Serotonin Concentration and Release in Epilepsy

The functions of 5-HT on the central nervous system (CNS) are numerous and appear to involve control of appetite, sleep, memory and learning, temperature regulation, mood, behavior, cardiovascular function, muscle contraction, endocrine regulation, maturation of neuronal and glial cells and synaptic connections, and, as discussed here, epilepsy (Barnes and Sharp 1999; Hoyer et al. 1994; Azmitia and Whitaker-Azmitia 1999). The idea that there may be a link between serotonin and the inhibition of epilepsy was suggested as early as 1957 by Bonnycastle et al. (1957). In their study they demonstrated that a series of anticonvulsants, including phenytoin, elevated brain serotonin levels.

Serotonergic neurotransmission modulates a wide variety of experimentally induced seizures and is involved in the enhanced seizure susceptibility observed in rodents genetically prone to epilepsy (Kilian and Frey 1973; Buterbaugh 1978; Przegalinski 1985; Hiramatsu et al. 1987; Dailey et al. 1992; Gerber et al. 1998; Filakovszky et al. 1999). Generally, agents that elevate extracellular 5-HT levels, such as 5-hydroxytryp-tophan and 5-HT reuptake blockers, inhibit both focal (limbic) and generalized seizures (Löscher 1984; Prendiville and Gale 1993; Yan et al. 1994). Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically, and electrically evoked convulsion (Browning et al. 1978; Statnick et al. 1996).

Seizure models in which 5-HT appears to play a prominent role include audiogenic seizures in genetically epilepsy prone rats (GEPR3 and 9) (Daily et al. 1989; Jobe et al. 1973), audiogenic seizures in DBA/2 J mice (Brennan et al. 1997; Tecott et al. 1995), limbic and thalamic seizures in cats (Wada et al. 1993), sensory-induced seizures in El mice (Hiramatsu et al. 1987), seizures induced by focal injection of bicuculline into area tempestas of deep prepiriform cortex of rats (Prendiville and Gale 1993), maximal electroshock seizures in mice and rats (Buterbaugh 1978; Browning et al. 1978), and in WAG/Rij rats, an accepted genetic model of human absence epilepsy (Gerber et al. 1998; Filakovszky et al. 1999; Löscher and Schmidt 1988; Coenen et al. 1992; Van Luijtelaar et al. 2002; Jakus et al. 2003; Graf et al. 2004), handling-induced convulsion in chromosome 4 congenic mice (Reilly et al. 2008). The rat model of myoclonic epilepsy is associated with a profound loss of serotonin throughout the brain (except in the striatum) (Welsh et al. 2002). In a recent study, the effect of 5-HT in an atypical absence model of AY-9944-treated rats was studied (Bercovici et al. 2006). The increased levels of 5-hydroxyindoleactic acid and 5-HT, as well as the altered rates of serotonin turnover, suggest that serotonergic transmission may be perturbed in the AY-9944-treated rats. Mazarati et al. (2006) reported that serotonin depletion by parachloroamphetamine increased the severity of limbic status epilepticus (summarized in Table 22.3).

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