Maternal deprivation and mood stabilizing drugs : effects on rat brain NPY

Abstract

Experiences of early adverse life events are more frequent among adult depressed patients than healthy subjects. Studies with non-human primates and rats show that maternal deprivation leads to changes in hypothalamic-pituitary adrenal (HPA)-axis activity/reactivity and increased levels of anxiety and alcohol preference. Neuropeptide Y (NPY) is widely and abundantly distributed in mammalian brain, in particular in limbic areas. NPY modulates a number of behavioral and physiological functions including anxiety, food intake, cognition, hippocampal excitability and HPA-axis activity.

Since accumulated clinical and experimental evidence suggests a role for NPY in the pathophysiology of mood disorders, the effects of maternal deprivation on rat brain NPY were investigated as a major aim of this thesis. Maternal deprivation for 180 min/day during postnatal day 2-14 or for 24 hrs on postnatal day 9 led to marked reductions in hippocampal levels of NPY-LI. These changes were associated with reduced saccharin preference and prepulse inhibition deficits, indicating that reductions in hippocampal NPY may be associated with anhedonia and cognitive disturbances. This notion is supported by the finding that central administration of NPY induced antidepressant-like activity in normal rats, in a manner comparable to that of imipramine.

A second aim of the present thesis was to investigate the effects of lithium and the antiepileptics topiramate and levetiracetam, which all have mood stabilizing effects in patients, on NPY-LI in maternally deprived, Hinders Sensitive Line (FSL) and amygdala-kindled rats, models that each display specific resemblances to hallmarks of depression. These treatments all lead to changes in hippocampal NPY mRNA, NPY-LI and NPY receptor binding, indicative of an increased NPYergic neurotransmission. Specifically, in maternally deprived animals, lithium reversed the separationinduced decrease of hippocampal NPY-LI levels to concentrations that were similar to those found in the control animals. Similarly, lowered hippocampal NPY-LI in the FSL rats was normalized following repeated, but not single, topiramate treatment, whereas topiramate had no effect on this measure in the FRL control animals. Levetiracetam delayed the development of kindling and also reduced the duration of afterdischarge and motor seizures. These behavioral manifestations coincided with the prevention of a kindling-induced upregulation of brain-derived neurotrophic factor and NPY -mRNA in the dentate gyros of the hippocampus and the prevention of a kindling-induced downregulation of Y1-, and Y5-like receptors in the dentate gyrus and Y2-like receptors in the CA3 area of the hippocampus. In contrast, none of these parameters were affected by levetiracetam in normal rats.

By extrapolation, the present findings therefore support the working hypothesis that a neurobiological correlate to an increased risk for mood disorders and comorbid anxiety may be a decreased concentration of NPY in the hippocampus, and that such a reduction in NPY may result from exposure to early life stress. In view of the observations that (1) NPY is a potent anticonvulsant and also exerts antidepressant properties, (2) NPY affects a variety of centrally mediated functions of possible significance to the symptomatic spectrum of mood disorders, (3) a dysfunctional NPY system has been reported in patients suffering from depression as well as epilepsy disorders, an expanded heuristic hypothesis call he proposed: a decreased concentration of NPY in the hippocampus may be associated with aspects of lowered mood, impaired cognitive function, alcohol-dependence, and increased stress sensitivity and seizure vulnerability. Lithium, the most commonly prescribed drug in mood- disorders, and antiepileptics, which all essentially possess mood stabilizing properties, may in part exert their therapeutic mechanisms of action by stimulating the synthesis of hippocampal NPY, thus being a common denominator for their mood stabilizing and anticonvulsant properties.