Behavioral ?ffects following repeated administration of newly synthesized ligands selective for distinct subtypes of GABAA receptor benzodiazepine binding site: comparison with standard psychopharmacologic drugs

Genetic studies have fostered the development of new ligands acting through benzodiazepine binding site of GABAA receptors: those selectively acting through alpha2/3 subunit-containing receptors as positive allosteric modulators (PAMs), with potential use in anxiety disorders and cognitive symptoms of schizophrenia, and those selective for alpha5 receptors as negative allosteric modulators (NAMs), targeted for different cognitive impairments. On the grounds of our previous results, this project will assess the behavioral profiles of three selective PAMs (SH-053-2’N, ZJW-II-40 and YT-III-38) and three selective NAMs (PWZ-029, SR-II-97 and YT-II-76) following acute and repeated administration (10 or 28 days) in rats. The two types of selective modulators will be tested in two separate blocks of experiments, in comparison with standard psychopharmacologic drugs risperidone and escitalopram, as well as diazepam or DMCM as positive controls. The ligands will be applied orally as suspensions of purposefully prepared and in vitro/in vivo characterized microparticles. The behavioral tests will include spontaneous locomotor test, elevated plus maze, rotarod test, grip strength, novel object recognition test, water maze, forced swim test and three paradigms of acoustic startle response. The results obtained in healthy rats would elucidate the differences in behavioral profiles depending on receptor selectivity of tested ligands and be a good basis for further disease-centered studies.