Rationale: Angiotensin II (Ang II), by activation of its Brain AngiotensinReceptors type 1 (AT1), plays an active role as neuromodulator inthe stress response and in dopamine (DA) release as well as in DA associatedbehaviors, including drug consumption, behavioral sensitization and learningand memory, among others. Likewise, psychostimulants drugs, such as amphetamine(Amph), are recognized for their mimetic activity over cathecholaminergicneurotransmission. Amph exposure can elicit different behavioral and cellularresponses depending on the experimental administration protocol used. Moreover,altered responses can be observed after long withdrawal periods, when animalsare re-exposed to the psychostimulant.
Objectives: To assess the acute and long-term Amph-inducedmodifications in learning and memory and in cellular related events; and toevaluate the involvement of AT1 receptors in these events.
Methods: male Wistar rats (250-300g) were used. To evaluateAmph acute effects, a single dose of Amph (0.5 or 2.5 mg/kg i.p.) wasadministered after post-training in the inhibitory avoidance test. To study theinvolvement of AT1 receptors in Amph acute effects, the AT1receptor blocker Losartan was administered i.c.v.immediately before a singledose of Amph (0.5mg/kg i.p.). To evaluate the long?term Amph effects, theanimals received a daily Amph (2.5 mg/kg, i.p.) injection for 5 days. Theneuroadaptive changes were evidenced after 1 week of withdrawal with an Amphchallenge dose (0.5 mg/kg i.p.). To study the participation of AT1receptors in long?term Amph effects, the AT1 receptor blockerCandesartan (3mg/kg p.o.) was administered for 5 days prior to repeated Amphadministration. In this case the inhibitory avoidance response, neuronalactivation pattern and hippocampal synaptic transmission were evaluated.
Results: The impairing effectin the passive avoidance response induced by post-training acute Amphadministration was partially reverted by Losartan. The long-term changesinduced by repeated Amph administration such as resistance to acute Amph interferencein the inhibitory avoidance response, neurochemical altered response and increasedhippocampal synaptic transmission were prevented by blockade of AT1 receptorsprevious to Amph administration.
Conclusion: TheAT1 receptors are involved in acute neurocognitive alterations aswell as in the neuroadaptive changes induced by Amph associated withneurocognitive responses.
