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

Abstract

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...

Topiramate Normalizes Hippocampal NPY-LI in Flinders Sensitive Line ‘Depressed’ Rats and Upregulates NPY, Galanin, and CRH-LI in the Hypothalamus: Implications for Mood-Stabilizing and Weight Loss-Inducing Effects

“…One phenotypic trait of the FSL rat is that it displays increased immobility in the forced swim test, which can be reversed by chronic but not acute antidepressant treatment (Yadid et al, 2000;Overstreet, 1993;Schiller et al, 1992). In the present study, hippocampal NPY-LI concentrations were significantly lower in FSL 'depressed' rats compared to FRL control rats, in agreement with previous findings (Jiménez Vasquez et al, 2000;Husum et al, 2001). Interestingly, Fawn Hooded rats, another genetic model of depression, also have reduced hippocampal concentrations of NPY-LI (Mathé et al, 1998).…”

“…In addition, FSL rats display reduced body weight, reduced locomotor activity, increased rapid eye movement (REM) sleep, cognitive deficits, and anhedonia in response to chronic mild stress (Yadid et al, 2000;Overstreet, 1993;Pucilowski et al, 1993), features that show resemblance to the symptom pattern of depression. We have previously shown that levels of neuropeptide Y (NPY), a highly conserved 36 amino-acid neuropeptide that is abundantly distributed in mammalian brain (Tatemoto et al, 1982), are reduced in the hippocampus of FSL rats (Husum et al, 2001;Jiménez Vasquez et al, 2000). Furthermore, in rodents and mice, exogenous NPY exerts antidepressant-like activity and modulates anxiety and stress behavior (Redrobe et al, 2002;Stogner and Holmes, 2000;Thorsell et al, 2000;Husum et al, 2000;Heilig et al, 1989).…”

Complex Biphasic Changes of Neuropeptide Concentrations in the Rat Limbic System During Pregnancy and Parturition~!2009-10-10~!2010-03-14~!2010-06-25~!

“…SP-LI in striatum has been found to be markedly changed in an animal model of depression [32]. In contrast, we found a significant decrease of NPY-LI in striatum, 16% lower postpartum than during pregnancy.…”

“…This peptide has been shown to be implicated in depressivelike behavior -evidence that comes from -amongst others [32,33] -the findings of differential NPY expression in a genetic animal model of depression [34].…”

Running has Differential Effects on NPY, Opiates, and Cell Proliferation in an Animal Model of Depression and Controls

“…Selective breeding of SpragueDawley (SD) rats with regard to their response to the anticholinesterase agent diisopropylfluorophosphate (DFP) (Overstreet et al, 1979;Russell et al, 1982) generated a sensitive (FSL) and a resistant strain (FRL). Subsequently, it was realized that FSL exhibits a phenotype that mimics a number of symptoms seen in human depression (Husum et al, 2001;Overstreet, 1993;Pucilowski et al, 1993). The FSL strain shows good face and predictive validity as a model of depression and in assessment of antidepressant treatments (Overstreet, 1993(Overstreet, , 1995.…”