Antidepressants recruit new neurons to improve stress response regulation.

Recent research suggests an involvement of hippocampal neurogenesis in behavioral effects of antidepressants. However, the precise mechanisms through which newborn granule neurons might influence the antidepressant response remain elusive. Here, we demonstrate that unpredictable chronic mild stress in mice not only reduces hippocampal neurogenesis, but also dampens the relationship between hippocampus and the main stress hormone system, the hypothalamo-pituitary-adrenal (HPA) axis. Moreover, this relationship is restored by treatment with the antidepressant fluoxetine, in a neurogenesis-dependent manner. Specifically, chronic stress severely impairs HPA axis activity, the ability of hippocampus to modulate downstream brain areas involved in the stress response, the sensitivity of the hippocampal granule cell network to novelty/glucocorticoid effects and the hippocampus-dependent negative feedback of the HPA axis. Remarkably, we revealed that, although ablation of hippocampal neurogenesis alone does not impair HPA axis activity, the ability of fluoxetine to restore hippocampal regulation of the HPA axis under chronic stress conditions, occurs only in the presence of an intact neurogenic niche. These findings provide a mechanistic framework for understanding how adult-generated new neurons influence the response to antidepressants. We suggest that newly generated neurons may facilitate stress integration and that, during chronic stress or depression, enhancing neurogenesis enables a dysfunctional hippocampus to restore the central control on stress response systems, then allowing recovery.

Cortico-limbic circuitry for conditioned nicotine-seeking behavior in rats involves endocannabinoid signaling.

RATIONALE: The endocannabinoid system plays an important role in conditioned drug seeking, but the neuronal mechanisms involved in this behavior are unclear. OBJECTIVES: Here, we evaluate the role of endogenous cannabinoids in the cortico-limbic circuitry in cue-induced nicotine-seeking behavior in rats. METHODS: Animals were first trained to self-administer nicotine (0.03 mg/kg/injection, IV) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and audiovisual stimuli. During subsequent sessions, nicotine was withdrawn and responding was reinforced by contingent presentation of the stimuli only. One month after nicotine removal, the cannabinoid CB1 receptor antagonist, rimonabant, was injected bilaterally into the shell of the nucleus accumbens (ShNAcc, 0.3, 3, or 30 ng/0.5 microl), the basolateral amygdala (BLA, 30 ng/0.5 microl), or the prelimbic cortex (PLCx, 30 ng/0.5 microl). RESULTS: Rimonabant injected into the ShNAcc dose-dependently reduced nicotine-seeking behavior without modifying spontaneous locomotor activity. Similar results were obtained when the drug (30 ng) was injected into the BLA or the PLCx. The anatomical specificity was confirmed in a control experiment using [(3)H]rimonabant. Fifteen minutes after drug injection, when the behavioral effects of rimonabant were already achieved, radioactivity was detected at the site of injection and had not diffused to adjacent regions. CONCLUSIONS: These findings demonstrate that increased endocannabinoid transmission critically triggers conditioned nicotine-seeking behavior in key cortico-limbic regions.

Differential roles of amygdaloid nuclei in the anxiolytic- and antidepressant-like effects of the V1b receptor antagonist, SSR149415, in rats.

