Translational research of antidepressants with an example of cannabidiol effects

Despite that not all symptoms of depression can be achieved in animals the translational animal models can mimic the aspects of human depressive disorders in terms of disease symptoms as well as their neurobiological mechanisms. Results of testing the antidepressant drug effects in behavioral animal models of depression are presented. In these models, depressive-like behavior is induced by various stress factors in laboratory animals. However, patients suffering from the Therapeutic Resistant Depression (TRD) do not have high-stress markers. Thus, animals with predisposing factors leading to heightened stress responsiveness as a tool for discovering drugs for human TRD treatment are also presented. Antidepressant treatment effects are reported to be achieved through complex infl uences on body responses associated to reward, stress, and infl ammation, the processes reported to be infl uenced by activities of the Endocannabinoid System. Cannabidol (the cannabinoid without abuse potential) is reported as an antidepressant agent. Mini Review


Introduction to translational research on depression
According to the defi nition of the "European Society for Translational Medicine (EUSTM)", translational medical research is defi ned as an interdisciplinary branch of the biomedical fi eld supported by three main pillars: benchside, bedside, community [1].
The translational medical research relies on the principles of transformation of the basic research results into clinical medical practice. The phenotype of human disease is modeled in laboratory animals by identifying candidates for biomarkers enabling testing of pathways and networks, which could then be validated in clinical practice, even for the choice of appropriate treatment. In the case of preclinical studies on depressive disorders, it has to be admitting that despite that not all symptoms of depression can be achieved in animals the animal models used are still essential not only for testing and validating the effects of new drugs with potential antidepressant activity but also for improvement of our knowledge on neurobiology of this psychiatric disorder.
Symptoms of depressive disorders in man (-persistent feelings of sadness, hopelessness, worthlessness, or emptiness;irritability, frustration or restlessness; -loss of interest in activities or hobbies that used to be enjoyable; -diffi culty sleeping, sleep disturbances, or sleeping too much; -fatigue and lack of energy;diffi cult thinking, remembering, concentrating, or making decisions; -appetite or weight changes; -recurrent thoughts of death or suicide; -physical symptoms such as headaches, stomach aches, or back pain) are associated with behavioral changes. Thus for investigating antidepressant drug effects in rodent behavioral tests attention has to be paid to disinhibition of behavior suppressed by some means (often induced by stress) that can be monitored objectively while into account has to be taken specifi c endophenotypic behavioral variations [2]. However, the animal models of depression should correlate as much as possible with all other changes observed in depressed patients: a) maladaptation with increased irritability; b) neurochemical changes: disorders of aminergic neurotransmission; c) neuroendocrine disorders: elevated adrenal steroid levels; d) immune defi cits. Although not all symptoms of human depression can be achieved in animals, the translational animal models of depression used are still useful to fi nd new drugs with potential antidepressant activity and also to improve our knowledge on the neurobiology of this psychiatric disorder [2][3][4][5][6][7].
We have proven that in the rat model of depression our olfactory bulbectomized rats had: 1): reduced levels of endocannabinoids [16]; 2): a) lower basal levels of DA and 5HT and their metabolites; b) increased levels of GABA and glutamate; c) showed higher intravenous self-administration of methamphetamine . CBD was also reported to facilitate neurogenesis what helps to attenuate besides psychotic-like and anxiety-like behaviors also depressive-like behavior [39].
In the cross-sectional Clinical Study on cannabidiol in human users [40] almost 62% of participants reported CBD using as a specifi c therapy for depression, anxiety, pain, and sleep disorders. A promising therapeutic profi le for cannabidiol as an antidepressant drug brought reports of its infl uence on cellular and molecular changes in brain regions related to the neurobiology of depression: a) increases in levels of BDNF (="peripheral biomarkers" of the Therapeutic Resistant Depression - [41,42]; b) increased synaptogenesis in the medial prefrontal cortex with increases of neurogenesis in the hippocampus [24].

Animal models and potential treatment of Therapeutic Resistant Depression (TRD)
Not all signs and symptoms of depression in man respond to the antidepressant treatments. About 60% of patients with Major Depressive Disorder (MDD) do not respond suffi ciently to the initial antidepressant treatment. Such condition is described in clinical psychiatry as the Treatment-Resistant Depression (TRD).
The diagnosis, epidemiology, and underlying biological mechanisms, as well as new treatment modalities for TRD, were for instance the topics of the "International Thematic Meeting of the College of Neuropsychopharmacology (CINP)" held in Prague, the Czech Republic in 2017. The main topics discussed (understanding the mechanisms underlying the pathophysiology of human TRD and also fi nding translational animal models that could mimic the whole pathological complexity of TRD) might be a key to identifying new therapeutic approaches [46,47].

Summary
The presented behavioral animal models of human depression prove their importance in searching for effective antidepressants. For fully successful translational research of the pathophysiology and treatment of human depressions (including TRD), it will be important (if technical options are available) to focus, already in the preclinical phase, not only on behavioral markers but also on identifi cationg possible dysfunctions or lesions of brain structures and their correlation with clinical fi ndings in patients with these types of disorders.