Brain renin-angiotensin system (RAS) is involved in long term amphetamine-induced neurocognitive alterations

MARCHESE, N.A.; CASARSA, B.; PAZ, M. C.; BAIARDI, G.; BREGONZIO, C.

Concepción

Workshop; First Joint Meeting on Alcohol and other Drugs of Abuse: from molecules to human disorders; 2013

LASBRA-LARNEDA

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. The brain 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. Our aim was to evaluate the involvement of brain RAS, through its AT1-R, on long term amphetamine-induced modifications in behavioral and learning processes, in animals exposed to an acute stressor. 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 and the holeboard test after cold exposure. The animals were sacrificed and the brains were processed for c-fos expression as a marker of neuronal activation. The results indicated that AMPH administration prevented the expression of the deleterious effect induced by cold exposure in long term memory, the AT-R blockade avoided this neuroadaptation. In accordance with these results are the neuronal activation pattern in hippocampus (CA1, CA3) and basolateral amygdala. Working memory results showed that repeated AMPH exposure and cold stress impaired the performance in the test. In both cases, the AT1 receptor blockade prevented them. No additive effects were observed when both situations were combined. We conclude that AT1-R play an active role in AMPH-induced alterations in learning and memory processes modifying the responses to sympathetic stimulation by stress.