The Renin-Angiotensin System (RAS) was first described as a peripheral hormonal system. Over the years several local RAS have been described in different organs. In the brain, the RAS is a well-documented neuromodulator of multiple brain circuits. AT1 receptor (AT1-R) activation is involved in learning and memory processes, in the stress response and in catecholamine neurotransmission.
Exposure to amphetamine (AMPH) induces neuroadaptations that modify behavioral responses to future pharmacological or environmental challenges. Alterations in working, recognition and long term memory have been reported in AMPH users.
Our aim was to evaluate the involvement of brain RAS, through its AT1-R, on long term amphetamine-induced modifications in learning processes.
Wistar male rats (250-300g) treated with AT1-R blocker (candesartan 3 mg/kg p.o., days 1-5), followed by AMPH (2,5 mg/kg, ip, days 6-10), were evaluated 1 week later on the passive avoidance test after receiving a pharmacological (AMPH 0.5 mg/kg) or physiological (cold stress: 4ºC for 4 h) challenge. Following the test session, the animals were sacrificed and the brains were processed for c-fos immunoreactivity (fos-IR) as a marker of neuronal activation. The results were analyzed with Kruskal Wallis test (step trough latencies) and ANOVA (fos- IR).
The results indicated that history of repeated AMPH administration does not allow the expression of the deleterious effect in long term memory induced by acute exposure to AMPH or cold stress. In both situations the AT1-R blockade prevented this modified response. C-fos expression in the hippocampus, indicates a diminished neuronal activation in animals receiving an AMPH or cold stress challenge in all studied groups.
In agreement with our previous findings, we conclude that AT1-R play an active role in AMPH-induced neuroadaptations altering learning and memory processes. It should be taken in consideration the potential use of AT1 receptor antagonist in the therapy of drug of abuse disorders.
