Interplay between the key proteins of serotonin system in SSRI antidepressants efficacy

Introduction: Selective serotonin reuptake inhibitors (SSRIs) are the most effective and most used antidepressant drugs. Acting by inhibiting serotonin (5-HT) transporter, SSRIs display a typical 3–4-week delay in their therapeutic effects, with nearly 40% of depressed patients remaining treatment-resistant. Recent evidence suggests complex interplay between 5-HT receptors and key proteins of 5-HT metabolism in molecular mechanisms of such delay and resistance to SSRIs.

Area covered: This paper concentrates on the interplay between 5-HT receptors in the delay of therapeutic effect of SSRIs, and the interaction between tryptophan hydroxylase 2 and 5-HT transporter in the SSRI resistance. Specifically, it discusses: (1) the data on the association between antidepressant drug efficacy and genetically defined characteristics of key proteins in the 5-HT signaling (TPH2, MAOA, SERT and 5-HT_1A receptor), (2) the effect of dimerization of 5-HT₇ and 5-HT_1A receptors on the internalization and functioning of 5-HT_1A presynaptic receptors, (3) the role of Tph2 deficiency in the resistance to SSRIs treatment. We shift the emphasis from individual proteins to their interactions in explaining antidepressant action of SSRI.

Expert opinion: These interactions should be considered when developing more effective antidepressant drugs as well as for predicting and improving the efficacy of antidepressant therapies.     

Sex differences in behavior and neuropharmacology of zebrafish

Sex is an important variable in biomedical research. The zebrafish (Danio rerio) is increasingly utilized as a powerful new model organism in translational neuroscience and pharmacology. Mounting evidence indicates important sex differences in zebrafish behavioral and neuropharmacological responses. Here, we discuss the role of sex in zebrafish central nervous system (CNS) models, their molecular mechanisms, recent findings and the existing challenges in this field. We also emphasize the growing utility of zebrafish models in translational neuropharmacological research of sex differences, fostering future CNS drug discovery and the search for novel sex‐specific therapies. Finally, we highlight the interplay between sex and environment in zebrafish models of sex‐environment correlations as an important strategy of CNS disease modeling using this aquatic organism.     

Traumatic Brain Injury Models in Zebrafish (Danio rerio)

Neuroscience and Behavioral Physiology - Current medicine has a high level of interest in studies of the pathogenesis of traumatic brain injury (TBI). This comes particularly from high levels of...     

Behavioral neuroscience, exploration, and K.C. Montgomery's legacy

Exploration is a key animal and human behavior. Kay C. Montgomery (1921-1956) has made an important contribution to behavioral neuroscience of exploration, as well as motivation and learning. His works have many important applications to current experimental models of stress, fear and memory, continuing to influence research in this field. This paper, dedicated to the 85th anniversary of Montgomery's birth, and 50 years since his tragic death, summarizes Montgomery's contribution to behavioral neuroscience, and discusses its current importance for further progress in this field. It is aimed at neuroscientists with strong interests in both theory of animal exploration and motivation, and the history of behavioral neuroscience.     

What's wrong with my mouse model? Advances and strategies in animal modeling of anxiety and depression

Stress plays a key role in pathogenesis of anxiety and depression. Animal models of these disorders are widely used in behavioral neuroscience to explore stress-evoked brain abnormalities, screen anxiolytic/antidepressant drugs and establish behavioral phenotypes of gene-targeted or transgenic animals. Here we discuss the current situation with these experimental models, and critically evaluate the state of the art in this field. Noting a deficit of fresh ideas and especially new paradigms for animal anxiety and depression models, we review existing challenges and outline important directions for further research in this field.     

Anxiety and otovestibular disorders: linking behavioral phenotypes in men and mice

Human anxiety and vestibular disorders have long been known to co-occur. Paralleling human clinical and non-clinical data, mounting genetic, pharmacological and behavioral evidence confirms that animal anxiety interplays and co-exists with vestibular/balance deficits. However, relatively few animal models have addressed the nature of this relationship. This paper examines side-by-side human psychiatric and otovestibular phenotypes with animal experimentation data, and outlines future directions of translational research in this field. Discussed here are recently developed specific animal models targeting this interplay, other traditional animal tests sensitive to altered anxiety and vestibular domains, and the existing problems with translation of animal data into human phenotypes. The role of hearing deficits and their contribution to anxiety and vestibular phenotypes are also outlined. Overall, the overlap between anxiety and balance disorders emerges as an important phenomenon in both animal and clinical studies, and may contribute markedly to the complexity of behavioral and physiological phenotypes. Animal experimental models that focus on the interplay between anxiety and vestibular disorders are needed to improve our understanding of this important biomedical problem.     

Hybridizing behavioral models: A possible solution to some problems in neurophenotyping research?

The use of batteries of single-domain tests for neurophenotyping research is a common strategy to achieve higher data density and explore different behavioral domains. This approach, however, is accompanied by several methodological challenges, briefly discussed here. As an alternative, this paper advocates the wider use of extensive "hybrid" protocols that assess multiple domains in parallel, or logically/logistically combine experimental paradigms, in a way that disproportionately maximizes the number of tested phenotypes per experimental manipulation. Several examples of this approach are given in this paper, demonstrating the potential to reduce time, cost and subject requirements for the experiments. Offering behavioral analyses that are lacking in the standard single-domain tests, such "hybrid" models enable innovative modeling of neuropsychiatric disorders by more thorough and broader investigation of complex phenotypical characteristics.     

Increased severity of chemically induced seizures in mice with partially deleted Vitamin D receptor gene

Vitamin D is a neuroactive steroid hormone with multiple functions in the brain. Numerous clinical and experimental data link various Vitamin D-related dysfunctions to epilepsy. Here, we study the role of Vitamin D receptors (VDRs) in experimental epilepsy in mice. To examine this problem, we assessed the seizure profiles in VDR knockout mice following a systemic injection of pentylenetetrazole (70 mg/kg). Overall, compared to the wild-type (WT) 129S1 mice (n=10 in each group), the VDR knockout group significantly demonstrated shorter latencies to the onset, higher Racine scores and increased mortality rates. Our findings suggest that VDRs modulate seizure susceptibility in mice, and that the Vitamin D/VDR endocrine system may be involved in the pathogenesis of epilepsy.     

Behavioural anomalies in mice evoked by "Tokyo" disruption of the Vitamin D receptor gene

Vitamin D is a steroid hormone with many important functions in the brain, mediated through the nuclear Vitamin D receptor (VDR). Mounting clinical data link VDR mutations to various psychiatric phenotypes. We have reported previously that mutant mice lacking functional VDR ("Tokyo" VDR mutant mice) display several behavioural anomalies, including high anxiety and aberrant grooming. Given the important role of Vitamin D and VDR in brain development and functioning, we hypothesized that several other important behavioural domains may be affected by disruption of the VDR gene in mice. Here we report that VDR mutants display unaffected depressive-like behaviour, but show abnormal social behaviours, reduced social barbering and aggressiveness, impaired nest building and aberrant maternal (pup neglect, cannibalism) behaviours. Taken together, these findings confirm the important role postulated for the VDR in the regulation of behaviour, and suggest the mice lacking functional VDR may be a useful tool to model different brain disorders.