Abstracts

Rationale: We recently described a model of status epilepticus (SE) in juvenile rats which is followed by a severe chronic increase in aggressive behavior. This study examines the effects of anticonvulsive drug (ASD) treatment on behavior and epileptogenesis in that model. We found a dissociation between these long-term consequences of SE with levetiracetam, but not with other ASDs.

Methods: We induced SE in postnatal day 28 rats with lithium and pilocarpine. Drugs or vehicle were injected intraperitoneally (ip) 70 min after pilocarpine. We treated with dizocilpine (MK-801) 0.5 mg/kg; fosphenytoin (50 mg/kg phenytoin equivalents); levetiracetam (LEV, 200 or 1000 mg/kg); diazepam (DZ 5 mg/kg); or Dz (5 mg/kg) + LEV (200 mg/kg). All groups received atropine (10 mg/kg ip) at the same time as drug or vehicle. Three months later, we tested for territorial aggression under the resident-intruder paradigm. We measured the number of episodes of dominance (mounting and pinning) and agonistic behavior (boxing and biting). All animals were also monitored for incidence and severity of spontaneous recurrent seizures (SRSs).

Results: Fosphenytoin had no significant effect on SRS or aggression compared to untreated SE. Treatment with the NMDA antagonist dizocilpine reduced epileptogenesis: only 1 of 6 rats developed SRSs of low frequency (0.7 ± 0.7 seizure/day). It also reduced aggression: dominant behavior was similar to non-SE controls (1.4 ± 0.4 vs 0.4 ± 0.2, NS) and agonistic behavior was minimal, with no biting and little boxing (1.5 ± 0.5 vs 0). Dz, Dz + LEV and LEV 200 did not reduce the incidence of SRSs but reduced their frequency (respectively 2.8 ± 0.9, 2.1 ± 1 and 4.1 ± 2.0 seizures/day vs 17.5 ± 5.1 SRS/day in untreated SE). In the resident-intruder test, they reduced  dominant mounting (2.6 ± 0.7, 3.5 ± 1.3 and 2.0 ± 0.8 vs 2.1 ± 0.3 in C) and boxing  (2.6 ± 0.7 and 2.5 ± 0.8 vs 2.4 ± 0.2 in C) to a level close to non-SE controls. LEV 1000 similarly reduced SRS frequency (2.1 ± 0.8 vs 17.5 ± 5.1 SRS/day) but increased dominant and agonistic behavior beyond the level seen in untreated SE rats (dominant mounts as residents LEV 1000 4.4 ± 1.7 vs untreated SE 1.1 ± 0.4; as intruders 3.5 ± 1.2 vs 1.7 ± 0.6). They also displayed prominent agonistic behavior. Boxing episodes were more frequent than in the untreatd SE group (6.3 ± 1.8 vs 5.0 ± 1.2).

Conclusions: There was a dissociation between the effects of treatment on SRS frequency and behavior. While diazepam and dizocilpine reduced both, high-dose levetiracetam treatment of SE paradoxically improved SRS frequency but worsened some aspects of the chronic increase in aggressive behavior seen in this model of SE in juvenile rats..

Funding: Supported by the VA Researcn Service, by NINDS grants and by the James and Debbie Cho Foundation