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Experimental protocols for the study of stress in animals and humans
No full text1. Stress is the response of an organism to a stressor of physical, chemical, or emotional nature.
2. Exposure to stressors induces behavioral and neuroendocrine consequences in experimental animals as well as in humans, and this complex response can be adaptive or maladaptive.
3. Experimentally, the exposure to different stressors is used in order to study the evoked responses and the mechanisms underlying them, or to modify the behavior of animals in an attempt to reproduce reliable models of psychiatric symptoms with a stress-related component in humans.
4. In animals of the same species, strain, sex and age maintained in controlled environmental conditions we can expect reproducible behavioral and neuroendocrine responses to stressful protocols, that are proportional to the intensity of the stressor and the duration of the exposure. The reproducibility of the response is crucially bound to the controlled experimental conditions used.
5. In human experiments, the main difficulties in controlling experimental conditions are not related to the stressor (intensity and duration of exposure ethically acceptable), but are mainly related to the large interindividual variability in sensitivity to any kind of traumatic stimulus or event that can sometimes be explained on the basis of genetic variables or particular personal histories
Quantitative autoradiography of central beta adrenoceptor subtypes: comparison of the effects of chronic treatment with desipramine or centrally administered l-isoproterenol
No full textThis study compares the regulation of the subtypes of central beta adrenoceptors produced by treatment of rats with desipramine (10 mg/kg i.p. twice daily for 10 days) to that caused by central infusion of l-isoproterenol (5 micrograms/hr for 7 days). Beta adrenoceptors were measured by quantitative autoradiography of the binding of [125I]iodopindolol ([125I]IPIN) to coronal sections of rat brain as well as the binding of this radioligand to homogenates of certain areas of brain. Administration of desipramine caused significant reductions in the total specific binding of [125I]IPIN in many areas of the brain, including regions of the amygdala, cerebral cortex, hippocampus, hypothalamus and thalamus. This reduction in the total specific binding of [125I]IPIN was primarily the result of a reduction in its binding to beta-1 adrenoceptors in most brain regions. With the exception of the paraventricular nuclei of the thalamus, no desipramine-induced change in the binding of [125I]IPIN to beta-2 adrenoceptors was observed in any region of the brain. Treatment of rats with desipramine did not alter the binding of [125I]IPIN to the caudate putamen, globus pallidus or the cerebellum. Intracerebroventricular fusion of the nonselective beta adrenoceptor agonist, isoproterenol, reduced the maximum binding site density of the binding of [125I]IPIN to homogenates of cerebellum and hypothalamus, but not to homogenates of cerebral cortex. Autoradiography of the binding of [125I]IPIN to brain sections from rats treated with isoproterenol revealed reductions in many subcortical areas and the cerebellum. In contrast to the effects produced by treatment with desipramine, reductions in the binding of [125I]IPIN after infusions of isoproterenol were a result of a decrease in the binding of [125I]IPIN to beta-2 adrenoceptors in most brain regions. Infusion of isoproterenol reduced the binding of [125I]IPIN to beta-2 adrenoceptors in 10 areas of brain in which the binding of the ligand to beta-1 adrenoceptors was not affected significantly. Inasmuch as there is a selective regulation of beta-1 adrenoceptors by the norepinephrine uptake blocker, desipramine, it may be inferred that these receptors are under the influence of endogenous norepinephrine. By contrast, the density of central beta-2 adrenoceptors are regulated more easily by an exogenous beta adrenoceptor agonist, even one like isoproterenol which is a full agonist at both beta-1 and beta-2 adrenoceptors
Developmental expression of the GABAA receptor alpha 1 subunit mRNA in the rat brain
No full textRecent studies have suggested that the GABAA, receptor complex, the site of action of the inhibitory neurotransmitter gamma amino-butyric acid (GABAA) and the anxiolytic benzodiazepines, is heterogeneous. Moreover, its composition may change during development. To better understand the molecular basis of receptor heterogeneity, the levels and distribution of the mRNA encoding the alpha 1 receptor subunit were examined in the developing and adult rat brain with quantitative in situ hybridization histochemistry. Our studies demonstrate that alpha 1 subunit mRNA expression changes during ontogeny. At late embryonic stages and in the first postnatal week, low levels of the mRNA were detected in the cortex, inferior colliculus, and hippocampus. The mRNA levels in these regions increased during the second and third postnatal weeks. Furthermore, a dramatic change in the distribution of the alpha 1 subunit mRNA was seen in the second postnatal week when the message first became detectable in the cerebellar cortex. During subsequent development and in the mature brain, the alpha 1 subunit mRNA was most abundant in the cerebellum, olfactory bulb, and inferior colliculus, although the absolute levels of mRNA varied by as much as sixfold in selected brain regions. The mature distribution of alpha 1 subunit mRNA, along with its temporal appearance in the cerebellum, suggests that this subunit is a constituent of the Type 1 benzodiazepine site of the GABAA receptor complex. Furthermore, the onset of alpha 1 subunit mRNA expression in the cerebellar cortex coincides with a period of extensive synapse formation, raising the possibility that synaptic interactions modulate the appearance of this GABAA receptor subunit in the cerebellum
Editorial: Food and Its Effect on the Brain: From Physiological to Compulsive Consumption
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Reversal of stable behavioural modifications through NMDA receptor inhibition in rats