RATIONALE: SSR149415 ((2S, 4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide), the first selective nonpeptide vasopressin V1b receptor antagonist has been shown to induce antidepressant-and anxiolytic-like effects following systemic administration, whereas intraseptal infusion of the drug engender antidepressant-but not anxiolytic-like effects. OBJECTIVES: Based on recent evidence that V1b receptors are located within the amygdaloid complex, a structure which is well known for its modulatory role of emotional processes, the possible involvement of the different amygdaloid nuclei in the anxiolytic- and/or antidepressant-like effects of SSR149415 was examined. METHODS: Male Sprague-Dawley or Wistar rats were infused with SSR149415 into the central (CeA), the basolateral (BlA), or the medial (MeA) nucleus of the amygdala and tested 10 min after microinjection in the elevated plus-maze or the forced-swimming test, two models typically used for assessing the anxiolytic and antidepressant effects of drugs, respectively. RESULTS: Microinjection of SSR149415 into the BlA (1-10 ng), but not into the CeA or the MeA, increased the percentage of time spent in the open arms of the elevated plus-maze, indicating anxiolytic-like effects. Furthermore, in the forced-swimming test, microinjection of the drug into the CeA (1, 10, and 100 ng), BlA (1-10 ng), or MeA (100 ng) decreased immobility, an effect which is indicative of an antidepressant-like action. Together, these findings indicate that while the antidepressant-like effects of SSR149415 are mediated by different amygdaloid nuclei, its anxiolytic-like effects appear to involve only the basolateral nucleus of the amygdala. Moreover, these results add further evidence to the role of extrahypothalamic vasopressinergic systems in the control of emotional responses.

Selective blockade of NK2 or NK3 receptors produces anxiolytic- and antidepressant-like effects in gerbils.

There is a growing interest in the potential anxiolytic- and antidepressant-like effects of compounds that target neurokinin receptors. Since the structure and the pharmacology of the human neurokinin receptor resembles that of gerbils, rather than that of mice or rats, we decided to investigate the anxiolytic- and /or antidepressant-like effects of NK1 (SSR240600), NK2 (saredutant) and NK3 (osanetant) receptor antagonists in gerbils. It was found that saredutant (3-10 mg/kg, p.o.) and osanetant (3-10 mg/kg, p.o.) produced anxiolytic-like effects in the gerbil social interaction test. These effects were similar to those obtained with the V1b receptor antagonist SSR149415 (3-10 mg/kg, p.o.), diazepam (1 mg/kg, p.o.) and buspirone (10 mg/kg, p.o.). Fluoxetine and SSR240600 were devoid of effects in this test. In the tonic immobility test in gerbils, saredutant (5-10 mg/kg, i.p.) and osanetant (5-10 mg/kg, i.p.) produced similar effects to those observed with fluoxetine (7.5-15 mg/kg, i.p.), SSR149415 (10-30 mg/kg, p.o.) and buspirone (3 mg/kg, i.p.). Diazepam and SSR240600 were inactive in this paradigm. In conclusion, the present study indicates further that NK2 and NK3 receptor antagonists may have therapeutic potential in the clinical management of anxiety and depression.

5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: more than 30 years of research.

An overview of the behavioral data arising from the vast literature concerning the involvement of 5-hydroxytryptamine (5-HT) neurotransmission in the regulation of anxiety is presented. More than 1300 experiments were carried out in this area and they provide evidence that: (1) results obtained in ethologically based animal models of anxiety with drugs stimulating 5-HT transmission are most consistent with the classic 5-HT hypothesis of anxiety in that they show an increase in animals' emotional reactivity; (2) no category of anti-anxiety models are selectively sensitive to the anxiolytic-like effects of drugs targetting 5-HT1A, 5-HT2A or 5-HT2C receptor subtypes; (3) anxiolytic-like effects of 5-HT3 receptor antagonists, in the great part, are revealed by models based on spontaneous behaviors. Taken together, these observations lead to the conclusion that different 5-HT mechanisms, mediated by different receptor subtypes, are involved in the genesis of anxiety.

Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders?

