Brain Angiotensin II type 1 (AT1) receptors are involved in acute and long-lasting amphetamine-induced neurocognitive alterations

MARCHESE NA; ARTUR DE LA VILLARMOIS E; BASMADJIAN M; PEREZ MF; BAIARDI, G; BREGONZIO C

Rio de Janeiro

Workshop; 9º IBRO World Congress on Neuroscience; 2015

IBRO

Angiotensin II (Ang II), by activation of its Brain AngiotensinReceptors type 1 (AT1), plays anactive role as neuromodulator in the stress response and in dopamine (DA) release as well asin DA associated behaviors, including drug consumption, behavioral sensitization and learningand memory, among others. Likewise, psychostimulants drugs, such as amphetamine (Amph),are recognized for their mimetic activity over cathecholaminergic neurotransmission. Amphexposure can elicit different behavioral and cellular responses depending on the experimentaladministration protocol used. Moreover, altered responses can be observed after longwithdrawal periods, when animals are re‐exposed to the psychostimulant.Objectives: To assess the acute and long‐term Amph‐induced modifications in learning andmemory and in cellular related events; and to evaluate the involvement of AT1 receptors inthese events.Methods: male Wistar rats (250‐300g) were used. To evaluate Amph acute effects, a singledose of Amph (0.5 or 2.5 mg/kg i.p.) was administered after post‐training in the inhibitoryavoidance test. To study the involvement of AT1 receptors in Amph acute effects, the AT1receptor blocker Losartan was administered i.c.v. immediately before a single dose of Amph(0.5mg/kg i.p.). To evaluate the long‐term Amph effects, the animals received a daily Amph(2.5 mg/kg, i.p.) injection for 5 days. The neuroadaptive changes were evidenced after 1 weekof withdrawal with an Amph challenge dose (0.5 mg/kg i.p.). To study the participation of AT1in long‐term Amph effects, the AT1 receptor blocker Candesartan (3mg/kg p.o.) wasadministered for 5 days prior to repeated Amph administration. In this case the inhibitoryavoidance response, neuronal activation pattern and hippocampal synaptic transmission wereevaluated. The impairing effect in the passive avoidance response induced by post‐trainingacute Amph administration was partially reverted by Losartan. The long‐term changes inducedby repeated Amph administration such as resistance to acute Amph interference in theinhibitory avoidance response, neurochemical altered response and increased hippocampalsynaptic transmission were prevented by blockade of AT1 receptors previous to Amphadministration.Conclusion: The AT1 receptors are involved in acute neurocognitive alterations as well as in theneuroadaptive changes induced by Amph associated with neurocognitive responses.