No full textIn order to study the effect of long-term dizocilpine infusion on memory, two different paradigms of stably modified behaviour were used in rats. The first was the escape deficits (ED) induced and maintained either by repeated daily administrations of SKF 38393, a rather selective D1 dopamine receptor agonist, or by repeated stress; the second was sensitisation to the effect of cocaine on motility. Fluoxetine (FLX), imipramine (IMI) and clomipramine (CMI) were equally effective in reversing the reduced reactivity of animals in both ED models. Dizocilpine showed a similar efficacy to that of classic antidepressants on the pharmacologically-induced ED, but failed to affect the stress-induced ED. In rats previously sensitised to cocaine and then infused with dizocilpine for 7 days after suspension of cocaine administration, the state of sensitisation, remained intact; however, in animals receiving dizocilpine plus a concomitant daily injection of cocaine, dizocilpine significantly reduced cocaine sensitisation. These results potentially suggest a new approach to the treatment of drug addiction and other psychiatric disorders. Finally, it was concluded that NMDA receptor blockade not only prevents, but also reverses many, if not all, learned behaviours, and that this phenomenon differs from the effect of antidepressants
Study of mirtazapine antidepressant effects in rats
No full textMirtazapine 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
GABAA receptor messenger RNA expression in the deep cerebellar nuclei of Purkinje cell degeneration mutants is maintained following the loss of innervating Purkinje neurons
No full textRecent studies have suggested that innervation modulates GABAA receptor gene expression in the rodent cerebellum. To examine this question, the expression and levels of GABAA receptor subunit messenger RNAs in the deep cerebellar nuclei of Purkinje cell degeneration mice and littermate controls were examined by quantitative in situ hybridization histochemistry. In the Purkinje cell degeneration mutant, the selective postnatal degeneration of Purkinje neurons disrupts GABAergic input from the cerebellar cortex to the deep nuclei. Despite this loss of Purkinje cells, virtually all large neurons of the deep cerebellar nuclei of Purkinje cell degeneration animals expressed the alpha 1, beta 2, and gamma 2 subunit messenger RNAs. These subunit messenger RNAs were observed at all experimental times from postnatal day 24 to postnatal day 90, a period ranging from the onset of behavioral abnormalities in the mutant to the completion of Purkinje cell loss. At no time were additional beta subunit messenger RNAs, normally absent from the deep cerebellar nuclei in control mice, detected in this region of the mutant. Quantitative analysis of the hybridization signals over individual neurons revealed that Purkinje cell loss differentially affected the expression of GABAA receptor subunit messenger RNAs. While the levels of the beta 2 and gamma 2 subunit messenger RNAs in individual neurons were comparable in mutants and controls at all ages, differences in alpha 1 subunit messenger RNA expression were observed. At postnatal day 24, the level of alpha 1 subunit mRNA in individual neurons of the mutant was only 60% that found in the control. At later stages (postnatal day 60 to postnatal day 90), the levels of alpha1 subunit messenger RNA expression increased in the mutant, and similar grain densities were detected over mutant and control neurons.
These studies demonstrate that Purkinje cell innervation is not required to maintain the expression of messenger RNAs encoding the alpha1, beta2 and gamma 2 GABAA receptor subunits in the deep cerebellar nuclei of the Purkinje cell degeneration mutant. However, Purkinje cell input appears to selectively modulate the level of the alpha1 subunit messenger RNA, suggesting that GABAA receptor genes are differentially regulated
Under continuous dizocilpine infusion an N-methyl-D-aspartate receptor independent form of cocaine sensitization develops in rats
No full textN-methyl-D-aspartate (NMDA) receptor blockade is thought to prevent the development of cocaine-induced sensitization. Moreover, when cocaine is administered daily along with dizocilpine infusion to previously sensitized rats, the extinction of sensitization occurs. We report here two sets of experiments: (1) Rats were infused with dizocilpine through a subcutaneous mini-pump (0.1 mg/kg/day) during the induction of cocaine sensitization and, after 2 or 7 days of wash-out, were challenged with: cocaine, dizocilpine plus cocaine or 3-((+/-)2-carboxypiperazin-4-yl)-propyl-L-phosphonic acid (CPP) plus cocaine. Cocaine induced stereotypy scores significantly lower than that produced by the two drug combinations. Animals infused with dizocilpine alone did not present stereotypies when challenged either with dizocilpine or with dizocilpine plus cocaine. (2) Rats previously sensitized to cocaine received dizocilpine by infusion and daily cocaine treatments for a week. During the first days of infusion, sensitization appeared to be significantly decreased, but it resumed the initial intensity on days 6-7. After 2 and 9 days of wash-out, the expression of sensitization could be retrieved only by dizocilpine plus cocaine. Two distinct forms of sensitization to cocaine thus seem to exist: one dependent on and the second independent of NMDA receptor activity
Desensitization of the D1 dopamine receptors in rats reproduces a model of escape deficit reverted by imipramine
No full textThe present study investigated the effect of long-term D1 dopamine receptor stimulation on an animal model of depression derived from the learned helplessness paradigm. 2. The model used is based on the escape deficit produced by a series of unavoidable shocks administered to rats 24 h before the test session. SKF 38393 administered acutely, completely prevented the development of animal hyporeactivity, while given repeatedly produced tolerance to its own protective effect. Moreover it also reduced the spontaneous escape reactivity of rats not exposed to the inescapable shocks. Animals chronically receiving SKF 38393 and showing a clearcut escape deficit, were treated daily with either imipramine, fluoxetine, or clomipramine. After 21 days of combined treatment the 3 antidepressants appeared equally effective in reverting the behavioral deficit. Moreover, long term administration of both imipramine or SKF 38393 down regulated D1 dopamine receptor number in the prefrontal cortex, while the association of the two drugs resulted in a receptor density similar to that of control rats. 3. The present results further support the crucial role played by D1 dopamine receptors in the control of animal reactivity to stressful stimuli and in the mechanism of action of imipramine. Moreover they show that the D1 dopamine receptor related escape deficit is sensitive also to compounds selectively acting through the serotonergic neuronal system
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