This review provides an overview of preclinical and clinical evidence of a role for the neuroactive peptides cholecystokinin (CCK), corticotropin-releasing factor (CRF), neuropeptide Y (NPY), tachykinins (i.e., substance P, neurokinin [NK] A and B), and natriuretic peptides in anxiety and/or stress-related disorders. Results obtained with CCK receptor antagonists in animal studies have been highly variable, and clinical trials with several of these compounds in anxiety disorders have been unsuccessful so far. However, future investigations using CCK receptor antagonists with better pharmacokinetic characteristics and animal models other than those validated with the classical anxiolytics benzodiazepines may permit a more precise evaluation of the potential of these compounds as anti-anxiety agents. Results obtained with peptide CRF receptor antagonists in animal models of anxiety convincingly demonstrated that the blockade of central CRF receptors may yield anxiolytic-like activity. However, the discovery of nonpeptide and more lipophilic CRF receptor antagonists is essential for the development of these agents as anxiolytics. Similarly, there is clear preclinical evidence that the central infusion of NPY and NPY fragments selective for the Y1 receptor display anxiolytic-like effects in a variety of tests. However, synthetic nonpeptide NPY receptor agonists are still lacking, thereby hampering the development of NPY anxiolytics. Unlike selective NK1 receptor antagonists, which have variable effects in anxiety models, peripheral administration of selective NK2 receptor antagonists and central infusion of natriuretic peptides produce clear anxiolytic-like activity. Taken as a whole, these findings suggest that compounds targeting specific neuropeptide receptors may become an alternative to benzodiazepines for the treatment of anxiety disorders.

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist, alleviates disturbances of novelty discrimination in a social context in rats, a putative model of selective attention deficit.

RATIONALE: Selective attention deficit, characterised by the inability to differentiate relevant from irrelevant information, is considered to underlie many cognitive deficits of schizophrenia, and appears to be only marginally responsive to treatment with current antipsychotics. OBJECTIVES: We compared the activity of the putative atypical antipsychotic SSR181507 (a dopamine D(2) receptor antagonist and 5HT(1A) receptor agonist) with reference compounds, on disturbances of novelty discrimination in a social context in rats, a behavioural paradigm that putatively models selective attention deficit. METHODS: A first (familiar) juvenile rat was presented to an adult rat for a period (P1) of 30 min. A second (novel) juvenile was then introduced at the end of P1 for a period (P2) of 5 min. The ability of the adult rat to discriminate between the two juveniles, presented at the same time, was evaluated by measuring the ratio of the time spent in interaction with the novel vs the familiar juvenile during P2. RESULTS: Adult rats spent more time exploring the novel than the familiar juvenile. This novelty discrimination capacity was disrupted by: (1) parametric modification of the procedure (reduction of time spent in contact with the familiar juvenile during P1); (2) acute injection of psychotomimetics that are known to induce schizophrenia-like symptoms in humans, such as phencyclidine (PCP; 3 mg/kg, i.p.) and d-amphetamine (1 mg/kg, i.p.) and (3) neonatal treatment with PCP (three injections of 10 mg/kg, s.c.), a model based on the neurodevelopmental hypothesis of schizophrenia. The potential atypical antipsychotic SSR181507 (0.03-3 mg/kg, i.p.) and the atypical antipsychotics clozapine (0.1-1 mg/kg, i.p.) and amisulpride (1-3 mg/kg, i.p.) attenuated deficits in novelty discrimination produced by parametric manipulation and by acute or neonatal treatment with PCP. The typical antipsychotic haloperidol (up to 0.3 mg/kg, i.p.) attenuated only deficits in novelty discrimination produced by parametric modification. CONCLUSION: Collectively, these results suggest that SSR181507 can alleviate disturbances of novelty discrimination in a social context in rats, and that this paradigm may represent a suitable animal model of selective attention deficits observed in schizophrenia.

Mouse defensive behaviors: pharmacological and behavioral assays for anxiety and panic.

