Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V _1b receptor antagonist, SSR149415, suggest an innovative approach for the treatment of stress-related disorders

Abstract

The limbic localization of the arginine vasopressin V1b receptor has prompted speculation as to a potential role of this receptor in the control of emotional processes. To investigate this possibility, we have studied the behavioral effects of SSR149415, the first selective and orally active non-peptide antagonist of vasopressin V 1b receptors, in a variety of classical (punished drinking, elevated plus-maze, and light͞dark tests) and atypical (fear͞anxiety defense test battery and social defeat-induced anxiety) rodent models of anxiety, and in two models of depression [forced swimming and chronic mild stress (CMS)]. When tested in classical tests of anxiety, SSR149415 produced anxiolytic-like activity at doses that ranged from 1 to 30 mg͞kg (i.p. or p.o.), but the magnitude of these effects was overall less than that of the benzodiazepine anxiolytic diazepam, which was used as a positive control. In contrast, SSR149415 produced clear-cut anxiolyticlike activity in models involving traumatic stress exposure, such as the social defeat paradigm and the defense test battery (1-30 mg͞kg, p.o.). In the forced swimming test, SSR149415 (10 -30 mg͞kg, p.o.) produced antidepressant-like effects in both normal and hypophysectomized rats. Moreover, in the CMS model in mice, repeated administration of SSR149415 (10 and 30 mg͞kg, i.p.) for 39 days improved the degradation of the physical state, anxiety, despair, and the loss of coping behavior produced by stress. These findings point to a role for vasopressin in the modulation of emotional processes via the V 1b receptor, and suggest that its blockade may represent a novel avenue for the treatment of affective disorders.A rginine vasopressin (AVP) is a cyclic nonapeptide that is synthesized centrally in the hypothalamus. Although it participates in the hypothalamic-pituitary-adrenal axis, regulating pituitary ACTH (corticotropin) secretion by potentiating the stimulatory effects of corticotropin releasing factor (CRF), extrahypothalamic AVP-containing neurons have been characterized in the rat, notably in the medial amygdala, that innervate limbic structures such as the lateral septum and the ventral hippocampus (1). In these latter structures, AVP was suggested to act as a neurotransmitter, exerting its action by binding to specific G protein-coupled receptors, i.e., V 1a and V 1b (2-4), which are widely distributed in the central nervous system, including the septum, cortex, and hippocampus (2, 5).Because the pioneering studies of David De Wied and colleagues (6, 7), it has been widely accepted that AVP is involved in various types of behavioral processes (8). Early work paid attention to the possible role of this peptide in learning and memory, in particular with regard to avoidance behavior (for review, see ref. 9), but also in antypiresis, scent marking, and social communication (for reviews, see refs. 10 and 11). For instance, several studies showed that centrally administered AVP in rats reverses drug-induced memory loss and affects long-term memory processes, improvi...

Profound Impairment in Social Recognition and Reduction in Anxiety-Like Behavior in Vasopressin V1a Receptor Knockout Mice

“…A third group found that AVP receptor antagonism increased anxiety-like behavior (Liebsch et al, 1996;Appenrodt et al, 1998;Everts and Koolhaas, 1999). The V1bR has also been implicated in anxiety, and treatment with an orally active V1bR antagonist resulted in a decrease in anxiety-related behavior in rats (Griebel et al, 2002). This finding was contradicted by the report that V1bR knockout mice do not show any changes in anxiety-related behavior (Wersinger et al, 2002).…”

“…The data supporting the role of V1bR in social recognition and anxiety is sparse and inconsistent. Treatment with a novel, orally active V1b antagonist resulted in reduced anxietyrelated behavior while characterization of a V1b knockout mouse found no difference in anxiety-related behavior, but mildly impaired social recognition (Griebel et al, 2002;Wersinger et al, 2002).…”

The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

“…For example, chronic immobilization stress has been shown to increase V 1b receptor mRNA levels in the rat brain (Aguilera and Rabadan-Diehl, 2000). Selective blockade of the V 1b receptor by the nonpeptide antagonist SSR149415 was shown to block restraint stress-induced ACTH release (Serradeil-Le Gal et al, 2002) and produce anxiolytic-like activity in several procedures (Griebel et al, 2002a). The magnitude of these effects was overall less than that of the benzodiazepine anxiolytic diazepam in classical anxiety tests such as the elevated plus-maze.…”

Involvement of Arginine Vasopressin and V1b Receptor in Heroin Withdrawal and Heroin Seeking Precipitated by Stress and by Heroin

“…A growing body of evidence suggests that vasopressinergic neuronal activity in the amygdala and hypothalamus represents an important element in the neurobiology of stress-related behaviors. In fact, acute stress increases extracellular levels of arginine vasopressin (AVP) in the rat amygdala and hypothalamus (Ebner et al, 2002;Wigger et al, 2004), and activation of V1b receptors by AVP modulates anxiogenic and depressive behaviors in rats (Griebel et al, 2002;Wigger et al, 2004).…”

“…This compound was selected because of its ability to antagonize the V1b receptor; the receptor type involved in the modulation of ACTH release by endogenous vasopressin and of other brain functions (De Wied et al, 1993;Aguilera and Rabadan-Diehl, 2000). SSR149415 is a non-peptide antagonist highly selective for the V1b receptor (60-to 800-fold more than for the V1a receptor) (Serradeil-Le et al, 2003;Guillon et al, 2004), and shown to possess both anxiolytic and antidepressant properties, as well as to block several neuroendocrine (ACTH release), neurochemical (noradrenaline release), and autonomic (hyperthermia) responses to various stressors in rodents (Griebel et al, 2002Serradeil-Le et al, 2003;Overstreet and Griebel, 2005).…”