Research ReportGABA-A receptor modulators alter emotionality and hippocampal theta rhythm in an animal model of long-lasting anxiety

- A non-convulsant dose of PILO triggers long-lasting anxiogenic-like behaviors.
- PILO enhances hippocampal theta activity in rats 24 h or 1 month after treatment.
- PILO-induced responses are sensitive to manipulation of the GABA-A receptor.
- The present work supports a new research model of long-lasting anxiety.

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 (24 h to 3 months). To investigate the underlying mechanisms, rats treated with PILO (150 mg/kg) were injected 24 h or 1 month later with an anxiolytic (diazepam, 1 mg/kg, DZP) or anxiogenic (pentylenetetrazole, 15 mg/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 24 h 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 24 h 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.