The natural defensive behaviors of laboratory mice have been evaluated in both seminatural and highly structured situations; and characterized in terms of eliciting stimuli, response to pharmacological agents, behavior patterns, and outcome or effect on the social and physical environment. The defense patterns of laboratory mice and rats are generally similar, but mice show risk assessment on initial exposure to highly threatening stimuli while rats do not, while rats display alarm vocalizations, missing in mice. Quantitative differences in freezing and flight for laboratory mice and rats appear to largely reflect domestication effects, with wild mice and rats more similar to each other. This nexus of detailed within-species and comparative data on defense patterns makes it possible to reliably elicit specific defenses in mice or rats in an experimental context, providing well-validated assays of the natural defensive behaviors themselves, as opposed to 'models' of defense. The mouse--rat comparisons indicate considerable cross-species generality for these defense patterns, as does a scattered but considerable literature on other mammalian species, generally involving field studies and typically focusing on those aspects of defensive behavior that are visible at a distance, such as vigilance, or flight. Although potential homologies between normal mouse and human defense systems should ideally involve all four pattern components (stimulus, organismic factors, response characteristics, outcome), predictive validity in terms of response to drugs active against specific defensive psychopathology is the most extensively investigated of these. Flight, as measured in the Mouse Defense Test Battery shows a consistently appropriate response to panicolytic, panicogenic, and panic-neutral drugs, while some other predictive 'panic models' (dPAG-stimulation; DMH-inhibition; possibly conditioned suppression of drinking paradigms) also elicit and (indirectly) measure behaviors potentially related to flight. Models unrelated to flight (e.g. ultrasonic vocalization to conditioned stimuli); or for which flight elements may a relatively minor contributor to the behavior measured (Elevated T-maze) are less predictive of panicolytic or panicogenic action. These findings indicate that natural defensive behaviors provide a well-characterized pattern for analysis of effects of genetic or other physiological manipulations in the mouse, and may also serve as a model for analysis of defense-related human psychopathology.

Characterization of the profile of neurokinin-2 and neurotensin receptor antagonists in the mouse defense test battery.

Defensive behaviors of lower mammals confronted with a predatory stimulus provide an appropriate laboratory model for investigating behavior relevant to human emotional disorders. The mouse defense test battery (MDTB) has been developed because it combines many of the aspects of defense. Briefly, it consists of five tests either associated with potential threat (contextual defense) or the actual presence of an approaching threat (a rat). These latter focus on changes in flight, risk assessment and defensive threat and attack behaviors. Investigations with anxiolytic compounds have shown that these defense reactions may be used to differentiate between several classes of anxiolytic drugs. Here we used the MDTB to compare the behavioral profile of the benzodiazepine diazepam with that of neuropeptide receptor antagonists which have been shown to be involved in the modulation of stress response, namely the NK(2) receptor antagonists, SR48968 (0.01-1mg/kg) and SR144190 (1-10mg/kg), and the NT(1) receptor antagonist, SR48692 (1-30mg/kg). Results showed that all compounds decreased defensive threat/attack, but only diazepam and, to a lesser extent, SR48692 significantly modified risk assessment or flight. Further, none of the neuropeptide receptor antagonists modified contextual defense. Overall, the behavioral profile displayed by diazepam and these latter compounds in the MDTB are consistent with an anxiolytic-like action. However, our results suggest that, while NK(2) and NT(1) receptor antagonists may have limited efficacy on anxiety-related responses including cognitive aspects (i.e. risk assessment), they may have a potential against some forms of anxiety disorders which involve adaptative responses to extreme stress stimuli (e.g. direct confrontation with the threat stimulus).

Differentiation of anxiolytic and panicolytic drugs by effects on rat and mouse defense test batteries.

The use of ethoexperimental techniques to elicit and maximize the full range of defensive behaviors of rats and mice enables a very precise analysis of the effects of drugs on these behavior patterns. Two rat defense test batteries (the fear/defense test battery or F/DTB and the anxiety/defense test battery or A/DTB) have provided evidence that anxiolytic drugs, even from different classes, produce a common pattern of changes in specific behaviors. A recently developed mouse defense test battery (MDTB) has enabled description of mouse defensive behaviors to a predator, for comparison to those of rats, and a series of studies of drug effects on the behaviors measured in the MDTB provides evidence of cross-species generality of anxiolytic drug effects, or lack of effect, on specific defensive behaviors. In addition, tests with panicogenic and panicolytic drugs in the MDTB indicate that these enhance and reduce, respectively, flight reactions, which generally are not altered by anxiolytic compounds. Thus, results from the MDTB, taken in conjunction with those of the two rat test batteries and other defense analyses in rats and mice, provide evidence that many defensive behaviors are similar across rodent species, while the differences obtained provide a consistent pattern across situations. Moreover, the defense test batteries may be used to differentiate the effects of drugs effective against generalized anxiety as opposed to panic, through effects on specific defensive behaviors.

Benzodiazepine and serotonergic modulation of antipredator and conspecific defense.

The mammalian defense repertory comprises an array of individual behaviors that are extraordinarily sensitive to relevant features of the threat stimulus and the situation in which it occurs. In parallel with increasing awareness of the specificity and complexity of defensive behaviors and of their potential relevance to psychopathologies (e.g. anxiety, panic, and depression) is an escalating use of natural threat stimuli such as attacking conspecifics or predators in paradigms aimed at evaluating drug effects on defense. A review of the literature on benzodiazepine (BZ) and serotonin (5-HT) effects on conspecific and antipredator defense, including defensive analgesia, indicates that both types of stimuli elicit a wide array of relevant defensive behaviors. These studies suggest specificity of drug effects on particular behaviors, rather than a general alteration of all aspects of defense. However, stimulus variability and possible confounding of effects are a considerable problem with conspecific defense paradigms, while antipredator paradigms utilizing human experimenters as the predator may be difficult to use with the domesticated laboratory animal subjects. In addition, sensitivity to the organization of defensive behaviors and to differences between species in defense patterns is necessary to adequate interpretation of results. Nonetheless, these paradigms have permitted major advancements in analysis of the behavioral defense systems and their sensitive use in drug studies will greatly facilitate an understanding of the physiology of defense.

A comparative study of the effects of selective and non-selective 5-HT2 receptor subtype antagonists in rat and mouse models of anxiety.

Although there is some evidence that compounds acting at 5-HT2 receptors show anxiolytic activity, little is known about the specific involvement of the different 5-HT2 receptor subtypes in the modulation of anxiety-related responses. In the present study, the behavioural effects of mianserin, a non-selective 5-HT2 receptor antagonist, MDL 100,907, a selective 5-HT2A receptor antagonist, and SB 206553, a selective 5-HT2B/2C receptor antagonist, were investigated in two rat (the Vogel drinking conflict and the elevated plus-maze tests) and two mouse (i.e. the mouse defense test battery (MDTB) and the light/dark choice test) models of anxiety. Diazepam was used as a positive control. In the Vogel drinking test, mianserin (10 mg/kg) and SB 206553 (3-30 mg/kg), but not MDL 100,907, increased punished responding. Similarly, mianserin (1 mg/kg) and SB 206553 (3-10 mg/kg), but not MDL 100,907, increased entries into the open arms of the elevated plus-maze. These effects are consistent with anxiolytic-like actions of mianserin and SB 206553, although the magnitude of the effects of these two compounds was less than those of diazepam. In addition, in the MDTB, the 5-HT2 antagonists did not clearly affect the defensive reactions of mice exposed to a rat stimulus and they failed to reverse the avoidance of the illuminated box in the light/dark choice test. These results indicate a lack of anxiolytic-like action of the compounds in mice. These behavioural profiles suggest that blockade of the 5-HT2A receptor may not reduce anxiety and demonstrate that 5-HT2B and/or 5-HT2C receptor subtypes may be primarily involved in the anxiolytic-like effects of mianserin and SB 206553 in rats.

Further evidence for differences between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands in murine models of "state" and "trait" anxiety.

