Abstracts

Rationale: Similarities exist between epilepsy and schizophrenia: both are probably neurodevelopmental in origin, influenced by genetic and environmental factors, and result from ‘two- or multi-hit’ causation. The incidence of psychosis is increased in people with epilepsy, particular those with non-convulsive seizures including absences. We examined whether GAERS, a rat model of genetic absence epilepsy, also shows psychosis-like behaviours, and whether any alterations were present prior to the expression of absence seizures.Methods: Female GAERS (n=14) and Non-Epileptic Control (NEC) rats (n=12) of either 6 or 13 weeks of age (i.e. before and after the onset of the epilepsy) were subjected to two behavioral tests widely used in modeling aspects of schizophrenia: psychostimulant-induced locomotor hyperactivity, and prepulse inhibition (PPI) of the acoustic startle response. Locomotor activity was tested for 90 minutes following drug administration in a photocell chamber. Startle responses and PPI were determined using acoustic startle chambers.Results: D-amphetamine (0.5mg/kg ip) produced a significantly enhanced locomotor response in GAERS compared with NEC at both time points studied (total activity counts at 7 weeks: GAERS 11469±2299 vs NEC 5342±1846; at 13 weeks: GAERS 20730±861 vs NEC 14047±2163; p<0.01), suggesting that GAERS have a hyperresponsive dopaminergic system. Hyperactivity was not different after phencyclidine (2.5 mg/kg ip) or saline vehicle. GAERS also displayed an increased startle response which was also present prior to, and after the development of seizures (at 13 weeks: GAERS 592±71 arbitrary movement units vs NEC 197±38, p<0.001), but no difference in baseline levels of PPI. Furthermore, disruption of PPI with apomorphine (0.3 mg/kg sc), MK-801 (0.1 mg/kg sc) and 8 OH-DPAT (0.5 mg/kg sc) was similar in GAERS and NEC, suggesting normal sensorimotor gating in GAERS.Conclusions: GAERS display a hyperlocomotor response to d-amphetamine, a model of psychosis, which may be caused by altered dopamine release or dopamine receptor densities. GAERS also display an enhanced startle response compared to NEC, suggesting increased anxiety which confirms our research presented previously. Furthermore, these deficits were present prior to the development of absence seizures, indicating that they are not just secondary to the epilepsy but that there may be common causative factors predisposing these animals to develop both epilepsy and psychosis-like behavior. GAERS provide an opportunity to study the neurodevelopmental, genetic and therapeutic aspects of psychotic co-morbidities associated with epilepsy. This research is supported by an NHMRC project grant (400088), and a NARSAD Independent Investigator Award (TOB).