title: Pharmacological modulation of mood, behaviour and cognition
Creators: name: Yin, X
Publisher: name: University of Tasmania
Year: 2019

description: Chronic stress can lead to major depressive disorder (MDD) as well as depression-related comorbidities, such as anxiety and memory loss. Frequent treatment failure of the currently used conventional monoamine-based antidepressants indicate the urgent need to develop novel antidepressants that act by a different mechanism. There is good evidence that pain and depression create a vicious cycle. While pain worsens the symptoms of depression, the resulting depression worsens the feelings of pain. Opioids are clinically used as the most important treatment against severe pain. With the identification of the three classic opioid receptors, (mu-opioid receptor (MOP), delta-opioid receptor (DOP) and kappa-opioids receptor (KOP)), an increasing number of novel ligands have been described that not only show opioid receptor-dependent analgesic but also antidepressant-like effects in pre-clinical models. These antidepressant-like effects of opioid receptor ligands are thought to be a consequence of their ability to modulate cellular stress responses as well as their effects on learning, memory and behaviour. On the other hand, it was proposed that oxidative stress plays a relevant role in the pathogenic mechanisms underlying MDD. Reactive oxygen and nitrogen species modulate levels and activity of multiple neurotransmitters that are involved in the neurobiology of depression. Clinical studies in MDD patients reported reduced levels of endogenous antioxidants, impaired mitochondrial function and a disturbed redox equilibrium. However, several studies reported opioid-induced mitochondrial dysfunction by a mechanism that involves the generation of reactive oxygen species (ROS). In line with this, morphine has also been described to increase oxidative stress rather than to reduce it. Thus, the connection between opioids, depression and oxidative stress appears significantly more complex. At present, antidepressant-like effects of both clinically used and experimental MOP or DOP agonists have been described in pre-clinical and clinical studies. We therefore hypothesized that opioids that simultaneously activate the MOP and DOP receptor, such as the UTAS-derived experimental bi-functional opioid 1003 (unpublished data), could also produce antidepressant-like effects. To test this hypothesis, we first assessed the behavioural effects of morphine (MOP agonist) in models of depression (learned helplessness model, LH), anxiety (light and dark model, LD), locomotion (open field model, OF) and pain (hot plate (HP) and tail flick (TF) tests). Parallel to previous studies, morphine showed promising antidepressant-like effects that were similar to the clinically used tricyclic antidepressant imipramine. However, morphine also enhanced avoidance learning and produced significantly higher physical activity after repeated administrations. This raises the possibility that morphine leads to behavioural changes that only mimic an antidepressant-like effect in this specific model. Therefore, the interactions between locomotion, learning and the antidepressant-like effects of drugs in the LH model require careful analysis and interpretation of multiple parameters. In this model, compared to morphine, the same dose of our novel bi-functional opioid receptor ligands (1001 and 1003) failed to produce any behavioural effects. Nevertheless, 1001 and 1003 somewhat reduced the oxidative damage in the dentate gyrus (DG) of both anterior and posterior hippocampus (HPC), an area of the brain that is highly involved in the regulation of mood, learning and memory. Therefore, to understand the relevance of oxidative stress in MDD, a clinically used and much more potent antioxidant was assessed in our animal model. In rats that were exposed to repeated inescapable foot shocks in the LH model, antioxidant treatment significantly reduced oxidative cell damage in the DG of the anterior HPC and at the same time fully reversed the cognitive impairment associated with this model. However, this antioxidant treatment did not have any effects on the depressive-like symptoms in this model, nor did it modulate pain perception or anxiety levels. Overall, these results highlight that opioids could be developed as antidepressants but also emphasize the need to investigate their off target effects in much more detail to judge the relevance of pre-clinical models before the start of clinical trials. The results of this study strongly suggest that oxidative stress in the HPC is a consequence of depression rather than a causative pathology. On the other hand, our results indicate that depression-induced cognitive deficiencies are a consequence of oxidative stress as antioxidant treatment was able to normalize this pathology. In addition to the evaluation of two novel bifunctional opioids for their potential use as anti-depressants, this project has provided new data towards the close relationship between pain, depression, cognition, and oxidative stress.