title: The effects of varenicline on sensory gating and exploratory behavior with pretreatment with nicotinic or 5-HT3A receptor antagonists.
abstract: Individuals with schizophrenia smoke at high frequency relative to the general population. Despite the harmful effects of cigarette smoking, smoking among schizophrenic patients improves cognitive impairments not addressed or worsened by common neuroleptics. Varenicline, a nonselective neuronal nicotinic receptor (NNR) agonist and full agonist of 5-HT3A receptors, helps reduce smoking among schizophrenic patients. To determine whether varenicline also improves a cognitive symptom of schizophrenia, namely, impaired sensory gating, a transgenic mouse with schizophrenia, th-fgfr1(tk-), was used. Varenicline dose-dependently increased prepulse inhibition (PPI) of the startle response, a measure of sensory gating, in th-fgfr1(tk-) mice and normalized PPI deficits relative to nontransgenic controls. With the highest dose (10 mg/kg), however, there was a robust elevation of PPI and startle response, as well as reduced exploratory behavior in the open field and elevated plus maze. Pretreatment with the nonspecific NNR antagonist mecamylamine attenuated the exaggerated PPI response and, similar to the 5-HT3A receptor antagonist ondansetron, it prevented the reduction in exploratory behavior. Collectively, these results indicate that varenicline at low-to-moderate doses may be beneficial against impaired sensory gating in schizophrenia; however, higher doses may induce anxiogenic effects, which can be prevented with antagonists of NNRs or 5-HT3A receptors.
authors.affiliation: aDepartment of Pathology and Anatomical Sciences bDepartment of Psychology, State University of New York at Buffalo, Buffalo, New York cTargacept Inc., Winston-Salem, North Carolina, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Kucinski
authors.forename: Scott
authors.initials: S
authors.lastname: Wersinger
authors.forename: Ewa K
authors.initials: EK
authors.lastname: Stachowiak
authors.forename: Chani
authors.initials: C
authors.lastname: Becker
authors.forename: Pat
authors.initials: P
authors.lastname: Lippiello
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
authors.forename: Michal K
authors.initials: MK
authors.lastname: Stachowiak
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects*; D005260:Female; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology*; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D055139:Sensory Gating / Q000187:drug effects*; D058827:Serotonin 5-HT3 Receptor Agonists / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D000068580:Varenicline