiated the anticonvulsant effects of 5-HT receptor antagonists.
- 5-HT3 and 5-HT4 receptor antagonists reduced locomotor activity, an effect amplified by yohimbine.
- Age-dependent variations in the effects of these antagonists were observed.
Conclusions:
- 5-HT1c, 5-HT3, 5-HT4 receptors, and alpha 2-adrenoceptors play significant roles in audiogenic seizures in young DBA/2 mice.
- 5-HT3 and 5-HT4 receptors are involved in regulating locomotor activity.
- Evidence suggests a functional interaction between serotonin and alpha 2-adrenergic systems in the CNS.
- Differential developmental patterns of 5-HT receptor subtypes may influence their role in neurological processes.