Angiotensin II involvement in the development and persistence of amphetamine-induced sensitization: Striatal dopamine...

Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT₁ receptors (AT₁-R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT₁-R role in the development and maintenance of AMPH-induced sensitization. Also, the AT₁-R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5 days and tested 21 days after withdrawal. An AT₁-R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT₁-R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c-Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1 day after AT₁-R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT₁-R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT₁-R blockade altered the performance of social interaction. Our results highlight the AT₁-R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT₁-R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self-perpetuation. Therefore, AT₁-R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia.