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ABSTRACT: Neuropeptide Y (NPY) has been implicated in anxiolytic- and antidepressant-like behaviour as well as seizure-suppressant effects in rodents. Although these effects appear to be predominantly mediated via other NPY receptors (Y1 and/or Y2), several studies have also indicated a role for Y5 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY, Y1 or Y2 receptors in the hippocampus or amygdala has previously been shown to modulate emotional behaviour and seizures in rodents. The present study explored the potential effects of gene therapy with the Y5 receptor, by testing effects of recombinant adeno-associated viral vector (rAAV) encoding Y5 (rAAV-Y5) in anxiety- and depression-like behaviour as well as in kainate-induced seizures in adult mice. The rAAV-Y5 vector injected into the hippocampus and amygdala induced a pronounced and sustained increase in Y5 receptor mRNA expression and functional Y5 receptor binding, but no significant effects were found with regard to anxiety- and depression-like behaviours or seizure susceptibility. Instead, rAAV-mediated Y5 receptor transgene overexpression resulted in moderate hyperactivity in the open field test. These results do not support a potential role for single transgene overexpression of Y5 receptors for modulating anxiety-/depression-like behaviours or seizures in adult mice. Whether the induction of hyperactivity by rAAV-Y5 could be relevant for other conditions remains to be studied.
Neuropeptides 02/2012; 46(2):71-9. · 1.55 Impact Factor
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ABSTRACT: Neuropeptide Y (NPY) exerts anxiolytic- and antidepressant-like effects in rodents that appear to be mediated via Y1 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY in the hippocampus or amygdala has previously been shown to confer anxiolytic-like effect in rodents. The present study explored an alternative and more specific approach: overexpression of Y1 receptors. Using a recombinant adeno-associated viral vector (rAAV) encoding the Y1 gene (rAAV-Y1), we, for the first time, induced overexpression of functional transgene Y1 receptors in the hippocampus of adult mice and tested the animals in anxiety- and depression-like behavior. Hippocampal Y1 receptors have been suggested to mediate seizure-promoting effect, so the effects of rAAV-induced Y1 receptor overexpression were also tested in kainate-induced seizures. Y1 receptor transgene overexpression was found to be associated with modest anxiolytic-like effect in the open field and elevated plus maze tests, but no effect was seen on depression-like behavior using the tail suspension and forced swim tests. However, the rAAV-Y1 vector modestly aggravated kainate-induced seizures. These data indicate that rAAV-induced overexpression of Y1 receptors in the hippocampus could confer anxiolytic-like effect accompanied by a moderate proconvulsant adverse effect. Further studies are clearly needed to determine whether Y1 gene therapy might have a future role in the treatment of anxiety disorders.
Journal of Neuroscience Research 02/2012; 90(2):498-507. · 2.74 Impact Factor
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ABSTRACT: Inflammation is an important hallmark of all neurodegenerative diseases and activation of different glial populations may be involved in the progression of some of these disorders. Especially, the activation of astroglia can lead to long-term detrimental morphological changes, such as scar formation. Therefore, improved strategies to modulate inflammation in these cells are currently being investigated. We investigated the interaction of phosphodiesterase (PDE) 4 inhibitors, such as rolipram, with other agents raising cellular cAMP levels. When used alone, none of the PDE4 inhibitors increased cAMP levels. The adenylate cyclase activator forskolin, the β(2)-adrenergic agonist clenbuterol and the mixed β(1)/β(2)-adrenergic agonist isoproterenol increased intracellular cAMP levels of cortical murine astrocytes. This increase was synergistically elevated by rolipram or the PDE4 inhibitor RO-201724, but not by inhibition of PDE3. Inflammatory stimulation of the cells with the cytokines TNF-α, IL-1β and IFN-γ strongly induced PDE4B and augmented overall PDE4 activity, while PDE3 activity was low. Clenbuterol and forskolin caused downregulation of cytokines and chemokines such as IL-6 and MCP-1. This effect was further enhanced by rolipram, but not by the PDE3 inhibitor milrinone. The cAMP-raising drug combinations attenuated the upregulation of TNF-α and IL-6 mRNA and the secretion of IL-6, but did not affect initial NF-κB signalling triggered by the stimulating cytokines. These results indicate that PDE4 may be a valuable anti-inflammatory target in brain diseases, especially under conditions associated with stimulation of cAMP-augmenting astrocyte receptors as is observed by clenbuterol treatment.
