The AT1 Angiotensin II receptor blockade attenuates the development of amphetamine-induced behavioral sensitization in a two-injection protocol.

PAZ, MC; ASSIS, A; CABRERA, R; CANCELA, LM; BREGONZIO, C.

SYNAPSE

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2010

0887-4476

It has been shown that a single exposure to amphetamine is sufficient to induce long-term behavioral, neurochemical and neuroendocrine sensitization in rats. Dopaminergic neurotransmission in the nucleus accumbens and the caudate-putamen plays a critical role in the addictive properties of drugs of abuse. Angiotensin (Ang) II receptors are found on the soma and terminals of mesolimbic dopaminergic neurons and it has been shown that Ang II acting through its AT1 receptors facilitates dopamine release. The hypothesis was tested that Ang II AT1 receptors are involved in the neuroadaptative changes induced by a single exposure to amphetamine and that such changes are related to the development of behavioral and neurochemical sensitization. For this purpose, the study examined the expression of amphetamine-enhanced (0.5 mg/kg i.p.) locomotor activity in animals pretreated with candesartan, an AT1 blocker, (3 mg/kg p.o x 5 days), three weeks after an amphetamine injection (5 mg/kg i.p.). Dopaminergic hyper-reactivity was tested by measuring the 3H-DA release in vitro from caudate-putamen and nucleus accumbens slices, induced by K+ stimulus. It was confirmed the behavioral sensitization in the two-injection protocol and candesartan pretreatment attenuate this response. It was also found that AT1 blockade pretreatment did not affect the locomotor response to dopamine agonists. In respect to the neurochemical sensitization tested using ex vivo 3H-DA release experiments it was found that AT1 receptor pretreatment blunted the enhanced response induced by K+ stimulus. The results support the idea that the development of neuroadaptive changes induced by amphetamine involves brain AT1 Ang II receptor activation.