Prelimbic prefrontal cortex neuroinflammation and working memory deficits involve AT1-R activation in an amphetamine-sensitized animal model of schizophrenia

BASMADJIAN M; ARMONELLI S; OCCHIEPPO VB; MARCHESE NA; BAIARDI G; BREGONZIO C

Berlin

Congreso; 11th FENS Forum of Neuroscience; 2018

Federation of European Neuroscience Societes FENS

Dopamine misbalance, including limbic hyperactivity and cortical hypoactivity is a hallmark of amphetamine exposure,producing behavioral sensitization and cognitive alterations and resembling some features of schizophrenia. These long-lasting neuroadaptations are concomitant with neuroinflammation. Angiotensin II, through AT1 receptors (AT1-R), modulates dopamine neurotransmission playing a key role in cognitive processes. Furthermore, AT1-R are strongly involved in inflammatory responses.Methods:Our aim was focus on AT1-R involvement in the development of behavioral and neuroinflammatory alterations in an amphetamine-sensitized animal model of schizophrenia. For this purpose male Wistar rats (250-300g) were daily administered with AT1-R blocker Candesartan (CV 3mg/kg p.o.) for 10 days and amphetamine (2.5 mg/kg i.p.) from day 6 to 10. On day 21 of amphetamine withdrawal, working and short memory performance was evaluated byY-maze and novel object recognition tests, respectively. The brains were prepared 24h later for GFAP and CD11b immunohistochemistry to evaluate neuroinflammation. The results were analyzed using 2-way ANOVA followed by Bonferroni test.Results:Amphetamine-sensitization was prevented by AT1-R blockade. Moreover, amphetamine induced working memory deficit without short memory alterations. Increased astroglial and microglial reactivity was observed only at prelimbic prefrontal cortex, a brain area highly related to working memory. These neuroinflammatory and cognitive alterations were prevented by AT1-R blockade. Conclusion:In the present amphetamine-sensitized animal model, the neuroadaptative and neuroinflammatory responses involve AT1-R activation. Since the available treatments for schizophrenia present low efficacy and high incidence of side-effects, our contribution could be consider in the field of new pharmacological possibilities.