Neurochemistry International 08/2011; 59(6):837-46. · 2.86 Impact Factor
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S H Christiansen
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ABSTRACT: Induction of seizures by electroconvulsive stimulation (ECS) is amongst the most efficacious treatments for major depression. However, the working mechanism by which ECS exerts its antidepressant effects remains elusive. The galanin system is regulated by ECS in seizure-prone brain regions and has been shown to modulate depression-like behaviour. To further explore its potential role in the antidepressant effects of ECS the galanin system was investigated by in situ hybridisation and [(125)I]-galanin receptor binding during repeated ECS in the locus coeruleus, dorsal raphe and discrete nuclei of the hypothalamus. Adult mice were treated with ECS once daily for 14 consecutive days, a paradigm previously shown to exert antidepressant-like effects. Significant increases in galanin transcription were found in the locus coeruleus and dorsomedial nuclei of the hypothalamus. In addition, GalR2 mRNA levels in the ventro- and dorsomedial nuclei of the hypothalamus were upregulated whereas no GalR1 mRNA upregulation was observed. [(125)I]-galanin receptor binding was downregulated in the ventromedial nuclei of the hypothalamus and dorsal raphe. These data show that the galanin system is regulated by repeated ECS in brain regions involved in monoaminergic neurotransmission and stress modulation thus indicating a possible role of the galanin system in the therapeutic effects of ECS.
Neuropeptides 08/2011; 45(5):337-41. · 1.55 Impact Factor
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ABSTRACT: Stressful life events and chronic stress are implicated in the development of depressive disorder in humans. Neuropeptide Y (NPY) and galanin have been shown to modulate the stress response, and exert antidepressant-like effects in rodents. To further investigate these neuropeptides in depression-like behaviour, NPY and galanin gene expression was studied in brains of mice subjected to chronic restraint stress (CRS) and concomitant treatment with the antidepressant fluoxetine (FLX). CRS caused a significant increase in depression-like behaviour that was associated with increased NPY mRNA levels in the medial amygdala. Concomitant FLX treatment reverted depression-like effects of CRS and led to significant increases in levels of NPY and galanin mRNA in the dentate gyrus, amygdala, and piriform cortex. These findings suggest that effects on NPY and galanin gene expression could play a role in the antidepressant effects of FLX.
Behavioural brain research 01/2011; 216(2):585-91. · 3.22 Impact Factor
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ABSTRACT: Even though induction of seizures by electroconvulsive stimulation (ECS) is a treatment widely used for major depression in humans, the working mechanism of ECS remains uncertain. The antiepileptic effect of ECS has been suggested to be involved in mediating the therapeutic effect of ECS. The neuropeptide galanin exerts antiepileptic and antidepressant-like effects and has also been implicated in the pathophysiology of depression. To explore a potential role of galanin in working mechanisms of ECS, the present study examined effects of repeated ECS on the galanin system using QRT-PCR, in situ hybridization, and [(125) I]galanin receptor binding. ECS was administered to adult mice daily for 14 days, and this paradigm was confirmed to exert antidepressant-like effect in the tail suspension test. Prominent increases in galanin gene expression were found in several brain regions involved in regulation of epileptic activity and depression, including the piriform cortex, hippocampal dentate gyrus, and amygdala. Likewise, GalR2 gene expression was up-regulated in both the central and the medial amygdala, whereas GalR1 gene expression showed a modest down-regulation in the medial amygdala. [(125) I]galanin receptor binding in the piriform cortex, hippocampus, and amygdala was found to be significantly down-regulated. These data show that the galanin system is regulated by repeated ECS in a number of brain regions implicated in seizure regulation and depression. These changes may play a role in the therapeutic effect of ECS.
Journal of Neuroscience Research 10/2010; 88(16):3635-43. · 2.74 Impact Factor
