Aggression, anxiety and vocalizations in animals: GABA A and 5-HT anxiolytics

A continuing challenge for preclinical research on anxiolytic drugs is to capture the affective dimension that characterizes anxiety and aggression, either in their adaptive forms or when they become of clinical concern. Experimental protocols for the preclinical study of anxiolytic drugs typically involve the suppression of conditioned or unconditioned social and exploratory behavior (e.g., punished drinking or social interactions) and demonstrate the reversal of this behavioral suppression by drugs acting on the benzodiazepine-GABA A complex. Less frequently, aversive events engender increases in conditioned or unconditioned behavior that are reversed by anxiolytic drugs (e.g., fear-potentiated startle). More recently, putative anxiolytics which target 5-HT receptor subtypes produced effects in these traditional protocols that often are not systematic and robust. We propose ethological studies of vocal expressions in rodents and primates during social confrontations, separation from social companions, or exposure to aversive environmental events as promising sources of information on the affective features of behavior. This approach focusses on vocal and other display behavior with clear functional validity and homology. Drugs with anxiolytic effects that act on the benzodiazepine-GABA A receptor complex and on 5-HT 1A receptors systematically and potently alter specific vocalizations in rodents and primates in a pharmacologically reversible manner; the specificity of these effects on vocalizations is evident due to the effectiveness of low doses that do not compromise other physiological and behavioral processes. Antagonists at the benzodiazepine receptor reverse the effects of full agonists on vocalizations, particularly when these occur in threatening, startling and distressing contexts. With the development of antagonists at 5-HT receptor subtypes, it can be anticipated that similar receptor-specificity can be established for the effects of 5-HT anxiolytics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46351/1/213_2005_Article_BF02245590.pd

The Newly Developed CRF1-Receptor Antagonists, NGD 98-2 and NGD 9002, Suppress Acute Stress-Induced Stimulation of Colonic Motor Function and Visceral Hypersensitivity in Rats

Corticotropin releasing factor receptor 1 (CRF(1)) is the key receptor that mediates stress-related body responses. However to date there are no CRF(1) antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF(1) antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF(1) antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC(50) of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67–87% and decreased WAS-induced-FPO by 23–53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF(1) antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD

Impact of mast cells in depression disorder: inhibitory effect of IL-37 (new frontiers)

The purpose of this article is to study the involvement of inflammatory mast cells (MCs) in depression which may be inhibited by IL-37. We evaluate mast cells in depression on the basis of our previous experimental data, and using the most relevant studies reported in the literature. Dysfunction of mood, feelings, and thoughts is a major risk factor for several metabolic diseases and may influence the physiology of the body leading to depression. Depression, present in mastocytosis, is an important endogenous process that promotes the activation of meningeal cell receptors through a low-grade neurogenic chronic inflammation, and MCs. Mast cells are localized along meningeal blood vessels and connective tissues, as well as between the ganglion cells and nerve fibers. They are present in the hypothalamus of mammalian brains capable of communication with nerves. MCs are classically activated by binding to IgE cross-link Fc\u3b5RI high-affinity receptor leading to release a plethora of mediators responsible for the generation of inflammatory cytokines. Corticotropin-releasing hormone (CRH), produced by MCs, has been found in microglial cells where it regulates immune cells and contributes to the pathogenesis of neurodegenerative diseases including depression. Inflammatory cytokines released by MCs aggravate depression and could be partially inhibited by IL-37. A detailed understanding of the interaction between the immune system, including MCs and depression, is necessary in order to address an effective therapy which could include IL-37. As a consequence, the concepts reviewed here have treatment implications