High Serotonin and 5‐Hydroxyindoleacetic Acid Levels in Limbic Brain Regions in a Rat Model of Depression; Normalization by Chronic Antidepressant Treatment

Zangen, Abraham; Overstreet, David H.; Yadid, Gal

doi:10.1046/j.1471-4159.1997.69062477.x

Cited by 161 publications

(92 citation statements)

References 40 publications

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“…The observation that lithium was without effect in this test does not obviate the validity of either the FSL rats as a model of depression or the validity of the swim test, as lithium treatment is essentially prophylactic and not antidepressant. Furthermore, increased levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) in limbic regions of FSL compared to the FRL strain are decreased by chronic treatment with antidepressants in FSL but not changed in FRL rats (Zangen et al 1997) which, conceivably, parallels the observed behavior in the swim test. Another characteristic of the FSL rats is that their bodyweight is reduced in comparison to FRL rats.…”

Section: Discussionmentioning

confidence: 79%

“…In the forced swim test, chronic treatment with imipramine, desipramine or sertraline, but not lithium, counteracted the exaggerated immobility of FSL rats, while no effect was observed in the FRL rats (Shiromani et al 1990;Schiller et al 1992;Overstreet 1993;Yadid et al 2000;Zangen et al 1997). The observation that lithium was without effect in this test does not obviate the validity of either the FSL rats as a model of depression or the validity of the swim test, as lithium treatment is essentially prophylactic and not antidepressant.…”

Section: Discussionmentioning

confidence: 88%

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Changed Concentrations of Tachykinins and Neuropeptide Y in Brain of a Rat Model of Depression Lithium Treatment Normalizes Tachykinins

Husum

Vasquez

Mathé

2001

Neuropsychopharmacology

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Lithium's therapeutic mechanism of action is unknown. In lithium-treated normal rats, increased striatal concentrations of neurokinin A (NKA)-like immunoreactivity (LI), substance P (SP-LI) and neuropeptide Y (NPY-LI) have been reported. To investigate whether these effects might be of therapeutic relevance, Flinders Sensitive Line rats (FSL),Lithium, reintroduced in psychiatry 50 years ago, is highly effective in the treatment of mania as well as long-term prophylaxis of bipolar disorder (Baastrup et al. 1970). Although the acute actions of lithium to reduce signaling through the phosphoinositol-protein kinase C and cyclic AMP protein kinase A second messenger systems are well documented (Mørk 1990; Lenox and Watson 1994; Manji and Lenox 1999; Manji et al. 1995 Manji et al. , 1999, the mechanisms underlying the mood-stabilizing actions of lithium have not been fully elucidated. Neurokinin A (NKA) and substance P (SP) belong to the tachykinin family of peptides which are widely distributed in the central nervous system. NKA and SP are generated by post-translational processes from tachykinin precursor proteins. These proteins are encoded by three types of tissue-specific mRNAs denoted ␣ , ␤ , and ␥ preprotachykinin (ppt) mRNA and are different splicing alternatives of the ppt-A gene (Nawa et al. 1983; Kotani et al. 1986; Krause et al. 1987). Changes in tachykinin neurotransmission have been proposed as a possible mechanism of action of lithium. Thus, subchronic lithium treatment was found to increase ppt mRNA and NKA-like immunoreactivity (LI) and SP-LI in striatum and frontal cortex of Fischer rats (Hong et al. 1983;Sivam et al. 1989). Previous work from our laboratory confirmed the findings that concentrations of NKA-LI and SP-LI increase in striatum following longterm lithium treatment, and extended them by showing, that concentrations of neuropeptide Y (NPY), and somatostatin, both immunoreactivity and -mRNA, and neurotensin-LI were also increased in striatum and other brain regions of Sprague-Dawley rats (Zachrisson et al. 1995;Mathé et al. 1990aMathé et al. , 1994 Jousisto-Hanson et al. 1994). It thus appears that several neuropeptide systems in various brain regions are affected by long-term lithium treatment. The observed changes may be related to the therapeutic actions of lithium or could be effects of lithium per se. The present study addresses this question by investigating the effects of chronic dietary lithium in an animal model of depression. The Flinders Sensitive Line (FSL) was established by selective breeding of Sprague-Dawley rats for high sensitivity to diisopropylfluorophosphate (DFP), an anticholinesterase agent (Overstreet et al. 1979). The FSL rats exhibit several features which resemble the symptom pattern of depression. These include reduced bodyweight, reduced locomotor activity, increased rapid eye movement (REM) sleep and cognitive deficits (Overstreet 1993;Yadid et al. 2000). Furthermore, exposure of FSL rats to chronic mild stress results in a state of "anhedonia," measured a...

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 88%

Changed Concentrations of Tachykinins and Neuropeptide Y in Brain of a Rat Model of Depression Lithium Treatment Normalizes Tachykinins

Husum

Vasquez

Mathé

2001

Neuropsychopharmacology

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“…The content of monoamines in the limbic regions of FSL rats is not affected by repeated exogenously applied DHEA (unpublished findings, R Genud and G Yadid) in contrast to treatment with conservative anti-depressants (Overstreet et al, 2005;Zangen et al, 1997), which further suggests that DHEA may affect depressive behavior differently than the established mechanism for antidepressants (Shapira et al, 1994).…”

Section: Discussionmentioning

confidence: 97%

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

Genud

Merenlender

Gispan-Herman

et al. 2008

Neuropsychopharmacol

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Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate g-aminobutyric-acid-type-A (GABA A R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (s1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitiveline (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the d-subunit of GABA A , but not of s1R mRNA, in FSL rats compared to SD rats. The d-subunit controls the sensitivity of the GABA A R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA A agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA A ), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA A Rs in the NAc and VTA.

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“…Rats were decapitated 24 h after last behavior analysis and their brains were removed rapidly. Serial 0.5 mm sections were cut and tissue punches of the basolateral amygdala, CA1 of the Hippocampus, as previous described, 31 were frozen at À70 1C until extraction.…”

Section: Behavioral Data Analysismentioning

confidence: 99%

WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model

et al. 2007

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Post-traumatic stress disorder (PTSD) is an anxiety disorder that may develop after the experiencing or witnessing of a life-threatening event. PTSD is defined by the coexistence of three clusters of symptoms: re-experiencing, avoidance and hyperarousal, which persist for at least 1 month in survivors of the event (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). Using an established model of PTSD, we addressed the well-accepted clinical finding that only a minority (about 20%) of the individuals exposed to a traumatic event develop PTSD. Moreover, we followed individual rat behavior for up to a month, and then treated the PTSD-like animals with citalopram. Our data demonstrate high face (20% of rats exposed to a reminder of the stressor develop symptoms characteristic of PTSD) and predictive (response to citalopram) validities. Based on these validities we identified alterations in the Wolframin gene in the CA1 and amygdala regions, specifically in exposed PTSD-like rats, which were normalized after treatment with citalopram. We suggest the Wolframin gene as a putative biomarker for PTSD. Since Wolframin gene undergoes alternative splicing and has polymorphism in the population, it may serve a future marker for identification of the vulnerable population exposed to a traumatic event.

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High Serotonin and 5‐Hydroxyindoleacetic Acid Levels in Limbic Brain Regions in a Rat Model of Depression; Normalization by Chronic Antidepressant Treatment

Cited by 161 publications

References 40 publications

Changed Concentrations of Tachykinins and Neuropeptide Y in Brain of a Rat Model of Depression Lithium Treatment Normalizes Tachykinins

Changed Concentrations of Tachykinins and Neuropeptide Y in Brain of a Rat Model of Depression Lithium Treatment Normalizes Tachykinins

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model

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