neurokinin-a and Anxiety-Disorders

Saredutant (SR48968), a potentially novel treatment option for major depressive disorders (MDD) and generalized anxiety disorder (GAD), is a drug from Sanofi-Aventis currently in phase III clinical trials. MDD is a common mental disorder that affects 121 million people worldwide, nearly 4% of the adult population (www.who.int/mental_health/management/depression/definition/en/). MDD continues to be one of the leading causes of disability with more than three quarters of the diagnosed cases having effective treatments available (www.who.int/mental_health/management/depression/definition/en/). However, even though MDD affects a large portion of the population, effective treatment options with low incidence of adverse events remain a major concern for the pharmaceutical industry. Adverse events (GI side effects1, weight gain, somnolence/insomnia, etc. (Demyttenaere K. (2003) Risk factors and predictors of compliance in depressionEur. Neuropshychopharm.13S69-S75)) from the typical treatments remain the major reason for premature stopping or poor compliance of treatment. New treatments to the market must bear in mind these adverse events, and the pharmaceutical industry is currently looking for drugs with new mechanisms of action and those that are better tolerated.

Topics: Antidepressive Agents; Anxiety Disorders; Benzamides; Clinical Trials, Phase III as Topic; Depressive Disorder, Major; Humans; Neurokinin A; Patient Compliance; Piperidines; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors

Anxiety disorders are pervasive psychiatric disorders causing great suffering. The high (HAB) and low (LAB) anxiety-related behaviour rats were selectively bred to investigate neurobiological correlates of anxiety. We compared the level of neuropeptides relevant for anxiety- and depression-related behaviours in selected brain regions of HAB and LAB rats. Increased anxiety and depression-like behaviours of male and female HAB rats in the elevated plus-maze and forced swim tests were accompanied by elevated levels of neuropeptide Y (NPY) in the prefrontal (PFC), frontal (FC) and cingulate cortex (CCx), the striatum, and periaqueductal grey (PAG). Moreover, HAB rats displayed sex-dependent, elevated levels of calcitonin gene-related peptide (CGRP) in PFC, FC, CCx, hippocampus, and PAG. Higher neurokinin A (NKA) levels were detected in CCx, striatum, and PAG in HAB males and in CCx and hypothalamus in HAB females. Increased neurotensin was detected in CCx and PAG in HAB males and in hypothalamus in HAB females. Elevated corticotropin-releasing hormone (CRH) levels appeared in female HAB hypothalamus. Significant correlations were found between anxiety-like behaviour and NPY, CGRP, NKA, and neurotensin, particularly with NPY in CCx and striatum, CGRP in FC and hippocampus, and NKA in entorhinal cortex. This is the first report of NPY, CGRP, NKA, Neurotensin, and CRH measurements in brain regions of HAB and LAB rats, which showed widespread NPY and CGRP alterations in cortical regions, with NKA and neurotensin changes localised in sub-cortical areas. The results may contribute to elucidate pathophysiological mechanisms underlying anxiety and depression and should facilitate identifying novel therapeutic targets.

Topics: Animals; Anxiety; Anxiety Disorders; Brain; Calcitonin Gene-Related Peptide; Female; Male; Neurokinin A; Neuropeptide Y; Neurotensin; Rats