The behavioural effects of several BZ (omega) receptor ligands were compared in mice using the light/dark choice task, an animal model of "state" anxiety, and the free-exploration test, which has been proposed as an experimental model of "trait" anxiety. The drugs used included non-selective full (alprazolam, clorazepate, chlordiazepoxide and diazepam), partial agonists (bretazenil, imidazenil and Ro 19-8022) and BZ-1 (omega 1) selective receptor ligands (abecarnil, CL 218,872 and zolpidem). In the light/dark choice task, non-selective full agonists elicited clear anxiolytic-like effects increasing time spent in the lit box and simultaneously reducing attempts at entry into the illuminated cage followed by withdrawal responses, a measure of risk assessment. With the exception of abecarnil, both non-selective partial agonists and BZ-1 (omega 1) selective receptor ligands displayed reduced efficacy compared to the full agonists as they decreased risk assessment responses without altering time in the lit box. In addition, the weak anxiolytic-like actions displayed by selective BZ-1 (omega 1) agents were evident only at doses which reduced locomotor activity, indicating that this effect may be non-specific. In the free-exploration test, non-selective BZ (omega) receptor agonists markedly increased the percentage of time spent in the novel compartment and reduced the number of attempts to enter whereas selective BZ-1 (omega 1) receptor ligands displayed a weaker neophobia-reducing effect as they reduced risk assessment responses only. As was the case in the light/dark choice task, this latter effect was observed at locomotor depressant doses. These findings indicate that while both full and partial BZ (omega) receptor agonists are equally effective against "trait" anxiety, full agonists may be superior in reducing "state" anxiety. In addition, the lack of specific effects of selective BZ-1 (omega 1) receptor ligands in reducing both types of anxiety suggests that the BZ-1 (omega 1) receptor subtype cannot be considered as the primary target mediating the anxiolytic action of drugs interacting with the GABAA benzodiazepine receptor complex.

Pharmacological studies on synthetic flavonoids: comparison with diazepam.

The present experiments compared the central BZ-omega binding characteristics and pharmacological profiles of two synthetic flavonoids (6-bromoflavone and 6-bromo-3'-nitroflavone) with those of the benzodiazepine (BZ) diazepam. In vitro experiments showed that while diazepam displaced [3H]flumazenil binding to the GABA(A) receptor in membranes from rat cerebellum and spinal cord, two brain areas enriched in the BZ-omega1 and BZ-omega2 receptor subtypes, with nearly equivalent half maximally effective concentrations, 6-bromo-3'-nitroflavone was somewhat more potent in displacing [3H]flumazenil binding to membranes from rat cerebellum (IC50 = 31 nM) than from spinal cord (IC50 = 120 nM), indicating selectivity for the BZ-omega1 receptor subtype. 6-Bromoflavone displayed weak (IC50 = 970 nM) affinity for the BZ-omega1 and no affinity for the BZ-omega2 (IC50 > 1000 nM) receptor subtypes. Diazepam, but not the synthetic flavonoids increased the latency to clonic seizures produced by isoniazid, thereby indicating that neither 6-bromoflavone nor 6-bromo-3'-nitroflavone display detectable intrinsic activity at GABA(A) receptors in vivo. Results from two conflict tests in rats showed that 6-bromoflavone (3-10 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) elicited anxiolytic-like activity in the punished drinking test, while both drugs were inactive in the punished lever pressing test. The positive effects displayed by the synthetic flavonoids in the punished drinking procedure were smaller than that of diazepam and were not antagonized by the BZ receptor antagonist flumazenil. In two models of exploratory activity, 6-bromoflavone (3-30 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) produced anxiolytic-like effects in the rat elevated plus-maze test, whereas both compounds failed to modify the behavior of mice in the light/dark test over a wide dose-range. The effects in the elevated plus-maze were antagonized by flumazenil. In the mouse defense test battery, where mice were confronted with a natural threat (a rat), 6-bromoflavone and 6-bromo-3'-nitroflavone failed to decrease flight reactions after the rat was introduced into the test area and risk assessment behavior displayed when subjects were constrained in a straight alley, and only weakly affected risk assessment of mice chased by the rat and defensive biting upon forced contact with the threat stimulus. In a drug discrimination experiment 6-bromoflavone and 6-bromo-3'-nitroflavone up to 30 and 3 mg/kg, respectively, did not substitute for the BZ chlordiazepoxide. Taken together, these results failed to demonstrate that the synthetic flavonoids 6-bromoflavone and 6-bromo-3'-nitroflavone possess anxiolytic-like properties similar or superior to that of diazepam, as was suggested previously. Furthermore, they question the contribution of BZ-omega receptors to the behavioral effects of 6-bromoflavone and 6-bromo-3'-nitroflavone.

