Study of mirtazapine antidepressant effects in rats

5noreservedMirtazapine is a widely used antidepressant and the aim of this study was to further investigate its antidepressant activity in rats. Thus, the efficacy of long-term mirtazapine treatment was assessed in three models of depressive symptoms induced by stress exposure: the acute escape deficit, the chronic escape deficit, and the stress-induced disruption of the acquisition of an appetitive behavior sustained by a palatable food (vanilla sugar). Administration of mirtazapine for 2 weeks prevented the escape deficit development induced by acute exposure to unavoidable stress. This protective effect was antagonized by the administration of a β-adrenergic or a 5-HT1A receptor antagonist just before stress exposure; that is, mirtazapine effect was dependent on functional β-adrenergic and 5-HT1A receptor systems. Repeated stress exposure indefinitely prolongs the condition of escape deficit and a 40-day mirtazapine treatment reversed this model of chronic escape deficit. Satiated rats learn to choose in a Y-maze the arm baited with vanilla sugar, and exposure to stress during Y-maze training prevents this learning. Repeated mirtazapine administration completely antagonized the disrupting effect of chronic stress on the acquisition of this instrumental behavior. We consider these effects to be crucial in the definition of antidepressant activity.mixedRAUGGI, R.; CASSANELLI, A.; RAONE, A.; TAGLIAMONTE, A.; GAMBARANA, C.Rauggi, R.; Cassanelli, A.; Raone, A.; Tagliamonte, A.; Gambarana, C

Animal models for the study of antidepressant activity

5noreservedThree behavioral paradigms are presented for the study of the mechanism of action of antidepressant treatments and for the screening of new antidepressant drugs. The first model (acute escape deficit) exploits the decreased ability of a rat exposed to an unavoidable stress to avoid a noxious stimulus, and it allows us to evaluate the preventive activity of a treatment on the development of escape deficit. The second paradigm (chronic escape deficit) begins as acute escape deficit, that is then indefinitely sustained by the repeated administration of mild stressors; this model allows us to evaluate the efficacy of a treatment to revert the escape deficit. The third is a model of anhedonia based on the finding that exposure to repeated unavoidable stress prevents the acquisition of an appetitive behavior induced and maintained by a highly palatable food (vanilla sugar) in rats fed ad libitum; this paradigm assesses the efficacy of a treatment to restore an animal's motivation. A long-term (2 to 3 week) treatment with classical antidepressants, such as imipramine or fluoxetine, resulted in a clear-cut preventive and/or revertant activity in the three models. © 2001 Elsevier Science B.V.mixedGAMBARANA, C.; SCHEGGI, S.; TAGLIAMONTE, A.; TOLU, P.L.; DE MONTIS, M.G.Gambarana, C.; Scheggi, S.; Tagliamonte, A.; Tolu, P. L.; DE MONTIS, M. G

Dopamine and cyclic AMP-regulated phosphoprotein-32 phosphorylation pattern in cocaine and morphine-sensitized rats

This study reports some of the modifications in dopaminergic signalling that accompany cocaine and morphine behavioural sensitization. Cocaine-sensitized rats showed increased phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein Mr 32 kDa (DARPP-32) at threonine-75 (Thr75) and decreased DARPP-32 phosphorylation at Thr34, in the caudate–putamen (CPu) and nucleus accumbens (NAc) 7 days after sensitization assessment. Conversely, in morphine-sensitized rats, no apparent modifications in DARPP-32 phosphorylation pattern were observed. Morphine-sensitized rats have increased binding and coupling of µ-opioid receptors and increased dopaminergic transmission in striatal areas and, upon morphine challenge, exhibit dopamine D1 receptor-dependent stereotypies. Thus, the DARPP-32 phosphorylation pattern was studied in morphine-sensitized rats at different times after morphine challenge. Morphine challenge increased levels of phospho-Thr75 DARPP-32 and decreased levels of phospho-Thr34 DARPP-32 in a time-dependent manner in the CPu and NAc. In order to assess whether these modifications were related to modified cyclic AMP-dependent protein kinase (PKA) activity, the phosphorylation levels of two other PKA substrates were examined, the GluR1 and NR1 subunits of α-amino-3-hydroxy-5-methylisoxazole-4-propionate and NMDA receptors respectively. The phosphorylation levels of GluR1 and NR1 subunits decreased in parallel with those of phospho-Thr-34 DARPP-32, supporting the hypothesis that morphine challenge elicited a decrease in PKA activity in morphine-sensitized rats

Analysis of Hand Intra-Finger Couplings During Flexion Movements in the Free Space

