title: Positive allosteric modulator of GABAB receptor alters behavioral effects but not afterdischarge progression induced by partial hippocampal kindling.
abstract: Hippocampal seizures decreased the function of GABAB receptors, which may further increase seizure susceptibility and contribute to development of schizophrenia-like behaviors. Recent literature indicates that GABAB receptor agonist may normalize schizophrenia-like behaviors and prevent drug-induced behavioral sensitization. We hypothesized that positive modulation of GABAB receptor function during seizure induction will reduce seizure-induced schizophrenia-like behaviors. Using a partial hippocampal kindling model, afterdischarges were induced after injection of saline or dimethyl sulfoxide (vehicle-kindled rats), or a GABAB receptor positive allosteric modulator CGP7930, at 1 mg/kg i.p. (CGP1-kindled) or 5 mg/kg i.p. (CGP5-kindled). The increase in the primary afterdischarge duration during kindling was not different among the groups. However, the CGP5-kindled group showed a lower afterdischarge starting frequency as compared to vehicle-kindled or CGP1-kindled groups. Partial hippocampal kindling (21 afterdischarges) resulted in decreased prepulse inhibition and decreased gating of hippocampal auditory evoked potentials in vehicle-kindled and CGP1-kindled rats, as compared to saline-injected non-kindled rats, recorded 3-4 days after the last afterdischarge. However, CGP5-kindled rats showed normal prepulse inhibition and hippocampal auditory gating (compared to non-kindled rats), which was significantly higher than the respective measure in vehicle-kindled rats. CGP5-kindled group also showed methamphetamine-induced locomotion that was significant lower than the vehicle-kindled or CGP1-kindled group, but slightly higher than the saline-injected non-kindled rats. In conclusion, this study provides original data that a GABAB receptor positive allosteric modulator could therapeutically prevent or normalize some seizure-induced behavioral disruptions in a model of temporal lobe epilepsy.
authors.affiliation: Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, N6A 5C1, Canada. Electronic address: sleung@uwo.ca.
authors.forename: L Stan
authors.initials: LS
authors.lastname: Leung
authors.affiliation: Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
authors.forename: Miao
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
authors.forename: Liangwei
authors.initials: L
authors.lastname: Chu
authors.affiliation: Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Ma
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D005072:Evoked Potentials, Auditory / Q000187:drug effects / Q000502:physiology*; D018757:GABA Modulators / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D065808:Prepulse Inhibition / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D018080:Receptors, GABA-B / Q000502:physiology*
chemical_list: D018757:GABA Modulators; D018080:Receptors, GABA-B
keywords: Auditory gating; CGP7930; GABA(B) receptor; Hippocampus; Kindling; Locomotion; Methamphetamine; Prepulse inhibition