Angiotensin II involvement in the development and persistence of amphetamine‐induced sensitization: Striatal dopamine reuptake implications

BASMADJIAN, OSVALDO M.; OCCHIEPPO, VICTORIA B.; MONTEMERLO, ANTONELLA E.; RIVAS, GUSTAVO A.; RUBIANES, MARÍA D.; BAIARDI, GUSTAVO; BREGONZIO, CLAUDIA

EUROPEAN JOURNAL OF NEUROSCIENCE

WILEY-BLACKWELL PUBLISHING, INC

Año: 2024

0953-816X

Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitizationobserved in rodents as hyperlocomotion and increased dopaminerelease in response to a subsequent dose. Brain Angiotensin II modulatesdopaminergic neurotransmission through its AT1 receptors (AT1-R), positivelyregulating striatal dopamine synthesis and release. This work aims to evaluatethe 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 for5 days and tested 21 days after withdrawal. An AT1-R antagonist, candesartan,was administered before or after AMPH exposure to evaluate the participationof 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-Rblockade withdrawal treatment, with or without the addition of AMPHin 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-Rblockade increased the dopamine reuptake kinetics. Neither the AMPHadministration 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 blockademight attenuate the neuroadaptive changes that lead to AMPH sensitizationand its self-perpetuation. Therefore, AT1-R is a prominent candidate as atarget for pharmacological treatment of pathologies related to dopamineimbalance, including drug addiction and schizophrenia.