Acute stress differentially affects corticotropin-releasing hormone mRNA expression in the central amygdala of the "depressed" flinders sensitive line and the control flinders resistant line rats.

Preclinical and clinical evidence suggests that neuropeptides play a role in the pathophysiology of mood disorders. In the present study, we investigated the involvement of the peptides corticotropin-releasing hormone (CRH), neuropeptide Y (NPY) and nociceptin/orphanin FQ (N/OFQ) and of their receptors in the regulation of emotional behaviours. In situ hybridization experiments were performed in order to evaluate the mRNA expression levels of these neuropeptidergic systems in limbic and limbic-related brain regions of the Flinders Sensitive Line (FSL) rats, a putative genetic animal model of depression. The FSL and their controls, the Flinders Resistant Line (FRL) rats, were subjected to one hour acute restraint and the effects of the stress exposure, including possible strain specific changes on these neuropeptidergic systems, were studied. In basal conditions, no significant differences between FSL and FRL rats in the CRH mRNA expression were found, however an upregulation of the CRH mRNA hybridization signal was detected in the central amygdala of the stressed FRL, compared to the non stressed FRL rats, but not in the FSL, suggesting a hypoactive mechanism of response to stressful stimuli in the "depressed" FSL rats. Baseline levels of NPY and N/OFQ mRNA were lower in the FSL rats compared to the FRL in the dentate gyrus of hippocampus and in the medial amygdala, respectively. However, the exposure to stress induced a significant upregulation of the N/OFQ mRNA levels in the paraventricular thalamic nucleus, while in the same nucleus the N/OFQ receptor mRNA expression was higher in the FSL rats. In conclusion, selective alterations of the NPY and N/OFQ mRNA in limbic and limbic-related regions of the FSL rats, a putative animal model of depression, provide further support for the involvement of these neuropeptides in depressive disorders. Moreover, the lack of CRH activation following stress in the "depressed" FSL rats suggests a form of allostatic load, that could alter their interpretation of environmental stimuli and influence their behavioural response to stressful situations.

Search for biological correlates of depression and mechanisms of action of antidepressant treatment modalities. Do neuropeptides play a role?

Dysregulation of the monoaminergic systems is likely a sufficient but not a necessary cause of depression. A wealth of data indicates that neuropeptides, e.g., NPY, CRH, somatostatin, tachykinins and CGRP play a role in affective disorders and alcohol use/abuse. This paper focuses on NPY in etiology and pathophysiology of depression. Decreased peptide and mRNA NPY were found in hippocampus of both the genetic, e.g., the FSL strain, and environmental rat models of depression, e.g., chronic mild stress and early life maternal separation paradigms. Rat models of alcoholism also show altered NPY. Furthermore, NPY is also reduced in CSF of depressed patients. Antidepressive treatments tested so far (lithium, topiramate, SSRIs, ECT and ECS, wheel running) increase NPY selectively in rat hippocampus and in human CSF. Moreover, NPY given icv to rat has antidepressive effects which are antagonized by NPY-Y1 blockers. The data support our hypothesis that the NPY system dysregulation constitutes one of the biological underpinnings of depression and that one common mechanism of action of antidepressive treatment modalities may be effects on NPY and its receptors. In a novel paradigm, early life maternal separation was superimposed on "depressed" FSL and control rats and behavioral and brain neurochemistry changes observed in adulthood. The consequences were more deleterious in genetically vulnerable FSL. Early antidepressive treatment modulated the adult sequelae. Consequently, if these data are confirmed, the ethical and medical question that will be asked is whether it is permissible and advisable to consider prophylactically treating persons at risk.

Electroconvulsive stimuli selectively affect behavior and neuropeptide Y (NPY) and NPY Y(1) receptor gene expressions in hippocampus and hypothalamus of Flinders Sensitive Line rat model of depression.

