title: The T-type calcium channel antagonist Z944 disrupts prepulse inhibition in both epileptic and non-epileptic rats.
abstract: The role of T-type calcium channels in brain diseases such as absence epilepsy and neuropathic pain has been studied extensively. However, less is known regarding the involvement of T-type channels in cognition and behavior. Prepulse inhibition (PPI) is a measure of sensorimotor gating which is a basic process whereby the brain filters incoming stimuli to enable appropriate responding in sensory rich environments. The regulation of PPI involves a network of limbic, cortical, striatal, pallidal and pontine brain areas, many of which show high levels of T-type calcium channel expression. Therefore, we tested the effects of blocking T-type calcium channels on PPI with the potent and selective T-type antagonist Z944 (0.3, 1, 3, 10mg/kg; i.p.) in adult Wistar rats and two related strains, the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and Non-Epileptic Control (NEC). PPI was tested using a protocol that varied prepulse intensity (3, 6, and 12dB above background) and prepulse-pulse interval (30, 50, 80, 140ms). Z944 decreased startle in the Wistar strain at the highest dose relative to lower doses. Z944 dose-dependently disrupted PPI in the Wistar and GAERS strains with the most potent effect observed with the higher doses. These findings suggest that T-type calcium channels contribute to normal patterns of brain activity that regulate PPI. Given that PPI is disrupted in psychiatric disorders, future experiments that test the specific brain regions involved in the regulation of PPI by T-type calcium channels may help inform therapeutic development for those suffering from sensorimotor gating impairments.
authors.affiliation: Department of Physiology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors.forename: Wendie N
authors.initials: WN
authors.lastname: Marks
authors.affiliation: Department of Physiology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Greba
authors.affiliation: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Cain
authors.affiliation: Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
authors.affiliation: Department of Physiology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada. Electronic address: john.howland@usask.ca.
authors.forename: John G
authors.initials: JG
authors.lastname: Howland
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004832:Epilepsy, Absence / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D008297:Male; D010880:Piperidines; D065808:Prepulse Inhibition / Q000187:drug effects* / Q000502:physiology; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity
chemical_list: D000081:Acetamides; D001549:Benzamides; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010880:Piperidines; C000629485:Z944
keywords: GAERS; Wistar; sensorimotor gating; startle response