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...

Benzodiazepines are widely used anxiolytics and anticonvulsants, and their potent sedative properties are routinely used in presurgical anaesthesia. However, they are also known to induce a strong anterograde amnesia in patients. Specific benzodiazepine antagonists have recently been described, some of which have intrinsic pharmacological properties that are opposite to those of benzodiazepines. These have been called inverse agonists and they have been shown to be proconvulsant or convulsant whereas benzodiazepines are anticonvulsants. Inverse agonists are also anxiogenic rather than anxiolytic. Since benzodiazepines induce anterograde amnesia, we have investigated the possibility that inverse agonists might also have an opposite effect for this property and so enhance acquisition (learning) and (or) retention (memory). We report here that, in three different animal models, an inverse agonist of the beta-carboline group, methyl beta-carboline-3-carboxylate (beta-CCM), enhances animal performance in three different tasks used to investigate learning and memory.

The present study investigated the effects of the novel corticotrophin-releasing factor (CRF) 1 receptor antagonist 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A) in a variety of rodent models of anxiety, including conflict procedures (punished drinking and four-plate), exploration models (elevated plus-maze and light/ dark), a fear/anxiety defense test battery, and several procedures based on stress-induced changes in physiological (isolation-induced hyperthermia and tail pinch-induced cortical norepinephrine release) or behavioral (social defeat-induced anxiety, maternal separation-induced vocalization) parameters. Moreover, the effects of SSR125543A were investigated in acute (forced swimming) and chronic (chronic mild stress; CMS) models of depression. SSR125543A and the CRF 1 receptor antagonist antalarmin displayed limited efficacy in exploration-based anxiety models. In contrast, both compounds produced clear-cut anxiolytic-like activity in models involving inescapable stress, including the conflict procedures, the social defeat-induced anxiety paradigm and the defense test battery (3-30 mg/kg i.p. or p.o.). These effects paralleled those of the anxiolytic diazepam. In addition, SSR125543A and antalarmin antagonized stress-induced hyperthermia, distress vocalization, and cortical norepinephrine release. In the forced swimming test, 30 mg/kg p.o. SSR125543A and 3 to 30 mg/kg p.o. antalarmin produced clear antidepressant-like effects. These latter results were strengthened by the findings from the CMS, which showed that repeated administration of 10 mg/kg i.p. SSR125543A for 30 days improved the degradation of the physical state, the reduction of body weight gain, and anxiety produced by stress. Together, these data indicate that SSR125543A shows good activity in acute and chronic tests of unavoidable stress exposure, suggesting that it may have a potential in the treatment of depression and some forms of anxiety disorders.Corticotropin-releasing factor (CRF) has been identified as a neuropeptide that plays a central role in the coordination of neuroendocrine, autonomic, and behavioral responses to stress (Vale et al., 1981). It is the main regulator of basal and stress-induced release of the adrenocorticotropic hormone (ACTH) (Stout et al., 1995). Two CRF receptor subtypes, CRF 1 and CRF 2 , with distinct anatomical localization and pharmacology have been identified (Chalmers et al., 1996). CRF 1 receptor expression is most abundant in neocortical, cerebellar, and limbic structures, whereas CRF 2 receptor expression is generally prominent in subcortical structures. This anatomical information provided a basis for functional hypotheses related to CRF receptor subtypes and suggested that CRF may contribute significantly both to behavioral responses to stress and emotional behavior itself. This idea has been substantiated by numerous studies showing that i.c.v. application of CRF in rod...

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The staircase test consists of placing a naive mouse in an enclosed staircase with five steps and observing the number of steps climbed and rearings made in a 3-min period. All the clinically active anxiolytics tested (chlordiazepoxide, clorazepate, diazepam, lorazepam, meprobamate, phenobarbital) reduce rearing at doses which did not reduce the number of steps climbed. The majority of non-anxiolytic substances tested (haloperidol, chlorpromazine, imipramine, amitriptyline, amphetamine, morphine and carbamazepine) produced a parallel reduction of both behavioural variables. Ethosuximide had no effect on behaviour. The anticonvulsant sodium valproate produced an anxiolytic profile in this test, since it reduced rearing, while increasing step climbing. This result confirms the anxiolytic properties of valproate observed in other behavioural models. Our results indicate that the staircase test in mice is simple, rapid and selective for anxiolytics. The test is well suited for use as a primary screening method.