ABSTRACT
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.
Subject(s)
Amygdala/metabolism , Corticotropin-Releasing Hormone/genetics , Depression/metabolism , Gene Expression Regulation/physiology , RNA, Messenger/metabolism , Stress, Psychological/physiopathology , Animals , Depression/genetics , Depression/physiopathology , Disease Models, Animal , Male , Opioid Peptides/genetics , Opioid Peptides/metabolism , Rats , Rats, Inbred Strains , Receptors, Neuropeptide Y/genetics , Receptors, Neuropeptide Y/metabolism , Receptors, Opioid/genetics , Receptors, Opioid/metabolism , Stress, Psychological/genetics , Stress, Psychological/pathology , Nociceptin Receptor , NociceptinABSTRACT
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.
Subject(s)
Depression/therapy , Electroconvulsive Therapy/methods , Gene Expression Regulation/radiation effects , Neuropeptide Y/metabolism , Receptors, Neuropeptide Y/metabolism , Analysis of Variance , Animals , Autoradiography/methods , Behavior, Animal/radiation effects , Depression/genetics , Depression/pathology , Disease Models, Animal , In Situ Hybridization/methods , Male , Neuropeptide Y/genetics , Rats , Rats, Inbred StrainsABSTRACT
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.
