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

Repeated acetyl-L-carnitine administration increases phospho-Thr34 DARPP-32 levels and antagonizes cocaine-induced increase in Cdk5 and phospho-Thr75 DARPP-32 levels in rat striatum.

Acute cocaine administration increases phosphorylation of dopamine and cAMP-regulated phosphoprotein (Mr 32 kDa) (DARPP-32) at threonine (Thr)-34, whereas repeated cocaine administration increases DARPP-32 phosphorylation at Thr-75 in rat striatum. Repeated acetyl-L-carnitine (ALCAR) administration persistently increases dopamine outflow in the nucleus accumbens. The present study examined the effect of repeated ALCAR administration on DARPP-32 phosphorylation pattern in the nucleus accumbens and caudate-putamen. ALCAR increased phosphoThr-34 DARPP-32 levels and decreased phosphoThr-75 DARPP-32 levels, after 1 and 10 days of washout. We compared the effects of repeated cocaine and repeated ALCAR administrations on the behavioral response to cocaine challenge and on DARPP-32 phosphorylation pattern and cyclin-dependent kinase 5 (Cdk5) levels in the striatum. We also studied whether ALCAR administered daily during or after cocaine sensitization procedure would interfere with the effects of cocaine. When the response to cocaine challenge was assessed, cocaine- and ALCAR-treated rats showed a similar sensitized behavioral response, and rats receiving combined cocaine and ALCAR treatments, irrespectively of treatment order, also showed a sensitized response. A week after cocaine challenge, the 2 drugs had induced opposite modifications in DARPP-32 phosphorylation, as cocaine increased phosphorylation at Thr-75, while ALCAR increased phosphorylation at Thr-34. In cocaine plus ALCAR treated rats, irrespectively of treatment order, ALCAR administration antagonized cocaine effects on DARPP-32 phosphorylation. Moreover, cocaine, but not ALCAR, increased ΔFosB and Cdk5 expression, and the increase in Cdk5 was antagonized by ALCAR administration in rats receiving combined treatments. These effects were relatively persistent, as they were still present 7 days after the last treatment

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

Hypothalamus-pituitary-adrenal modifications consequent to chronic stress exposure in an experimental model of depression in rats

The modifications in the hypothalamus-pituitary-adrenal (HPA) axis function induced by repeated unavoidable stress exposure, according to a standardized procedure used for inducing an experimental model of depression, were studied. Rats exposed to this procedure show hyporeactivity to both pleasurable and aversive stimuli and this condition is antagonized by the repeated administration of classical antidepressant drugs. We also studied whether imipramine administration during stress exposure would interfere with the possible modifications in the HPA axis. Rats were exposed to a 4-week stress procedure with and without imipramine treatment and then tested for escape, as compared with non-stressed control animals. Twenty-four hours later all rats were bled through a tail nick for plasma corticosterone measurement before and after dexamethasone (10 microg/kg) or corticotropin-releasing hormone (CRH, 1 microg/kg) administration. Rats were then killed, adrenals and thymus weighed, brain areas dissected out and frozen for glucocorticoid receptors (GRs) and corticotropin-releasing hormone receptor 1 (CRHR1) immunoblotting and for the assessment of hypothalamic corticotropin-releasing hormone levels. RESULTS: Rats exposed to a 4-week unavoidable stress showed escape deficit and their basal plasma corticosterone levels were higher than those of control animals. Moreover, they had decreased response to dexamethasone administration, adrenal hypertrophy, and decreased GR expression in the hippocampus, hypothalamus, medial prefrontal cortex and pituitary. No significant modifications in CRHR1 expression were observed in the pituitary nor in different discrete brain areas. CRH levels in the hypothalamus and the plasma corticosterone response to CRH administration were found to be higher in stressed rats than in controls. Imipramine treatment offset all the behavioral and neurochemical stress-induced modifications. In conclusion, the present results strengthen the assumption that the escape/avoidance behavioral deficit induced by inescapable stress exposure is accompanied by steadily increased HPA activity, and that imipramine effect is strongly related to a normalization of HPA axis activity

The efficacy of reboxetine in preventing and reverting a condition of escape deficit in rats. Biol. Psychiatry,

Background: Different stress-induced experimental models of depression are currently used to study the efficacy and mechanism of action of classical or potential antidepressant compounds. We studied the effect of single and repeated administrations of reboxetine, an antidepressant that selectively inhibits noradrenaline reuptake, in the prevention and reversal of stress-induced escape deficit. Moreover, we examined the effect of chronic reboxetine on the stress-induced decrease of dopamine output in the nucleus accumbens shell (NAcS). Methods: Rats received a single or 21-day reboxetine administration before acute unavoidable stress exposure; 24 h later their escape response was examined. Rats were exposed to repeated unavoidable stress for 21 days, with or without reboxetine treatment, and then were tested for escape; 2 days later they were implanted with microdialysis probes in the NAcS. Results: A single reboxetine administration showed a protective activity on stress-induced escape deficit development, that significantly increased after 21 days of treatment. This effect was antagonized by propranolol, a selective -adrenergic antagonist. In rats exposed to chronic stress, a 21-day reboxetine treatment reinstated the avoidance response and NAcS dopamine output to control values. Conclusions: In these stress-induced paradigms long-term reboxetine administration showed a protective activity similar to that of classical antidepressants

Acquisition of an appetitive behavior prevents development of stress-induced neurochemical modifications in rat nucleus accumbens

In rats, exposure to chronic unavoidable stress produces a decrease in dopamine output in the nucleus accumbens shell that is accompanied by a decreased density of the dopamine transporter and an increased activity of the dopamine-D(1) receptor complex. These modifications have been hypothesized to be adaptive to decreased dopamine output in stressed rats. We investigated whether the learning of an appetitive behavior sustained by palatable food, which is associated with increased dopamine output in the nucleus accumbens shell as measured by microdialysis experiments, would affect the modifications induced by chronic stress exposure on dopamine transporter density and dopamine-D(1) receptor complex activity in the nucleus accumbens. Rats exposed to chronic unavoidable stress after acquisition of the appetitive behavior showed a higher dopamine extraneuronal release in the nucleus accumbens shell than that of stressed animals, and similar to that of control rats. Moreover, previous acquisition of the appetitive behavior prevented development of a stress-induced decrease in dopamine transporter density, measured by [(3)H]-WIN 35428 binding, a stress-induced increase in dopamine-D(1) receptor density, measured by binding of [(3)H]-SCH 23390, and SKF 38393-stimulated adenylyl cyclase activity in the nucleus accumbens. These results support the hypothesis that changes induced in pre- and postsynaptic dopaminergic transmission by chronic stress exposure are related to decreased dopamine output

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