The effects of compounds varying in selectivity as 5-HT(1A) receptor antagonists in three rat models of anxiety.

Compounds varying in selectivity as 5-HT(1A) receptor antagonists have recently been reported to produce benzodiazepine-like antianxiety effects in mice. To assess the cross-species generality of these findings, the present experiments compared the effects of diazepam (0.625-5 mg/kg) with those of several non-selective (MM-77, 0.03-1 mg/kg and pindobind-5-HT(1A), 0.1-5 mg/kg) and selective (WAY100635, 0.01-10 mg/kg, p-MPPI, 0.01-3 mg/kg and SL88.0338, 0.3-10 mg/kg) 5-HT(1A) receptor antagonists in three well-validated anxiolytic screening tests in rats: punished lever-pressing, punished drinking, and the elevated plus-maze. In the punished lever-pressing conflict test, none of the 5-HT(1A) receptor antagonists modified rates of punished responding, whereas in the punished drinking test, WAY100635 (0.3-1 mg/kg), SL88.0338 (3-10 mg/kg), p-MPPI (1 mg/kg), MM-77 (0.03-0.3 mg/kg), but not pindobind-5-HT(1A), produced clear anticonflict activity. However, the increase in punished responding with the 5-HT(1A) compounds was smaller than that produced by diazepam, indicating weaker anxiolytic-like activity. In the elevated plus-maze test, WAY100635 (0.1-0.3 mg/kg), SL88.0338 (0.3-10 mg/kg), MM-77 (0.01-3 mg/kg), pindobind-5-HT(1A) (0.1-3 mg/kg), but not p-MPPI, showed anxiolytic-like activity on traditional behavioral indices, increasing the percentage of time spent in open arms and the percentage of open arm entries. As was the case in the punished drinking test, the magnitude of the positive effects of the 5-HT(1A) compounds was generally smaller than that of diazepam. Of the ethological measures recorded in the plus-maze, all compounds markedly decreased risk assessment (i.e. attempts) over the entire dose-range, but only diazepam clearly increased directed exploration (i.e. head-dipping). Although the present results demonstrate that 5-HT(1A) receptor antagonists elicit anxiolytic-like effects in rats, this action appears to be test-specific and, unlike previous findings in mice, smaller than that observed with benzodiazepines. The data are discussed in relation to the possible relevance of species differences in 5-HT(1A) receptor function and the nature of the anxiety response studied.

Behavioral and neurochemical changes following predatory stress in mice.

