The classical effects regarded for the Renin–Angiotensin System (RAS) were related to its endocrine role in electrolytic homeostasis and control of blood pressure. Angiotensin II (AngII) control implies a rapid increase in vascular resistance, and long-term effects acting on vasculature, heart, kidney, sympathetic output, and the central nervous system (CNS), by promoting vasopressin and aldosterone release and regulating thirst and water intake [60–63].

Among the receptors that have been identified to be activated by AngII, the AT₁ receptor (AT₁-R) is the one mediating most of the peptide’s physiological and pathological functions. This surface receptor belongs to the G-protein-coupled receptor family, and has a conformation of seven transmembrane domains [63–65]. AT₁-R activates multiple intracellular signaling pathways; mainly, it promotes IP3 formation and Ca²⁺ release from intracellular compartments, adenylate cyclase inhibition, modulation of voltage-dependent Ca²⁺ channels and activation of PLC. Secondary pathways involving MAPK, ERK or JNK activation have also been described for its participation in trophy events. Independent G-protein activation pathways involve later desensitization and even internalization by endocytosis mediated by β-arrestins [63].

Over the years, it has come to be appreciated that a local autocrine or paracrine RAS exist in a number of tissues, which subsequently implies new roles for this system [66]. Moreover, tissues and systemic activities show significant differences. Even though circulating AngII levels may not be intensively high, AT₁-R expression in different organs can be abundant enough to promote intracellular signaling. Furthermore, locally produced AngII concentration may be higher than plasma levels, and elicit a response in tissues with relative low AT₁-R expression.

Numerous pieces of evidence support that AngII acts as a neuromodulator in different brain pathways. The activation of the AT₁-R subtype by AngII elicits neuronal depolarization through facilitatory activity over different channels. The AT₁-R facilitator effects would be possible through the inhibition of potassium channel or opening of a non-selective sodium–calcium channel. The resulting depolarization triggered by the neuropeptide over different signaling pathways would reflect a fine regulation in overall cellular activation [67–69].

Across the CNS, AngII plays an important role in central dopaminergic neurotransmission modulation, and there is evidence that a cross-regulation exists between these two systems. It has been demonstrated that AT₁-R modifies tyrosine–hydroxylase activity and hence alters monoamine production. DA release is elevated in a concentration-dependent manner when AngII is applied either to striatal slices or locally in the rat striatum. Furthermore, microdialisys of AngII in the same brain structure increases the level of DA and its metabolites (DOPAC and HVA). Similar effects have been obtained for DA concentration in NAc after AngII administration [70–72]. AT₁-R blockers did not only reverse these changes in the neurotransmitter levels but it also decreased its concentration without AngII stimulus, suggesting a regulatory role on basal DA release [72, 73]. All together, these results point towards the possible action of AngII pre-synaptically modulating the synthesis and release of DA through activation of AT₁-R, as they are located in the soma and terminals of dopaminergic neurons [74]. Moreover, recently it has been shown that an alteration in the dopaminergic system, such as decreased levels of DA, can induce an increase in local RAS components, as an attempt to compensate for the deficit in dopaminergic activity [74]. Therefore, AT₁-R expression is closely linked to DA levels, given that decreased levels of DA promotes an increase in AT₁-R expression, which can be reversed when the DA activity is reestablished. Similarly, the knockout mice for D₁ and D₂ receptors, have increased levels of AT₁-R, while transgenic mice overexpressing D₂ receptors show reduced levels [75, 76]. Moreover, aged rats show decreased levels of DA receptors and increased expression of AT₁-R simultaneously, when compared to young animals [77]. In the same way, acute or chronic manipulation of brain RAS with AT₁-R antagonists decreased D₂ and increased D₁ receptor expression without affecting striatal DA release or motor behavior [78]. Recent evidence highlights functional and physical interactions between AT₁-R and β- adrenergic, D₁ and D₂ receptors [79–81]. Blockade of the D₂/AT₁-R heterodimer by an AT₁-R antagonist, leads to enhanced dopaminergic transmission and has direct impact on the basal ganglia system involved in motor control. Thus, AngII levels would control striatal dopaminergic neurotransmission, and would serve to immediately regulate DA function [79]. Moreover, AngII has a modulatory neurochemical effect over DA-mediated behavior, such as the control of movement and reward processing, which might be susceptible to be controlled by pharmacological manipulation of the RAS [70, 72].

The functional relation between Amph and AngII activity has been studied over the last decade by this working group. Overall, it has been shown that Amph-induced long-term changes at the reward circuit involve AT₁-R activation with regard to responses of the reward circuit. We have observed that AT₁-R are involved in the behavioral and neurochemical adaptive responses induced by Amph exposure [5, 97]. Moreover, Amph exposure has been shown to induce long-term changes in AT₁-R density and in angiotensinogen mRNA in CPu, a rich DA area strongly related to drugs of abuse responses [98].

Recently, we have shown that AT₁-R play a functional role in Amph-induced alterations over neurocognitive processes. In our experimental model, acute Amph impaired memory retention in male rats in the one-trial inhibitory avoidance test when administered immediately post-training. This effect involved central AT₁-R activation, since central AT₁-R antagonist administration before the psychostimulant partially prevented drug-induced memory impairment [32].

Moreover, a previous experience of repeated Amph followed by 7 days of withdrawal modified the animals’ performance in the inhibitory avoidance test, observed as a resistance to the acute Amph interference effect in the behavioral response. Moreover, these animals showed an altered neuronal activation pattern in BLA after the test session. Long-term Amph-induced alterations were shown in hippocampus synaptic transmission, measured as a lower threshold necessary to generate LTP. It is noteworthy that AT₁-R blockade prevented the behavioral, neurochemical, and electrophysiological alterations observed in the repeated Amph group, pointing out a functional role for AT₁-R in the psychostimulant-induced neuroadaptations [32].

Brain RAS is a neuromodulatory system of superior brain activities and by its AT₁-R can actively modulate Amph-induced alterations. Because AT₁-R blockers are currently and safely used in clinics for different pathologies, our results suggest that they would be prominent candidates for pharmacological treatment in pathologies related to altered DA and cognitive alterations.