Anxiolytic and panicolytic effects of escitalopram in the elevated T-maze

Escitalopram is a highly selective inhibitor of serotonin re-uptake that is used to treat anxiety disorders. In the present study, we investigated the effects of acute, sub-chronic ( 14 days) and chronic ( 21 days) administration of escitalopram ( 2, 4 and 8 mg/kg, P0) on the performance of rats in the elevated T-maze. For comparison, imipramine ( 15 mg/ kg, P0) was also studied. The apparatus is made of three elevated arms of equal dimension, one enclosed transversal to the two open arms. Inhibitory avoidance of the open arms, trained in the enclosed arm, has been related to generalised anxiety disorder, while one-way escape from one open arm, to panic disorder. After acute administration, the three doses of escitalopram impaired avoidance ( anxiolytic effect), while imipramine was ineffective. Escape was unaffected by either drug. With sub-chronic administration, both drugs were ineffective on either avoidance or escape. After chronic treatment, avoidance was impaired by imipramine and by the two highest doses of escitalopram. In addition, escape was impaired (panicolytic effect) by imipramine and by the highest dose of escitalopram. Locomotion measured in a square arena was increased by the three doses of escitalopram, given chronically. Therefore, both imipramine and escitalopram had anxiolytic and panicolytic-like effects after chronic administration, but acutely only escitalopram decreased anxiety. Since no such effect was observed following subchronic administration, it is likely that the mechanisms of the early and late anxiolytic actions of escitalopram are different.

Mild cognitive deficits associated to neocortical microgyria in mice with genetic deletion of cellular prion protein

The cellular prion protein (PrP(c)) has been implicated with the modulation of neuronal apoptosis, adhesion, neurite outgrowth and maintenance which are processes involved in the neocortical development. Malformations of cortical development (MCD) are frequently associated with neurological conditions including mental retardation, autism, and epilepsy. Here we investigated the behavioral performance of female adult PrP(c)-null mice (Prnp(%)) and their wild-type controls (Prnp(+/+)) presenting unilateral polymicrogyria, a MCD experimentally induced by neonatal freeze-lesion in the right hemisphere. injured mice from both genotypes presented similar locomotor activity but Prnp(%) mice showed a tendency to increase anxiety-related responses when compared to Prnp(+/+) animals. Additionally, injured Prnp(%) mice have a poorer performance in the social recognition task than sham-operated and Prnp(%) injured ones. Moreover the step-down inhibitory avoidance task was not affected by the procedure or the genotype of the animals. These data suggest that the genetic deletion of PrP(c) confers increased susceptibility to short-term social memory deficits induced by neonatal freezing model of polymicrogyria in mice. (C) 2008 Published by Elsevier B.V.

5-HT2C receptor regulation of defensive responses in the rat dorsal periaqueductal gray

Activation of 5-HT2C receptors in limbic structures such as the amygdala and hippocampus increases anxiety. Indirect evidence obtained with non-selective 5-HT2C-interacting drugs suggests that the same may occur in the dPAG, a brainstem region consistently implicated in the genesis/regulation of panic attacks. In this study we used more selective agonists and antagonists to unveil the role played by dPAG 5-HT2C receptors in the regulation of anxiety- and panic-related defensive behaviors. Our results showed that intra-dPAG microinjection of the endogenous agonist 5-HT (20 nmol) or the 5-HT2C receptor agonists MK-212 (1 and 10 nmol) and RO-600175 (40 nmol) significantly increased inhibitory avoidance acquisition in rats tested in the elevated T-maze, suggesting an anxiogenic effect. 5-HT, but not the two 5-HT2C receptor agonists, inhibited escape performance. In the elevated T-maze, inhibitory avoidance and escape responses have been related to generalized anxiety and panic attacks, respectively. The behavioral effects caused by 5-HT and MK-212 were fully blocked by previous local microinjection of the 5-HT2C receptor antagonist SB-242084. Intra-dPAG injection of MK-212 also failed to affect escape expression in another test relating this behavior to panic, the electrical stimulation of the dPAG. Overall, the results indicate that 5-HT2C receptors in the dPAG are preferentially involved in the regulation of defensive behaviors related to anxiety, but not panic. This finding extends to the dPAG the prominent role that has been attributed to 5-HT2C receptors in anxiety generation. (C) 2010 Elsevier Ltd. All rights reserved.

Pharmacological Manipulation of Immune-Induced Food Aversion in Rats

Background: Mice allergic to ovalbumin (OVA) avoid drinking a solution containing this antigen. This was interpreted as related to IgE-dependent mast cell degranulation and sensory C fiber activation. Methods: We employed pharmacological manipulation to further investigate the mediators involved in immune-induced food aversion. Results: While nonimmunized rats preferred a sweetened OVA solution, immunized rats avoided it. We also employed a paradigm in which rats are conditioned to drink water for two 10-min sessions a day. Tolerant rats presented lower IgE titers, and this manipulation abrogated food aversion. Dexamethasone (1.0 mg/kg) prevented the aversion of OVA-immunized rats to the antigen-containing solution. Combined blockade of H(1) and 5-hydroxytryptamine (5-HT)(2) receptors by promethazine (3.0 mg/kg) plus methysergide (5.0 mg/kg) was unable to alter food aversion. Blockade of 5-HT(3) receptors by ondansetron (1.0 mg/kg) caused a twofold increase in the ingestion of the sweetened OVA solution by immunized rats, suggesting the involvement of 5-HT(3) receptors in food aversion. Finally, we showed that dexamethasone or promethazine plus methysergide, but not ondansetron, effectively prevented the IgE-dependent mast-cell-degranulation-induced increase in vascular permeability in rats. Conclusion: We suggest that regardless of whether or not they cause edema, IgE-mediated mast cell degranulation and consequent 5-HT(3) signaling are involved in the process that triggers avoidance to the source of the allergen in allergic rats. Copyright (C) 2008 S. Karger AG, Basel

In vitro macrophage activity: Biphasic effect of prolactin and indirect evidence of dopaminergic modulation

Objective: Prolactin (PRL), a peptide hormone produced by the pituitary gland, is involved in the interaction between the neuroendocrine and immune system. Since dopamine receptor antagonists increase serum levels of PRL, both PRL and dopamine receptors might be involved in the modulation of macrophage activity, providing means of communication between the nervous and immune systems. This study evaluated the effects of PRL and the dopamine antagonist domperidone (DOMP) on macrophage activity of female rats. Methods: Oxidative burst and phagocytosis of peritoneal macrophages were evaluated by flow cytometry. Samples of peritoneal liquid from female rats were first incubated with PRL (10 and 100 nM) for different periods. The same procedure was repeated to evaluate the effects of DOMP (10 and 100 nM). Results: In vitro incubation of macrophages with 10 nM DOMP decreased oxidative burst, after 30 min, whereas the PMA-induced burst was decreased by DOMP 10 nM after 2 and 4 h. Treatment with PRL (10 and 100 nM) for 30 min decreased oxidative burst and rate of phagocytosis (10 nM). After 2 h of incubation, 10 nM PRL decreased oxidative burst and phagocytosis intensity, but increased the rate of phagocytosis. On the other hand, after 4 h, PRL 10 and 100 nM increased oxidative burst and the rate of phagocytosis, but decreased intensity of phagocytosis. Conclusions: These observations suggest that macrophage functions are regulated by an endogenous dopaminergic tone. Our data also suggest that both PRL and dopamine exert their action by acting directly on the peritoneal macrophage. Copyright (C) 2008 S. Karger AG, Basel.