A study of neuropeptide Y in brains of 'depressed' and healthy rats

Abstract

Neuropeptide Y (NPY), a 36-amino acid peptide that was originally isolated from mammalian brain tissue, is widely distributed in both rat and human brain. NPY has a number of physiological actions and affects for example hypothalamic-pituitary-adrenal (HPA)-axis and circadian rhythms, modulates memory processing and food intake. Also, emerging evidence suggests that NPY may he involved in the pathophysiology of depression. Chronic treatments with antidepressant drugs, lithium, as well as repeated electroconvulsive stimuli (ECS), result in increased NPY-LI concentrations in selected brain regions of rats. Thus, one of the modes of action of ECT and antidepressants may be to elevate NPY in the CNS. The hypothesis of a downregulation of NPY system in depression is in part supported by human studies. Decreased NPY-LI concentrations in the CSF and plasma of depressed patients compared to controls and low levels of NPY-LI in the frontal cortex and caudate putamen in depressed suicide victims have been reported. Recently it has been reported that NPY mRNA was decreased in the prefrontal cortex of subjects affected with bipolar disorder. In addition, repeated electroconvulsive treatment (ECT) elevates NPY-LI in the CSF of depressed patients.

In this study, animal models of depression have been used to explore the possibility that NPY plays a role in depression. As a large body of evidence suggests that both genetic and environmental factors contribute to depressive disorders, we have used genetic animal models (the Fawn Hooded (FH) and the Flinders Sensitive Line (FSL) rats) and a stress model (maternal separation (MS)) of depression. Furthermore, as women are overrepresented in the depressed population, both male and female rats were included in some of our experiments. The respective "healthy" controls were Flinders Resistant Line (FRL), Wistar and non-maternally separated rats. Studies were conducted under baseline conditions and after repeated ECS or fluoxetine treatment. The present studies demonstrate that basal concentrations of NPY-LI in the hippocampus of the "depressed" FH, FSL and maternally separated (MS) rats are significantly lower than that of the controls. The alteration in NPY-Ll correlated well with the NPY mRNA expression. The basal NPYmRNA expression was lower in hippocampal CA and dentate gyrus of the FSL rats. We also found that Y1 binding sites are increased in the CA region of these animals. These results support our hypothesis that an NPY hypofunction, possibly secondary to decreased NPY synthesis, plays a role in depression. We also demonstrated that this deficit can he "normalized" by both repeated ECSs and fluoxetine treatments, probably by stimulating NPYergic neurotransmission in the limbic structures. Consequently, one heuristic hypothesis is that one of the modes of action of ECT and antidepressants may be to elevate NPY in the limbic system. Decreased basal NPY-LI levels in the "depressed" FSL and the FRL females as well as in the MS females compared to male controls were observed. It should be noted that the oestrous cycle did not modify NPY-LI levels in female FSL or FRL rats and thus it is not likely to be a confounding factor in obtained results. Whether the findings of lower NPY-LI levels in female compared to male "depressed" rats could explain increased rates of depression in women is purely speculative, but consistent with the results in present studies using different models of depression.

The work presented here adds further evidence for the involvement of NPY in depression and in the mechanisms of action of antidepressants.