Previously we reported that basal neuropeptide Y (NPY)-like immunoreactivity-(LI) in hippocampus of the "depressed" Flinders Sensitive Line (FSL) rats was lower compared to the control Flinders Resistant Line (FRL) and that electroconvulsive stimuli (ECS) raise NPY-LI in discrete brain regions. Here we studied NPY mRNA expression, NPY Y(1) receptor (Y(1)) mRNA expression and binding sites, and behavior under basal conditions (Sham) and after repeated ECS. Baseline NPY and Y(1) mRNAs in the CA1-2 regions and dentate gyrus were lower while the Y(1) binding was higher in the FSL. ECS had larger effects on both NPY and behavior in the FSL rats. ECS increased NPY mRNA in the CA1-2, dentate gyrus and hypothalamus in FSL, but only in the dentate gyrus in FRL. ECS also increased Y(1) mRNA in the CA1-2, dentate gyrus and the parietal cortex in both strains, while in the hypothalamus the increase was observed only in the FSL rats. Consistently with Y(1) mRNA increase, Y(1) binding was downregulated in the corresponding regions. ECS decreased FSL immobility in the Porsolt swim test. These findings suggest that NPY is involved in depressive disorder and that antidepressant effects of ECS may in part be mediated through NPY.

Effect of ethanol on brain neuropeptides in adolescent and adult rats.

OBJECTIVE: Alcohol misuse early in life is associated with an increased risk of alcoholism. It is possible that this increased risk in adolescent drinkers is in part related to the susceptibility of the adolescent brain to ethanol. This study assessed the effects of ethanol exposure on several neuropeptides to begin to elucidate potential substrates that could mediate the differential effects of ethanol on adolescent and adult rats. METHOD: Male Sprague Dawley rats were exposed to ethanol vapor or air during adolescence (30 days old, n = 9, controls = 8) or adulthood (80-90 days old, n = 9, controls = 8) for 10 days. Blood alcohol concentrations averaging 250 mg/dl were maintained during this period. After 7 weeks of cessation from ethanol vapor, brain tissue was collected from the frontal cortex, caudate, hippocampus, amygdala and hypothalamus to assess the immunoreactivity levels of neuropeptide Y (NPY-LI), corticotropin-releasing hormone, substance P (SP-LI) and neurokinins (NK-LI). RESULTS: Ethanol exposure decreased overall hippocampal NPY-LI and increased SP-LI and NK-LI in the caudate, but these effects were more prominent in adult rats. Rats in the adult treatment groups (both ethanol exposed and controls) also had significantly lower levels of frontal cortical NK-LI, frontal cortical SP-LI and hypothalamic SP-LI relative to rats in the adolescent treatment groups. CONCLUSIONS: These data indicate that brief exposure to alcohol has long-term effects on levels of NPY-LI, SP-LI and NK-LI. As these effects were primarily the result of changes in rats exposed to ethanol during adulthood, however, they are unlikely to contribute to the increased susceptibility of adolescents to the effects of chronic ethanol exposure.

Stereoselective metabolism of citalopram in plasma and cerebrospinal fluid of depressive patients: relationship with 5-HIAA in CSF and clinical response.

Plasma and cerebrospinal fluid (CSF) concentrations of the enantiomers of citalopram (CIT), its N-demethylated metabolite demethylcitalopram (DCIT) and its deaminated metabolite citalopram propionic acid derivative (CIT-PROP) were measured in plasma and CSF in 22 depressed patients after a 4-week treatment with 40 mg/d citalopram, which was preceded by a 1-week washout period. CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured at baseline and after the 4-week CIT medication period. Patients were assessed clinically, using the Hamilton Depression Rating Scale (21-item HAM-D): at baseline and then at weekly intervals. CSF concentrations of S-CIT and R-CIT were 10.6 +/- 4.3 and 20.9 +/- 6 ng/mL, respectively, and their CSF/plasma ratios were 52% +/- 9% and 48% +/- 6%, respectively. The CIT treatment resulted in a significant decrease (28%) of 5-HIAA (P < 0.0001) and a significant increase (41%) of HVA in the CSF. Multiple linear regression analyses were performed to identify the impact of plasma and CSF CIT enantiomers and its metabolites on CSF monoamine metabolites and clinical response. There were 10 responders as defined by a > or =50% decrease of the HAM-D score (DeltaHAM-D) after the 4-week treatment. DeltaHAM-D correlated (Spearman) significantly with CSF S-CIT (r = - 0.483, P < 0.05), CSF S-CIT-PROP (r = -0.543, P = 0.01) (a metabolite formed from CIT by monoamine oxidase [MAO]) and 5-HIAA decrease (Delta5-HIAA) (r = 0.572, P = 0.01). The demonstrated correlations between pharmacokinetic parameters and the clinical outcome as well as 5-HIAA changes indicate that monitoring of plasma S-CIT, CSF S-CIT and CSF S-CIT-PROP may be of clinical relevance.

