Antidepressant and pro-motivational effects of repeated lamotrigine treatment in a rat model of depressive symptoms

Background: The antiepileptic lamotrigine is approved for maintenance treatment of bipolar disorder and augmentation therapy in treatment-resistant depression. Previous preclinical investigations showed lamotrigine antidepressant-like effects without addressing its possible activity on motivational aspects of anhedonia, a symptom clinically associated with poor treatment response and with blunted mesolimbic dopaminergic responsiveness to salient stimuli in preclinical models. Thus, in rats expressing a depressive-like phenotype we studied whether repeated lamotrigine administration restored behavioral responses to aversive and positive stimuli and the dopaminergic response to sucrose in the nucleus accumbens shell (NAcS), all disrupted by stress exposure. Methods: Depressive-like phenotype was induced in non-food-deprived adult male Sprague-Dawley rats by exposure to a chronic protocol of alternating unavoidable tail-shocks or restraint periods. We examined whether lamotrigine administration (7.5 mg/kg twice a day, i.p.) for 14–21 days restored a) the competence to escape aversive stimuli; b) the motivation to operate in sucrose self-administration protocols; c) the dopaminergic response to sucrose consumption, evaluated measuring phosphorylation levels of cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) in the NAcS, by immunoblotting. Results: Lamotrigine administration restored the response to aversive stimuli and the motivation to operate for sucrose. Moreover, it reinstated NAcS DARPP-32 phosphorylation changes in response to sucrose consumption. Limitations: The pro-motivational effects of lamotrigine that we report may not completely transpose to clinical use, since anhedonia is a multidimensional construct and the motivational aspects, although relevant, are not the only components. Conclusions: This study shows antidepressant-like and pro-motivational effects of repeated lamotrigine administration in a rat model of depressive symptoms

Sistema per guidare un soggetto o utente attraverso un operatore remoto

U ovom radu opisan je život i djelovanje začetnice Montessori pedagogije, Marije Montessori. Iznesena su načela i glavna misao Montessori pedagogije, te osobine i zadaci Montessori odgajatelja. Veliki naglasak stavljen je na didaktičke materijale potrebne za izradu vježbi. Prikazani su elementi Montessori pedagogije u Montessori dječjoj kući 2, dnevni ritam i okruženje. Također su opisane i dnevne aktivnosti u odgojno-obrazovnoj skupini.This paper describes the life and activities of the initials of Montessori pedagogy, Maria Montessori. Presented the principles and main thought of Montessori pedagogy, and the characteristics and tasks of Montessori educators. Great emphasis is placed on didactically materials for making exercises. Shown elements oft he Montessori pedagogy in te Montessori children house 2, daily rhythm and environment. It also describes the daily activities in the educational educational group

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 effects of long - term administration of rubidium or lithium on reactivity to stress and on dopamine output in the nucleus accumbens in rats

Rubidium and lithium are alkali metals belonging to the same periodic series as sodium, potassium and cesium. In the present report the effects of lithium and rubidium on animal reactivity to stressful stimuli and on dopamine output in the nucleus accumbens were studied. A dose-response curve with rubidium, administered acutely before exposure to unavoidable stress, showed a maximal protective activity on escape deficit development at the dose of 0. 41 mEq/kg. Rubidium injected at doses of 0.008-0.08 mEq/kg 72 h before the unavoidable stress had the same efficacy as the acute 0. 41 mEq/kg dose. Tolerance to the effect of rubidium developed after 9 days of treatment and, on day 15, rats presented a spontaneous escape deficit. The acute effect of lithium, administered for 3.5 days at the dose of 0.8 mEq/kg, i.p. twice a day before the exposure to unavoidable stress, was analogous to that of rubidium, but after repeated treatment a spontaneous escape deficit developed. Rats showing an escape deficit secondary to chronic stress also presented decreased extraneuronal dopamine concentrations in the nucleus accumbens. Accordingly, microdialysis studies showed significantly lower extracellular dopamine levels in rats chronically treated with lithium or rubidium compared to control animals. Cocaine (5 mg/kg i. p.) administered acutely increased extracellular dopamine concentrations in control rats, as well as in rats chronically stressed or chronically treated with lithium or rubidium. However, the dopamine increase was significantly higher in controls compared to the other groups. In conclusion, long-term treatment with lithium or rubidium, or the exposure to chronic stress, produced a condition of behavioral hypo-reactivity accompanied by a decreased dopamine output in the nucleus accumben

Rats sensitized to morphine are resistant to the behavioral effects of an unavoidable stress

In agreement with the results of other authors, rats sensitized to morphine and challenged with 5 mgrkg of morphine after 7 days of wash-out showed intense stereotyped movements, the expression of which was selectively antagonized by SCH 23390. Sensitized rats were exposed to an unavoidable stress which consistently produces an escape deficit in control animals. after 3, 7 and 21 days of morphine wash-out. Twenty-four hours after the unavoidable stress, animals were tested for their capacity to escape and their performance was compared to that of control-stressed and naive rats. Morphine sensitization completely prevented the development of escape deficit. This protective effect was similar to that induced by a chronic imipramine treatment and, like the effect of imipramine, it was antagonized by the administration of SCH 23390 before the unavoidable stress. However, it was not affected by the administration of naloxone. Moreover, when rats presenting a clear-cut escape deficit, induced by a 10-day treatment with SKF 38393, were exposed to the morphine sensitization protocol, a complete recovery of their capacity to avoid a noxious stimulus was observed. Finally, the down-regulation of both the number of D1-dopamine receptors and of the coupled adenylyl cyclase activity in the pre-frontal cortex PFC. produced by long-term SKF 38393 administration was reverted by the superimposed morphine sensitization. Thus, the condition of morphine sensitization appears to share several common effects with chronic imipramine treatmen

Modifications in DARPP-32 phosphorylation pattern after repeated palatable food consumption undergo rapid habituation in the nucleus accumbens shell of non-food-deprived rats.

In non-food-deprived rats a palatable meal induces a transient increase in dopamine output in the prefrontal cortex and nucleus accumbens shell and core; habituation to this response develops with a second palatable meal, selectively in the shell, unless animals are food-deprived. A palatable meal also induces time-dependent modifications in the dopamine and cAMP-regulated phosphoprotein of Mr 32 000 (DARPP-32) phosphorylation pattern that are prevented when SCH 23390, a selective dopamine D(1) receptor antagonist, is administered shortly after the meal. This study investigated whether dopaminergic habituation in the shell had a counterpart in DARPP-32 phosphorylation changes. In non-food-deprived rats, two consecutive palatable meals were followed by similar sequences of modifications in DARPP-32 phosphorylation levels in the prefrontal cortex and nucleus accumbens core, while changes after the second meal were blunted in the shell. In food-deprived rats two consecutive meals also induced similar phosphorylation changes in the shell. Finally, SCH 23390 administered shortly after the first palatable meal in non-food-deprived rats inhibited DARPP-32 phosphorylation changes in response to the first meal, and prevented the habituation to a second meal in terms of dopaminergic response and DARPP-32 phosphorylation changes. Thus, dopamine D(1) receptor stimulation plays a role in the development of habituation