Reduction of Hypothalamic Vasopressinergic Hyperdrive Contributes to Clinically Relevant Behavioral and Neuroendocrine Effects of Chronic Paroxetine Treatment in a Psychopathological Rat Model

Abstract

The neuroendocrine and behavioral effects of chronic paroxetine treatment were investigated in two rat lines selectively bred for high anxiety-related behavior (HAB) or low anxiety-related behavior (LAB) emotionality. In addition to a characteristic behavioral phenotype with markedly passive stress-coping strategies, HAB rats show a hypothalamic vasopressinergic hyperdrive that is causally related to hypothalamic-pituitary-adrenocortical dysregulation as demonstrated in the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test. A total of 8 weeks of chronic paroxetine treatment induced a more active coping strategy in the forced swim test in HAB rats only. In contrast, paroxetine-treated LAB rats did not change their swimming behavior. To investigate the neuroendocrine alterations linked to these behavioral changes, a combined DEX/CRH test was performed. In HAB rats, the paroxetine-induced behavioral changes towards more active coping strategies were accompanied by a normalization of the CRH-stimulated increase in corticotropin (ACTH) and corticosterone secretion. Concomitantly, the hypothalamic vasopressinergic hyperdrive was found to be reduced in HAB but not LAB rats, as indicated by a decrease in vasopressin mRNA expression, whereas vasopressin 1a receptor binding was unaffected. These findings provide the first evidence that the vasopressinergic system is likely to be critically involved in the behavioral and neuroendocrine effects of antidepressant drugs. This novel mechanism of action of paroxetine on vasopressin gene regulation renders vasopressinergic neuronal circuits a promising target for the development of more causal antidepressant treatment strategies.

Impaired Repression at a Vasopressin Promoter Polymorphism Underlies Overexpression of Vasopressin in a Rat Model of Trait Anxiety

“…HAB animals have been well documented to show increased AVP mRNA expression, as well as elevated dendritic release of the neuropeptide in the PVN, which correlates with a hyper-reactive hypothalamic-pituitary-adrenal axis, pronounced anxiety, and comorbid depression-like behavior (Keck et al, 2003;. We now obtained direct evidence for line-specific differences in the sequence of the AVP promoter playing a causal role in this differential AVP expression.…”

“…Second, administration of an AVP V1a/b receptor antagonist directly into the PVN of freely behaving HAB rats, via inverse microdialysis, normalized their behavioral peculiarities , thus supporting the anxiogenic and depression-inducing potency of the central AVP system (Landgraf et al, 1995;Pitkow et al, 2001;Griebel et al, 2002); similarly, peripheral administration of the antagonist normalized neuroendocrine aberrations in HAB animals (Keck et al, 2002). Third, the mitigating effects of the antidepressant paroxetine on both behavioral and neuroendocrine aberrations of HAB rats were associated with a normalization of AVP expression in both the magnocellular and parvocellular subdivisions of the PVN (Keck et al, 2003). All these findings support the hypothesis that the SNP A(Ϫ1276)G underlying AVP overexpression, as described here, contributes to the behavioral and neuroendocrine phenotype of HAB rats.…”

“…Third, both the hyper-reactive hypothalamic-pituitary-adrenal axis and the pathological outcome of the dexamethasonecorticotropin-releasing hormone challenge test in HAB animals are driven by AVP overexpression and release (Keck et al, 2002). Moreover, treatment with the antidepressant paroxetine normalized AVP mRNA expression, the hypothalamic-pituitary-adrenal axis, and depression-like behavior but was without any effect in LAB rats (Keck et al, 2003). Therefore, to pursue further this issue and to gain insight into the molecular mechanism underlying the differential expression and release of AVP in the HAB and LAB lines, we decided to investigate the AVP locus as a candidate gene for AVP overexpression.…”

Anxiety and Hippocampus Volume in the Rat

“…In our adapted version of the forced swim test (Keck et al, 2003), the cylinder (height 60 cm, diameter 40 cm, Plexiglass) was filled with 191C tap water to a height of 50 cm. After the swim session, the rat was dried with a towel and placed back into the home cage.…”

Effect of Parabolic Flight on Plasma Arginine Vasopressin as A Sensitive Marker for Psychophysiological Stress in Humans

“…Accordingly, dysregulation of the brain AVP system, especially the over-activity of AVP neurons, is likely to contribute to the etiology and symptomatology of anxiety-and depression-related disorders (Murgatroyd et al, 2004;Simon et al, 2008;Surget and Belzung, 2008). In addition, animal models of high anxiety are characterized by an overexpression of central AVP (Landgraf, 2006), and treatment with an antidepressant led to a gradual reduction of AVP hypersecretion (Keck et al, 2003 al., 2004). Taken together, for an AVP hyper-responder to psychophysiological stress, unfamiliar or unpredictable life stress might impair HPA-axis regulation via the AVP/ CRH system and result in hypercortisolemia, which might increase the risk of developing a mood and anxiety disorder.…”