New Roles for the Neuropeptide Angiotensin II: Stress and Drug Abuse

Abstract

Angiotensin II (Ang II) is known as a peripheral hormone involved in the control of blood pressure and fluid homeostasis. The study and characterization of Ang II and its receptors in the brain has opened a new vision of its physiological role and also offers a variety of research fields. Ang II is involved in the response to stress, which stimulates the brain and the peripheral (hormonal) Ang II systems. Activation of brain angiotensin II AT1 receptors is required for stress-induced hormone secretion, including CRH, ACTH, corticoids and vasopressin, and for stimulation of central sympathetic activity. The blockade of peripheral but also brain AT1 receptors prevents the hormonal and sympathoadrenal response to isolation stress and prevents the formation of stress-induced gastric ulcers, through ischemia and inflammation. The AT1 receptor antagonists prevent inflammation (neutrophil infiltration and increase in ICAM-1 and TNF-α) in the gastric mucosa and partially inhibit sympathoadrenal stimulation, without affecting the protective effect of glucocorticoid release during stress. The coordination of behavioral and autonomic responses to stress is partially under the control of extrahypothalamic, including cortical, CRF neurons expressing CRF1 receptors. AT1 receptor activation is thus also involved in the cortical decrease of CRF1 binding induced by stress. A large number of studies have been conducted on the effect of drugs of abuse on hypothalamic and extrahypothalamic CRF systems in the brain and on the role of CRF in mediating the behavioral and physiological effects of drugs of abuse. It is also known that dopaminergic neurotransmission in the nucleus accumbens and caudate-putamen plays a critical role in the locomotor and stereotypic effects of psychostimulant drugs. Ang II receptors are found on the soma and terminals of dopaminergic neurons and it has been shown that Ang II, acting through its AT1 receptors, facilitates the release of dopamine in the rat striatum in vitro and in vivo. Repeated exposure to amphetamine, as with most addictive drugs, results in progressive and lasting enhancement of their psychomotor and positive reinforcing effects. Neuroadaptive changes in mesotelencephalic dopaminergic projections play a key role in the induction and expression of amphetamine sensitization. Recently, we found evidence showing that brain AT1 receptor activation is involved in the neuroadaptive changes induced by amphetamine. The results of studies on the physiological role of brain Ang II offer new pharmacological tools for the treatment of some stress-related disorders such as drug abuse.