An enriched environment restores normal behavior while providing cytoskeletal restoration and synaptic changes in the hippocampus of rats exposed to an experimental model of depression.

The exposure of rats to an enriched environment (EE) has several effects in common with the administration of antidepressants. However, there is still little information about the molecular underpinnings of these effects on rats subjected to experimental models of depression. The aim of this research was to evaluate the effects of EE on rats exposed to the learned helplessness paradigm (LH), a well-known model of the disease. We found that a 21 day exposure to EE reverts helplessness behavior to normal in LH animals. Inmunohistochemical labeling showed that this effect was accompanied by normalization of two structural proteins of hippocampal neurons to control values: the light neurofilament subunit (NFL) and the postsynaptic density 95 (PSD-95) protein, which were decreased in LH animals housed in standard cages. The decrease in the presynaptic protein synaptophysin (SYN) observed in LH animals remained unchanged after exposure to EE. There was no increase in neurogenesis as measured by quantification of double-labeled cells with 5-bromo-2'-deoxyuridine (BrdU) and the neuronal marker beta-tubulin class III. These results show that EE may have behavioral and synaptic effects on animals exposed to an experimental model of depression, and that such actions seem to be independent from neurogenesis.

Neuronal cytoskeletal alterations in an experimental model of depression.

It has been proposed that depression is associated with hippocampal morphological changes. The apical dendrite atrophy of hippocampal CA3 pyramidal neurons has been described in experimental models of depression. The aim of the present study was to determine which cytoskeletal components are involved in the morphological changes previously described in the hippocampus of depressed animals. The expression of different neuronal cytoskeletal markers was analyzed by immunohistochemistry in rats exposed to a learned helplessness paradigm, an experimental model of depression. Rats were trained with 60 inescapable foot shocks (0.6 mA/15 s) and escape latencies and failures were tested 4 days after training. Animals in which learned helplessness behavior persisted for 21 days were included in the depressed group. No foot shocks were delivered to control rats. Microtubule-associated protein 2 (MAP-2) and light (NFL; 68 kDa), medium (NFM; 160 kDa) and heavy (NFH; 200 kDa) neurofilament subunit immunostainings were analyzed employing morphometric parameters. In the depressed group, NFL immunostaining decreased 55% (P<0.05) and 60% (P<0.001) in CA3 and dentate gyrus, respectively. In the same areas, MAP-2, NFM and NFH immunostainings did not differ between depressed and control animals. Since NFL is present in the core of mature neurofilament, it is proposed that hippocampal depression-associated plastic alterations may be due to changes in the dynamics of the neurofilament assembly.

[Glutamatergic neurotransmission, depression and antidepressants]. / Neurotransmisión glutamatérgica, depresión y antidepresivos.

Depression is a psychiatric disorder that affects 20% of the population. Despite the efforts aimed to identify the mechanisms underlying its behavioral and affective symptoms, no consensus has been reached. In the last years two new theories, the glutamatergic and the genomic ones, have been proposed. Upon the first, the exposition to stressful stimuli increases hippocampal glutamatergic neurotransmission and triggers excitotoxic changes. The second one postulates that depression is closely correlated with neuronal atrophy due to a decrease in BDNF. The aim of this work is to review recent findings about the glutamatergic neurotransmission and its implication in animal models of depression, depressed patients and in both conditions after the antidepressant treatment. We also tried to identify possible links between these observations and the genomic theory.

Neurotransmisión glutamatérgica, depresión y antidepresivos. / [Glutamatergic neurotransmission, depression and antidepressants]

Depression is a psychiatric disorder that affects 20

of the population. Despite the efforts aimed to identify the mechanisms underlying its behavioral and affective symptoms, no consensus has been reached. In the last years two new theories, the glutamatergic and the genomic ones, have been proposed. Upon the first, the exposition to stressful stimuli increases hippocampal glutamatergic neurotransmission and triggers excitotoxic changes. The second one postulates that depression is closely correlated with neuronal atrophy due to a decrease in BDNF. The aim of this work is to review recent findings about the glutamatergic neurotransmission and its implication in animal models of depression, depressed patients and in both conditions after the antidepressant treatment. We also tried to identify possible links between these observations and the genomic theory.

Neurotransmisión glutamatérgica, depresión y antidepresivos / [Glutamatergic neurotransmission, depression and antidepressants]

Depression is a psychiatric disorder that affects 20

of the population. Despite the efforts aimed to identify the mechanisms underlying its behavioral and affective symptoms, no consensus has been reached. In the last years two new theories, the glutamatergic and the genomic ones, have been proposed. Upon the first, the exposition to stressful stimuli increases hippocampal glutamatergic neurotransmission and triggers excitotoxic changes. The second one postulates that depression is closely correlated with neuronal atrophy due to a decrease in BDNF. The aim of this work is to review recent findings about the glutamatergic neurotransmission and its implication in animal models of depression, depressed patients and in both conditions after the antidepressant treatment. We also tried to identify possible links between these observations and the genomic theory.

