Schizophrenia-like neuroadaptive changes induced by ketamine involve Angiotensin II

OCCHIEPPO VICTORIA B; BASMADJIAN, OSVALDO MARTIN; BREGONZIO CLAUDIA

Mar del Plata

Congreso; REUNION CONJUNTA SAIC. SAI. SAFIS; 2022

Schizophrenia is a chronic disease affecting 1% worldwide population, of which30% are refractory to the available treatments: thus, searching for newpharmacological targets is imperative. Ketamine administration is a validated preclinicalmodel that recreates the behavioral and neurochemical features of the pathology,including the parvalbumin-expressing interneurons dysfunction. Angiotensin II, throughAT 1 receptors (AT 1 -R), modulates the dopaminergic and GABAergic neurotransmission.We evaluated the AT 1 -R role in the long-term neuronal activation and behavioralalterations induced by repeated ketamine administration. Adult male Wistar ratsreceived AT 1 -R antagonist candesartan/vehicle (days 1-10) and ketamine/saline (days6-10). After 14 days of drug-free, neuronal activation and behavioral analysis wereperformed. Locomotor activity, social interaction and novel object recognition testswere assessed at basal conditions or after ketamine challenge. Immunostaining for c-Fos, GAD67 and parvalbumin were assessed after ketamine challenge in cingulate,insular, piriform, perirhinal, and entorhinal cortices, striatum, and hippocampus. Wefound that ketamine-induced long-lasting schizophrenia-like behavioral alterations, andregional-dependent neuronal activation changes, involving the GABAergicneurotransmission system and the parvalbumin-expressing interneurons, were AT 1 -R-dependent. Our results add new evidence to the wide spectrum of action of ketamineand strengthen the AT 1 -R involvement in endurable alterations induced bypsychostimulants administration, as well as their role in the development of psychiatricpathologies.