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

Experimental protocols for the study of stress in animals and humans.

1. 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

Efficacy in behavioural models of antidepressant activity.

Extracts of Hypericum perforatum have been tested in experimental models of depression in rodents and their efficacy in these models has been demonstrated after acute, subacute, or repeated administration. In order to identify the component responsible for this activity, extracts with different proportions of hyperforin, currently the most likely active antidepressant principle, have been tested. Different groups reported a correlation between efficacy in these models and the hyperforin content of the extract. Moreover, purified hyperforin is active at doses significantly lower than those necessary for observing an activity when the extract is used. In conclusion, we now have convincing experimental evidence of the efficacy of Hypericum perforatum extract in models of depression

Quantitative autoradiography of central beta adrenoceptor subtypes: comparison of the effects of chronic treatment with desipramine or centrally administered l-isoproterenol.

This 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

α-Methyl-para-tyrosine antagonizes the effect of chronic imipramine on learned helplessness in rats

alpha-Methyl-para-tyrosine, co-administered with imipramine to rats at a dose that only partially inhibits tyrosine hydroxylase, has been found to prevent completely the decrease of dopamine D1 receptor function. The present report shows that, in the same experimental conditions, alpha-methyl-para-tyrosine significantly antagonized the capacity of imipramine to prevent the development of learned helplessness behavior in rats. This suggests that a catecholaminergic mechanism is crucial in determining the effect of imipramine on the development of learned helplessness behavior. alpha-Methyl-para-tyrosine co-administration also prevented imipramine-induced down-regulation of beta-adrenoceptor function

Desensitization of the D1 dopamine receptors in rats reproduces a model of escape deficit reverted by imipramine

The 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

Region-specific expression of messenger RNAs encoding GABAA receptor subunits in the developing rat brain.

The distribution and levels of messenger RNAs encoding the alpha 1, beta 1, beta 2, beta 3, and gamma 2 subunits of the GABAA receptor in the developing and adult rat brain were investigated using quantitative in situ hybridization histochemistry and subunit-specific probes. Regional localization of the subunit messenger RNAs was determined with film autoradiography and expression in identified neuronal cell populations was examined using higher resolution techniques. Each of the GABAA receptor subunit messenger RNAs exhibits a distinct pattern of localization in the developing and adult brain. Of the subunits examined, the alpha 1, beta 2, and gamma 2 are the most abundant and are found in many brain regions, including the olfactory bulb, cortex, hippocampus, thalamic nuclei, and inferior colliculus. In addition, these subunit messenger RNAs are prominent in the cerebellum where virtually all cells of the deep cerebellar nuclei and Purkinje cell layer are labeled. The levels of most of the subunit messenger RNAs, with the exception of that encoding the beta 1 subunit, increase during postnatal development. While the alpha 1, beta 2, and gamma 2 subunit messenger RNAs rise in parallel in many regions and identified cell populations, different subsets of receptor subunit messenger RNAs are co-ordinately expressed at other sites. The greatest increases in subunit messenger RNA levels occur in the cerebellar cortex during the second postnatal week, a period coincident with cerebellar maturation. The co-distribution of different GABAA receptor subunit messenger RNAs in various regions of the developing and adult nervous systems supports the hypothesis that multiple receptor compositions exist. Moreover, that different subunit messenger RNAs exhibit coordinate changes in expression in different regions and cell populations suggests that receptor gene expression is modulated by cell type-specific signals. The temporal changes in subunit messenger RNA levels in the cerebellum raise the possibility that synaptogenesis may play a role in receptor gene regulation in this brain region