title: GABA-A receptor modulators alter emotionality and hippocampal theta rhythm in an animal model of long-lasting anxiety.
abstract: The cholinergic system is implicated in emotional regulation. The injection of non-convulsant doses of the muscarinic receptor agonist pilocarpine (PILO) induces long-lasting anxiogenic responses in rats evaluated at different time-points (24h to 3 months). To investigate the underlying mechanisms, rats treated with PILO (150mg/kg) were injected 24h or 1 month later with an anxiolytic (diazepam, 1mg/kg, DZP) or anxiogenic (pentylenetetrazole, 15mg/kg, PTZ) drug and evaluated in the elevated plus-maze (EPM). Prefrontal cortex (PFC) and hippocampal (HIP) electroencephalographic recordings and acetylcolinesterase (AChE) activity were also analyzed after PILO treatment. Anxiogenic responses observed in the EPM 24h or 1 month after PILO treatment (e.g., decreased time spent and number of entries into the open arms of the maze) were blocked by DZP but not affected by PTZ. No epileptiform events were registered in the HIP or PFC at 24h or 1 month after PILO injection, but enhanced theta activity was observed in the HIP. DZP decreased hippocampal theta of PILO-treated rats in contrast with PTZ, which increased this parameter in saline- and PILO-treated rats. The HIP and PFC AChE activity did not change after PILO treatment. Our findings demonstrate that the long-term effects on the emotionality of rats induced by PILO are associated with electrophysiological changes in the HIP and sensitive to pharmacological manipulation of the GABAergic system. The present work may support this new research model of long-lasting anxiety, while also highlighting the muscarinic system as a potential target involved in anxiety disorders.
authors.affiliation: Laboratory of Neuropharmacology, Department of Pharmacology, Center of Biological Sciences (CCB), Federal University of Santa Catarina (UFSC), Florianópolis, SC 88049-900, Brazil.
authors.forename: Alexandre Ademar
authors.initials: AA
authors.lastname: Hoeller
authors.forename: Marcelo
authors.initials: M
authors.lastname: Duzzioni
authors.forename: Filipe Silveira
authors.initials: FS
authors.lastname: Duarte
authors.forename: Leandro Rinaldi
authors.initials: LR
authors.lastname: Leme
authors.forename: Ana Paula Ramos
authors.initials: AP
authors.lastname: Costa
authors.forename: Evelyn Cristina da Silva
authors.initials: EC
authors.lastname: Santos
authors.forename: Claudini Honório
authors.initials: CH
authors.lastname: de Pieri
authors.forename: Alessandra Antunes
authors.initials: AA
authors.lastname: dos Santos
authors.forename: Aline Aita
authors.initials: AA
authors.lastname: Naime
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.forename: Thereza Christina Monteiro
authors.initials: TC
authors.lastname: de Lima
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology*; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004644:Emotions / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D010433:Pentylenetetrazole / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D013826:Theta Rhythm / Q000187:drug effects*
chemical_list: D018756:GABA Antagonists; D018757:GABA Modulators; D011963:Receptors, GABA-A; D010862:Pilocarpine; D003975:Diazepam; D010433:Pentylenetetrazole
keywords: (BDZ); (DZP); (EEG); (HIP); (PFC); (PILO); (PTZ); Anxiety; Diazepam; Electroencephalogram; Elevated plus-maze; Pentylenetetrazole; Pilocarpine; benzodiazepine; diazepam; electroencephalogram; hippocampus; pentylenetetrazole; pilocarpine; prefrontal cortex