Sodium depletion, which activates RAS, develops cross-sensitization effects leading to enhanced locomotor activity responses to amphetamine [97]. These experiments indicate that treatments implying RAS activation show reciprocal behavioral cross-sensitization with psychostimulants. In relation to these findings, our group, using a protocol of repeated amphetamine, found long-lasting changes affecting brain response to angiotensin II [98]. These alterations were revealed by exogenously intracerebrally injected angiotensin II in conscious rats, known to produce a marked increase in water and sodium intake, as well as an increased natriuresis [98]. All these effects have been previously and exhaustively described [99–103]; however, the results obtained in our study showed that previous exposure to repeated amphetamine administration modified the described effects of angiotensin II i.c.v. on these parameters in a long-term manner (1 week after amphetamine withdrawal) [104]. In this respect, it was found that repeated amphetamine exposure markedly decreased the sodium intake induced by angiotensin II; meanwhile, water intake was unaffected. Sodium intake behavior is likely to reflect the differential regulation of intracellular signaling pathways. In this regard, it has been hypothesized that differential AT₁ receptors signaling pathways play separable roles in water and saline intake stimulated by angiotensin II [105, 106]. There are results that support this hypothesis, demonstrating that G protein-dependent pathways appear to be more important for water intake stimulated by angiotensin II, whereas G protein-independent pathways may be more relevant for angiotensin II-stimulated sodium intake [107]. In accordance with this last fact are the results showing that repeated i.c.v. angiotensin II administration reduced the dipsogenic effect without affecting sodium intake [108]. Therefore, a possible explanation for amphetamine exposure effects is the alteration of intracellular signaling pathway involved in the effects of angiotensin II on sodium intake. This altered response obtained in amphetamine-exposed animals may involve the desensitization of AT₁ receptors through internalization of these receptors [109]. This last is supported by the evidence showing that angiotensin II i.c.v. induces internalization of AT₁ receptors [110]. Accordingly, a decrease in the response to angiotensin II after a persistent or repetitive stimulation of AT₁ receptors has been described [111]. Moreover, it has been shown that the early inducible genes, c-fos, c-jun, and delta-fos are involved in the control of transcription factors expression that ultimately mediate the desensitization to the angiotensin II signal [112]. In our laboratory, we found that angiotensin II i.c.v. induced a threefold increase in NAc and CPu neuronal activation; this effect was blunted by repeated amphetamine exposure. This decreased response could demonstrate an AT₁ receptor desensitization induced by repeated psychostimulant administration. In this regard, AT₁ receptor desensitization-reduced Fos expression has been described as a consequence of repetitive angiotensin II i.c.v. administration in different brain areas that co-expressed AT₁ receptors [112]. Interestingly, these results are in agreement with those obtained in regard to the decreased response in sodium intake to angiotensin II i.c.v.

It is known that exogenous i.c.v. angiotensin II administration stimulates oxytocin release from the pituitary gland [113, 114]. It has been found that the increase of sodium intake through sodium deprivation or adrenalectomy decreases basal oxytocin levels; meanwhile, treatments that stimulate oxytocin secretion (e.g., hypertonic saline, lithium chloride, and copper sulfate) inhibit sodium intake in sodium-deprived rats [115–117]. Moreover, blockade of central oxytocin receptors before i.c.v. angiotensin II administration resulted in a potentiation of angiotensin II-induced sodium intake, although in the absence of exogenously administered angiotensin II, blockade of oxytocin receptors does not interfere with the dipsogenic properties of angiotensin II, nor does it stimulate sodium intake [115]. In rats, the oxytocin receptor antagonist administration-induced sodium intake is blunted by AT₁ receptor antagonist administration [118]. This evidence supports the idea of an inhibitory oxytocinergic tone involved in the activation or disinhibition of AT₁ receptors [118].

The results obtained in our study using repeated amphetamine administration reveal a long-lasting effect of amphetamine exposure.

Moreover, it is possible to suggest that the decreased response in sodium intake induced by angiotensin II i.c.v. in amphetamine-exposed animals could be attributed to an increased oxytocin response to angiotensin II as a consequence of AT₁ receptors altered functionality. This explanation is supported by our results, showing that amphetamine exposure increased the number of Fos-oxytocin positive neurons in response to angiotensin II. The mechanisms by which angiotensin II i.c.v. induces natriuretic effects could involve brain oxytocin release [119]. It has been shown that angiotensin II i.c.v. activates oxytocin neurons in paraventricular and supraoptic nucleus [113–115]. In our study, the repeated amphetamine administration potentiated the activation of oxytocin neurons induced by angiotensin II i.c.v. in different oxytocinergic subnuclei of paraventricular and supraoptic nucleus, possibly showing an increased oxytocin response to angiotensin II because of the reduced AT₁ receptor functionality mentioned above. Therefore, the repeated amphetamine exposure could reduce AT₁ receptor functionality (desensitization-like) shown as a potentiated oxytocinergic response to i.c.v. angiotensin II that elicits a decrease in sodium intake, an increase in natriuresis, and decreases in plasma renin activity. These results are also supported by the increased number of Fos-oxytocin positive neurons in paraventricular and supraoptic nucleus in response to i.c.v. angiotensin II found in the amphetamine-exposed animals [104].

In conclusion, the results presented here support the view that long-lasting changes in brain RAS could be considered among the psychostimulant-induced neuroadaptations.