Mirtazapine seeking and withdrawal in free‐choice drinking model

Abstract

Drug addiction is one of the major public health concerns around the world. Addiction to prescription medications has been growing due to the psychoactive effects of these medications, availabilities, low price and no legal consequences were practiced against the abusers. One of these prescription medications is mirtazapine (MIRT). MIRT is an antidepressant that is recently reported in different case studies to be abused and could induce withdrawal symptoms. No previous study has investigated its abuse potential in animal model of drug addiction. Here we conducted a free‐choice drinking paradigm to investigate the voluntary drinking of MIRT in two different concentrations. Male bulb/c mice were allowed free access to two bottles of water for five days and their intake and body weight were recorded daily to calculate, based on consumed fluid, the concentrations of MIRT solutions. Mice were then divided into three groups; the first group had free access to two bottles of water. The second group (MIRT‐10) had free access to one bottle of water and one bottle of MIRT in a concentration that might yield daily intake of (10 mg/kg). The third group (MIRT‐20) had free access to one bottle of water and one bottle of MIRT in a concentration that might yield daily intake of (20 mg/kg). Interestingly, animals in MIRT‐20 showed a significant increase in MIRT intake as compared to MIRT‐10 group indicating that MIRT in higher doses can induce drug seeking effects. Following the drinking phase, and to confirm any effects on memory and recognition, animals underwent Novel Object Recognition test (NORT). Animals in MIRT‐20 showed a significant deterioration in the recognition of the novel objects as compared to the control and MIRT‐10 groups. This indicates the destructive nature of abusing MIRT on recognition and memory which is consistent with the effects of different drugs of abuse. All animals were then only exposed to two bottles of water to induce withdrawal symptoms. After five days of abstinence, animals in MIRT‐20 group showed a significant increase in the immobility time in forced swimming test and tail suspension test as compared to the control and MIRT‐10. This indicates that animals in MIRT‐20 might have depressive‐like symptoms as one of the indicators of withdrawal symptoms related to drug addiction. Together, MIRT was able to induce drug seeking behavior, deteriorate recognition, and cause withdrawal symptoms. This might confirm that MIRT has potential for inducing drug dependence and its use should be controlled by legal authorities. Further studies are needed to investigate the neurobiological basis of MIRT‐induced drug seeking behavior.