[New perspectives of the mechanism of action of antidepressants arised from genomic theory of depression]. / El mecanismo de acción de los antidepresivos a la luz de la teoría genómica de la depresión.

Depression is a highly prevalent condition in adult population. Research on the mechanism of action of antidepressant drugs is also expected to allow a better comprehension about its etiopathogenesis. First theories about neurobiology of depression pointed out the monoaminergic modifications elicited by antidepressants. However, these changes could not be correlated with the latency of action observed in their clinical use. In 1997, with the formulation of genomic theory of depression, old theories and new knowledge about cellular and molecular effects of antidepressant treatment became congruent. The main goal of this paper is to review this theory and the scientific papers in which it is supported. Scientific evidences against genomic theory of antidepressant action are also mentioned. CREB's participation in antidepressant response, as well as BDNF trophic effect and their intracellular signaling pathways are described, as many of these molecules could become targets for the action of new antidepressants.

Adaptive changes in the rat hippocampal glutamatergic neurotransmission are observed during long-term treatment with lorazepam.

RATIONALE: Chronic treatment with benzodiazepines induces tolerance to most of their pharmacological effects. The best-studied neurochemical correlation to this phenomenon involves GABAergic adaptive changes. However, some compensation by excitatory neurotransmission could also be postulated. OBJECTIVE: The aim of this work was to investigate the effect of chronic treatment with benzodiazepines on several parameters of hippocampal glutamatergic neurotransmission. METHODS: Rats were injected (IP) with a single dose or daily doses (21 days) of 1 mg/kg lorazepam (LZ) or vehicle. Thirty minutes after the last dose, animals were killed and parameters were measured in the dissected hippocampi. We determined one presynaptic parameter, in vitro glutamate release induced by a 60 mM K(+) stimulus. [(3)H]MK-801 binding to postsynaptic NMDA receptors and the NMDA-stimulated efflux of cGMP were also evaluated. RESULTS: While no changes were observed in any of the parameters after a single dose of the drug, we found an increase of 206% in in vitro glutamate release in chronically treated animals [two-way ANOVA: F(1,16)=6.22], together with an increment of 103% in the NMDA-stimulated cGMP efflux [two-way ANOVA: F(1,18)=14.05]. No changes either in K(D) or in B(max) values for [(3)H]MK-801 binding to hippocampal membranes were observed. CONCLUSIONS: Taken together, these changes strongly suggest that a compensatory increase in the glutamatergic response develops in the hippocampus during chronic treatment with LZ. Our findings might indicate a contribution of glutamatergic mechanisms to the tolerance to hippocampal-mediated effects of LZ, such as amnesic and anticonvulsant activities.

El mecanismo de acción de los antidepresivos a la luz de la teoría genómica de la depresión. / [New perspectives of the mechanism of action of antidepressants arised from genomic theory of depression]

Depression is a highly prevalent condition in adult population. Research on the mechanism of action of antidepressant drugs is also expected to allow a better comprehension about its etiopathogenesis. First theories about neurobiology of depression pointed out the monoaminergic modifications elicited by antidepressants. However, these changes could not be correlated with the latency of action observed in their clinical use. In 1997, with the formulation of genomic theory of depression, old theories and new knowledge about cellular and molecular effects of antidepressant treatment became congruent. The main goal of this paper is to review this theory and the scientific papers in which it is supported. Scientific evidences against genomic theory of antidepressant action are also mentioned. CREBs participation in antidepressant response, as well as BDNF trophic effect and their intracellular signaling pathways are described, as many of these molecules could become targets for the action of new antidepressants.

El mecanismo de acción de los antidepresivos a la luz de la teoría genómica de la depresión / [New perspectives of the mechanism of action of antidepressants arised from genomic theory of depression]

Depression is a highly prevalent condition in adult population. Research on the mechanism of action of antidepressant drugs is also expected to allow a better comprehension about its etiopathogenesis. First theories about neurobiology of depression pointed out the monoaminergic modifications elicited by antidepressants. However, these changes could not be correlated with the latency of action observed in their clinical use. In 1997, with the formulation of genomic theory of depression, old theories and new knowledge about cellular and molecular effects of antidepressant treatment became congruent. The main goal of this paper is to review this theory and the scientific papers in which it is supported. Scientific evidences against genomic theory of antidepressant action are also mentioned. CREB’s participation in antidepressant response, as well as BDNF trophic effect and their intracellular signaling pathways are described, as many of these molecules could become targets for the action of new antidepressants.