Amphetamine-induced sensitization as an animal model of schizophrenia: Behavioral characterization and role of angiotensin II AT1 receptors

BASMADJIAN, OSVALDO MARTÍN; OCCHIEPPO, VICTORIA BELÉN; MARCHESE, NATALIA ANDREA; BAIARDI, GUSTAVO; BREGONZIO, CLAUDIA

Mar del Plata

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2016

SAIC SAFE SAI

Amphetamine (amph) exposure induces adaptive responses observed as increased dopaminergic reactivity in mesolimbic pathway concomitant with decreased dopaminergic reactivity in the mesocortical one. Similar alterations have been described in the pathology of schizophrenia. For this reason, amph-induced sensitization is a validated animal model of schizophrenia; resembling described positive signs and cognitive deficits. Brain Angiotensin II, through AT1 receptors (AT1-R), modulates dopaminergic neurotransmission in limbic areas. Previously, we found that behavioral neuroadaptative responses to amph involved AT1-R activation. The aim for the present work was to study AT1-R involvement in behavioral responses in an animal model of schizophrenia using amph-induced sensitization. Male Wistar rats (250-320g), at standard laboratory conditions, were administered with AT1-R antagonist Candesartan/vehicle (3 mg/kg p.o., day 1-10) and amph/saline (2.5 mg/kg i.p., day 6-10). On day 31 we evaluated the locomotor sensitized response to saline/amph challenge (0.5 mg/kg i.p.) and the working memory (Y-maze test). Data were analyzed with two-way ANOVA followed by Bonferroni test and t-test. We corroborated that the amph protocol used induces behavioral sensitization to amph challenge and cognitive deficit, observed as a decreased spontaneous alternations in the Y-maze. Moreover, it was found an increased susceptibility to stress, expressed as augmented locomotor activity, 30 minutes after saline injection. So, we conclude that this protocol was effective to elicit some of the described signs of schizophrenia. Interestingly, the AT1-R antagonist blunted the neuroadaptative responses to the psychostimulant. Since the available therapeutic treatments have low efficacy and high incidence of side-effects, new pharmacological approaches become necessary. However, further studies are needed to postulate the AT1-R antagonists as an alternative pharmacological tool.