Genetically Modified Animals

Several knockout mouse models suggest a relationship between 5-HT and epilepsy. The audiogenic seizures syndrome is the first known defect caused by genetic manipulation of a 5-HT receptor subtype; this provides a robust model for examination of serotonergic mechanism in epilepsy. Mutant mice lacking the 5-HT2C receptor subtype are extremely susceptible to audiogenic seizures and are prone to spontaneous death from seizures, suggesting that serotonergic neurotransmission, mediated by 5-HT2C receptors, suppresses neuronal network hyperexcit-ability and seizure activity (Brennan et al. 1997; Tecott et al. 1995; Applagate and Tecott 1998). Fehr et al. (2002) developed a congenic strain that possesses a segment of chromosome 4 from the C57BL/6 J(B6) donor strain superimposed on a genetic background estimated to be >99% from the DBA/2 J (D2) mouse strain. The introduced segment spans the Mpdz gene. Mpdz encodes the multi-PDZ domain protein (MPDZ). Multi-PDZ domain protein's interaction with 5-HT2C receptors has been confirmed in vivo and is mediated via a PDZ domain in MPDZ (Becamel et al. 2001; Parker et al. 2003; 2002). This congenic strain exhibits significantly less severe alcohol withdrawal hyperexcitabilty than background strain mice. Reilly et al. (2008) compared the chromosome 4 congenic and background strains for their susceptibilities to CNS hyperexcitability in response to the selective 5-HT2C receptor antagonist SB 242084. They found that chromosome 4 congenic mice show significantly fewer severe convulsions in response to SB 242084 than background strain mice show. This is consistent with the hypothesis that allelic variation in Mpdz or a linked gene affects 5-HT2C receptor function and thereby influences convulsion severity (Tables 22.6 and 22.7).

In conclusion, genetic models, pharmacological studies, and all other data provide massive evidence for the role of 5-HT2C receptors in epileptogenesis and/or propagation. Actions of currently available drugs with significant affinity to this receptor or potential new molecules under development may provide effective tools in the treatment of a wide variety of different epilepsies.

Table 22.6 Effects of inhibition of 5-HT2C receptors on epilepsy in various animal models (Modified from Bagdy et al. 2007)

Antagonist

Effect

Model (generalized)

References

Ritanserin

4 Effect of TFMPP MES in mice

4 Effect of TFMPP MES in mice

Ketanserin (5-HT ) 4 Effect of TFMPP MES in mice

SB 206553 (5-HT2B C) 4 Effect of mCPP

SB 242084 (5-HT2C) 4 Effect of mCPP on SWD

SB 242084 (5-HT) 4 Effect of mCPP

SB 242084 (5-HT2C) 4 Severity of convulsion

Mouse electroshock test, penthylenetetrasol test in rat and mouse

WAG/Rij rat

Pentylenetetrazole-induced seizures in mice

Chromosome 4 congenic mice

Hoyer and Middlemiss

(1989), Van Wijngaarden et al.

Hoyer and Middlemiss

(1989), Van Wijngaarden et al.

Hoyer and Middlemiss

(1989), Van Wijngaarden et al.

Reilly et al. (2008)

MES maximal electroshock, WAG/Rij Wistar albino Glaxo rats, bred in Rijswijk, SWD spike-wave discharges, AM amygdale, TLE temporal lobe epilepsy, DOI 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, mCPP meta-chlorophenylpiperazine HCl, SB 242084, 6-chloro-5-methyl-1-(2-[2-methylpyrid-3-yloxy]pyrid-5-yl)carbamoyl]indoline dihydrochlo-ride, TFMPP 3-trifluoromethylphenylpiperazine monohydrochloride, SB206553 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo [2,3-/]indole

Table 22.7 Effects of the Lack of 5-HT2C receptors on epilepsy-related parameters in mice

Effect

Model

References

4 Audiogenic seizure 5-HT2C receptor knockout mice Tecott et al. (1995)

4 Spontaneous death from seizure 5-HT2C receptor knockout mice Brennan et al. (1997),

Applagate and Tecott (1998)

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