Journal ArticleDOI
Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats
Stephen D. Mague,Andrea M. Pliakas,Mark S. Todtenkopf,Hilarie C. Tomasiewicz,Yan Zhang,William C. Stevens,Robert M. Jones,Philip S. Portoghese,William A. Carlezon,William A. Carlezon +9 more
TLDR
Findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc “triggers” immobility behavior in the FST and raise the possibility that κ-antagonists may have efficacy as antidepressants, but lack stimulant or reward-related effects.Abstract:
We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at kappa-opioid receptors) in NAc neurons, these findings raised the possibility that kappa-receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the kappa-antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at kappa-receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar kappa-antagonists: 5'-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5'-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the kappa-antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the kappa-agonist [5alpha,7alpha,8beta]-N-methyl-N-[7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl]-benzenacetamide (U-69593) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the kappa-ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective kappa-antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc "triggers" immobility behavior in the FST. Furthermore, they raise the possibility that kappa-antagonists may have efficacy as antidepressants, but lack stimulant or reward-related effects.read more
Citations
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Journal ArticleDOI
The Mesolimbic Dopamine Reward Circuit in Depression
TL;DR: It is proposed that the NAc and VTA contribute importantly to the pathophysiology and symptomatology of depression and may even be involved in its etiology.
Journal ArticleDOI
New approaches to antidepressant drug discovery: beyond monoamines
Olivier Berton,Eric J. Nestler +1 more
TL;DR: A recent review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies as discussed by the authors.
Journal Article
New approaches to antidepressant drug discovery : beyond monoamines
Olivier Berton,Eric J. Nestler +1 more
TL;DR: This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies.
Journal ArticleDOI
The many faces of CREB
TL;DR: Emerging evidence suggests that strategies that exploit regional differences in upstream factors or that target specific CREB-regulated genes, rather than CREB itself, could make a promising contribution to the treatment of neuropsychiatric conditions.
Journal ArticleDOI
Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test.
TL;DR: A physiological model of performance in the rat FST has been proposed involving the regulation of 5-HT transmission by corticotropin releasing factor (CRF), which is based on extensive evaluation of agonists and antagonists of individual 5- HT receptor subtypes.
References
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Book
The Rat Brain in Stereotaxic Coordinates
George Paxinos,Charles Watson +1 more
TL;DR: This paper presents a meta-analyses of the determinants of earthquake-triggered landsliding in the Czech Republic over a period of 18 months in order to establish a probabilistic framework for estimating the intensity of the earthquake.
Journal ArticleDOI
Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.
G. Di Chiara,Assunta Imperato +1 more
TL;DR: The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis as mentioned in this paper.
Journal ArticleDOI
Depression: a new animal model sensitive to antidepressant treatments
R D Porsolt,M Le Pichon,M Jalfre +2 more
TL;DR: Results presented below indicate that immobility is reduced by different treatments known to be therapeutic in depression including three drugs, iprindole, mianserin and viloxazine which although clinically active show little or no ‘antidepressant’ activity in the usual animal tests.
Journal ArticleDOI
Neurobiology of depression.
Eric J. Nestler,Michel Barrot,Ralph J. DiLeone,Amelia J. Eisch,Stephen J. Gold,Lisa M. Monteggia +5 more
TL;DR: A neurobiologic understanding of depression also requires identification of the genes that make individuals vulnerable or resistant to the syndrome, and advances will fundamentally improve the treatment and prevention of depression.
Journal ArticleDOI
The rat brain in stereotaxic coordinates (2nd edn): by George Paxinos and Charles Watson, Academic Press, 1986. £40.00/$80.00 (264 pages) ISBN 012 547 6213
TL;DR: The second editon of Paxinos and Watson's rat stereotaxic atlas is, like the first, an indispensable commodity for neuroscientists utilizing rodent models for research as well as for students learning basic fundamentals of rat brain neuroanatomy.