Aquaporin-4 deletion attenuates opioid-induced addictive behaviours associated with dopamine levels in nucleus accumbens

There is a lack of safe and effective non-opioid medications for the treatment of opioid addiction. Aquaporin-4 (AQP4), a water channel protein expressed in astrocytes, regulates the progression of neurological diseases. Our previous work demonstrated that AQP4 deficiency in mice attenuated morphine-induced physiological dependence. However, the role of AQP4 in the neurobiology of behaviours related to opioid addiction in mice remains unclear. Here, we report that Aqp4-knockout mice exhibited attenuated heroin consumption and heroin-seeking behaviours. Furthermore, Aqp4-knockout mice displayed diminished hyperactivity induced by morphine and heroin and subsequently showed dramatically inhibited morphine-induced behavioural sensitization. This attenuated hyperlocomotion to opioids was accompanied by a decreased dopamine response to the opioid-induced increase in the levels of extracellular dopamine in the NAc. In addition, Aqp4-knockout mice displayed upregulation of dopamine transporters in the striatum, suggesting a probable neurobiological mechanism for uptake of the extracellular dopamine. The present findings suggest that deficiency of AQP4 decreases opiate-induced drug seeking and taking behaviours, and AQP4 may be involved in the treatment of addiction. Therefore, the development of a pharmacological antagonist to AQP4 may be valuable to investigate as opioid addiction therapy.