Lithium treatment alters brain concentrations of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in a rat model of depression.

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are proteins involved in neuronal survival and plasticity of dopaminergic, cholinergic and serotonergic neurons in the central nervous system. Since decreased size and impaired function of some neuronal populations may be relevant in depression it has been hypothesized that these molecules may have a functional role in the pathophysiology as well as treatment of depression. Using an animal model of depression, the Flinders Sensitive Line (FSL) rats and their controls, the Flinders Resistant Line (FRL), we investigated the effects of chronic lithium treatment on brain NGF, BDNF and GDNF. Lithium was administered as food supplementation during 6 wk. NGF, BDNF and GDNF measurements were performed by enzyme-linked immunosorbent assay (ELISA). Lithium altered the brain concentrations of neurotrophic factors in the hippocampus, frontal cortex, occipital cortex and striatum. Moreover, the changes were different in the two rat strains. Our data support the notion that neurotrophic factors play a role in depression and in the mechanism of the action of lithium.

Electroconvulsive stimuli alter nerve growth factor but not brain-derived neurotrophic factor concentrations in brains of a rat model of depression.

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are proteins involved in neuronal survival and plasticity of dopaminergic, cholinergic and serotonergic neurons in the central nervous system (CNS). Moreover, it has been hypothesized that these molecules play a role in the pathophysiology as well as treatment of depression. Using an animal model of depression, the Flinders Sensitive Line (FSL) rats and their controls, the Flinders Resistant Line (FRL), we investigated the effects of electroconvulsive stimuli (ECS) on brain NGF and BDNF. ECS or SHAM ECS were administered eight times, with a 48-h interval between each treatment. NGF and BDNF were measured with enzyme-linked immunosorbent assay (ELISA). In the hippocampus ECS increased NGF concentration in FSL but not FRL rats. ECS decreased NGF concentration in the frontal cortex of FSL rats. In both FSL and FRL rats ECS increased NGF levels in the striatum. In contrast, ECS did not change BDNF concentration in hippocampus, frontal cortex and striatum of FSL and FRL rats. Our data support the notion that neurotrophin concentrations may be altered by ECS.

Electroconvulsive stimuli alter the regional concentrations of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor in adult rat brain.

In this study we investigated whether electroconvulsive stimuli (ECS) altered the regional brain protein concentrations of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) in Sprague Dawley rats. Electroconvulsive stimuli were administered once daily for 8 days. At the end of the experiment, rats were killed, the brains were dissected into five regions, and the neurotrophic factors were extracted and measured by enzyme-linked immunosorbent assay. Electroconvulsive stimuli increased the concentrations of NGF in the frontal cortex and concentrations of BDNF in the hippocampus, the striatum, and the occipital cortex. In contrast, ECS decreased GDNF concentrations in the hippocampus and the striatum. Our data indicate that neurotrophic factors play a role in the mechanism of action of ECS and, by extrapolation, may play a role in the mechanism of action of electroconvulsive treatment.

Increased density of galanin binding sites in the dorsal raphe in a genetic rat model of depression.

The Flinders Sensitive Line rats showed an increased immobility response by 104% (P<0.01) in the forced swim test with respect to the Flinders Resistant Line rats (control). The Flinders Sensitive Line rats also had an increase of [(125)I]galanin (porcine) binding in the dorsal raphe (55+/-3.3 fmol/mg protein) with respect to the Flinders Resistant Line rats (38+/-3.6 fmol/mg protein) (42%, P<0.05) without changes in galanin receptor affinity and with a significant reduction (32.3%, P<0.05) of galanin-like immunoreactivity in the dorsal raphe. The results indicate that enhancement of galanin receptor function in the dorsal raphe rich in 5-HT neurons could be a mechanism involved in the production of depressive-like activity in this animal model of depression.