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

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

Selective modifications in the nucleus accumbens of dopamine synaptic transmission in rats exposed to chronic stress

Stressful events are accompanied by modifications in dopaminergic transmission in distinct brain regions. As the activity of the neuronal dopamine (DA) transporter (DAT) is considered to be a critical mechanism for determining the extent of DA receptor activation, we investigated whether a 3-week exposure to unavoidable stress, which produces a reduction in DA output in the nucleus accumbens shell (NAcS) and medial prefrontal cortex (mPFC), would affect DAT density and DA D1 receptor complex activity in the NAcS, mPFC and caudate-putamen (CPu). Rats exposed to unavoidable stress showed a decreased DA output in the NAcS accompanied by a decrease in the number of DAT binding sites, and an increase in the number of DA D1 binding sites and Vmax of SKF 38393 -stimulated adenylyl cyclase. In the mPFC, stress exposure produced a decrease in DA output with no modification in DAT binding or in DA D1 receptor complex activity. Moreover, in the CPu stress exposure induced no changes in DA output or in the other neurochemical variables examined. This study shows that exposure to a chronic unavoidable stress that produces a decrease in DA output in frontomesolimbic areas induced several adaptive neurochemical modifications selectively in the nucleus accumbens