The anatomy of the human hand is characterized by intrinsic coupling mechanisms at the level of the tendons and bone structure. The intra-finger constraints, in particular, represent coupled movements of the joints of the same finger. Previous studies verified the existence of intra-finger couplings for circular and prismatic grasps, and hypothesized the existence of such couplings for free flexion-extension movements of the fingers without, however, quantifying them. The aim of this work was: i) to calculate subject-specific intra-finger couplings during flexion movements in the free space by exploiting a marker-based motion capture system and a validated kinematic protocol to guarantee high accuracy of the reconstructed hand kinematics, ii) to understand the effect of the hand size and of the finger on the coupling relations, and iii) to establish generalized coupling coefficients that could be used to simplify the kinematic hand model. To this purpose, ten healthy subjects performed flexion-extension movements of the fingers. Subject-specific couplings were extracted through linear regression analysis on pairs of adjacent joint angle trajectories: proximal couplings represented the relation between the Proximal-Inter-Phalangeal and MetaCarpo-Phalangeal joints for the long fingers and between the MetaCarpo-Phalangeal and Carpo-MetaCarpal joints for the thumb, whereas distal couplings represented the relation between the Distal-Inter-Phalangeal and Proximal-Inter-Phalangeal joints for the long fingers and between Inter-Phalangeal and MetaCarpo-Phalangeal joints for the thumb. The subject-specific coupling coefficients were independent from the hand size, and a difference between the distal couplings of the thumb and of the index, middle and ring fingers was highlighted. Regression analysis on the average flexion trajectories calculated on the ten participants showed a linear trend for both proximal and distal couplings ( R^{2}>0.97 ) and small Root Mean Square Errors (1.63 deg on average). Coupling coefficients ranged 1.4 – 1.9 and 0.7 – 0.9 for the proximal and distal couplings respectively. Given its distinctive kinematic structure, the thumb exhibited a particular behaviour, as its proximal and distal couplings were the same. The extracted couplings represent normative coupling values on a population of ten individuals. The obtained results suggest the possibility of simplifying the kinematic hand model by imposing linear relations between the joints of each finger, thus reducing the number of independent degrees of freedom to one for each finger. This could be used to define input design parameters for the development of biomimetic hand prostheses and exoskeletons

A Chronic stress that impairs reactivity in rats also decreases dopaminergic transmission in the nucleus accumbens: a microdialysis study

Chronic stress induces in rats a decreased reactivity toward noxious stimuli (escape deficit), which can be reverted by antidepressant treatments. The present study reports that this condition of behavioral deficit is accompanied by a decreased level of extracellular dopamine in the nucleus accumbens shell. To assess whether this finding was the result of a decreased release or of an enhanced removal of dopamine, we acutely administered cocaine, and 2 h later d-amphetamine, to stressed and control rats. The increases in dopamine output observed in stressed animals after cocaine administration were significantly lower than those observed in control rats; whereas the total amount of dopamine released after d-amphetamine administration was similar in both groups of rats. These data suggest a reduced activity of dopaminergic neurons as the possible mechanism underlying dopamine basal level reduction in stressed animals. It is interesting that the stress group showed a locomotor response to cocaine not different from control rats, thus suggesting a condition of sensitization to dopamine receptor stimulation. Imipramine administered daily concomitantly with stress exposure completely reverted the escape deficit condition of chronically stressed rats. Moreover, stressed rats treated with imipramine showed basal and cocaine stimulated levels of extraneuronal dopamine similar to those observed in control animals

Synthetic peptides in the form of dendrimers become resistant to protease activity

9In previous papers, we observed that dendrimers of peptide mimotopes of the nicotinic receptor ligand site are strong antidotes against the lethality of the nicotinic receptor ligand alpha-bungarotoxin. Although their in vitro activity is identical to that of dendrimers, the corresponding monomeric peptide mimotopes are not effective in vivo. Because the higher in vivo efficiency of dendrimers could not in this case be related to polyvalent interaction, the stability to blood protease activity of monomeric versus tetrabranched dendrimeric mimotope peptides was compared here by incubating three different mimotopes with human plasma and serum. Unmodified peptides and cleaved sequences were followed by high pressure liquid chromatography and mass spectrometry. Tetrabranched peptides were shown to be much more stable in plasma and also in serum. To assess the notable stability of multimeric peptides, different bioactive neuropeptides, including enkephalins, neurotensin and nociceptin, were synthesized in monomeric and tetrabranched forms and incubated with human plasma and serum and with rat brain membrane extracts. All the tetrabranched neuropeptides fully retained biological activity and generally showed much greater stability to blood and brain protease activity. Some tetrabranched peptides were also resistant to trypsin and chymotrypsin. Our findings provide new insights into the possible therapeutic use of bioactive peptides.reservedmixedBRACCI L; FALCIANI C; LELLI B; LOZZI L; RUNCI Y; PINI A; M. DE MONTIS; TAGLIAMONTE A; NERI PBracci, Luisa; Falciani, Chiara; Lelli, Barbara; Lozzi, Luisa; Runci, Ylenia; Pini, Alessandro; DE MONTIS, MARIA GRAZIELLA; Tagliamonte, Alessandro; Neri, Paol

Effect of gamma-hydroxybutyric acid on human platelet aggregation in vitro

Endogenous formation of gamma-hydroxybutyric acid (GHB) has been described in humans. It is considered to be a neurotransmitter and/or neuromodulator although its precise physiological role remains unclear. This molecule is used in the treatment of alcoholism and alcohol withdrawal. GHB, at least in central nervous system, has ethanol-like activities and it is well-known that ethanol decreases platelet function. However, there are no information regarding the GHB and its effect on platelet function. Therefore, the goal of the study was to investigate the most notable GHB effects on human platelet aggregation in vitro