This article had several objectives. First it aimed at investigating the anxiogenic-like behaviors elicited by unavoidable cat exposure and/or cat odor across nine strains of mice (BALB/c, C57BL/6, C3H, CBA, DBA/2, NMRI, NZB, SJL, Swiss) in a modified version of the free-exploration test. The second objective was to investigate possible neurochemical changes following cat exposure in Swiss mice by measuring the turnover of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in several brain regions known to be involved in the modulation of emotional processes (hippocampus, hypothalamus and striatum). Finally, the third objective was to examine the effects of anxiolytic drug treatments on the anxiogenic responses elicited by a cat odor (i.e. a feces) in Swiss mice previously exposed to a cat using the free-exploration test. Results from the strain comparison showed that mice could be divided into three distinct groups: two non-reactive strains (NZB and SJL) which were relatively insensitive to predatory exposure and/or odor; five intermediate-reactive strains (Swiss, NMRI, CBA, C3H and BALB/c) which displayed clear anxiogenic-like responses only when exposed to both cat and, subsequently, to feces; and two high reactive strains (C57BL/6 and DBA/2) which showed anxiogenic-like reactions following cat exposure, regardless of the stimulus (clay or feces) present in the free-exploration cage. Neurochemical data revealed that, while brain levels of NA, DA, 5-HT in cat exposed Swiss mice were not significantly different from those of control animals, turnover rates of these monoamines were increased in the hippocampus (NA and 5-HT), hypothalamus and striatum (DA) after cat exposure. Results from pharmacological experiments indicated that repeated administration of the 5-HT reuptake inhibitor fluoxetine (5-20 mg/kg, twice a day, for 5 days) completely abolished avoidance of the cat feces in Swiss mice previously exposed to the predator. Neither acute nor repeated administration of the classical anxiolytic diazepam was able to reduce avoidance behavior of the anxiogenic stimulus in the free-exploration test. Taken together, these findings indicate that the exposure of mice to unavoidable predatory stimuli is associated with behavioral and neurochemical changes consistent with increased anxiety.

Behavioral effects of phenelzine in an experimental model for screening anxiolytic and anti-panic drugs: correlation with changes in monoamine-oxidase activity and monoamine levels.

This study investigated the effects of acute and chronic (one daily i.p. injection for 14 days) treatments with the non-selective irreversible monoamine-oxidase (MAO) inhibitor phenelzine (10 and 30 mg/kg) on defensive behaviors of Swiss mice in the mouse defense test battery (MDTB) which has been designed for screening anxiolytic and anti-panic drugs. In the MDTB, subjects were confronted with a natural threat (a rat) and situations associated with this threat. MAO-A and MAO-B activities and levels of brain monoamines (serotonin (5-HT), dopamine (DA) and norepinephrine (NE)) and their deaminated metabolites were subsequently measured. Behavioral results showed that acute administration of phenelzine did not specifically modify defensive behaviors. By contrast, after chronic treatment, phenelzine produced a significant reduction in avoidance distance when the rat was approaching, an effect which is consistent with an anti-panic-like action. In addition, phenelzine displayed weak anxiolytic-like effects as it increased risk assessment responses when mice were constrained in one part of the apparatus facing the rat which remained at a constant distance. No other specific drug effect was observed. These behavioral changes were associated with a dramatic increase in 5-HT levels, in particular after chronic treatment, while levels of DA and NE increased only slightly. Importantly, no significant differences in DA and NE levels between acute and chronic regimens were observed. Levels of deaminated metabolites of monoamines were markedly decreased. Measurements of MAO activity revealed substantial reductions in both type A and B forms with a full inhibition of both forms being observed only after chronic treatment with phenelzine. These results suggest that the effects of phenelzine may be due mainly to its effects on the 5-HT system and presumably related to the full inhibition of MAO-A and/or MAO-B.

SSR181507, a putative atypical antipsychotic with dopamine D2 antagonist and 5-HT1A agonist activities: improvement of social interaction deficits induced by phencyclidine in rats.

Social behaviour is frequently impaired in schizophrenic patients, and current antipsychotics appear poorly effective in alleviating this deficit. SSR181507 is a selective dopamine D2 receptor antagonist and 5-HT1A receptor agonist [Neuropsychopharmacology 28 (2003) 2064] with an atypical antipsychotic profile and additional antidepressant/anxiolytic activities [Neuropsychopharmacology 28 (2003) 1889]. Here, we sought to assess the efficacy of SSR181507, and of reference antipsychotics and antidepressant/anxiolytics, to counteract phencyclidine (PCP)-induced social interaction deficit in rats. Pairs of unfamiliar rats were placed for 10 min each day into a dimly lit arena, during four consecutive days. On the test day (5th day), each pair was placed into the arena 30 min after i.p. treatment with PCP (or vehicle) and a challenge compound or vehicle (same for both rats, i.p. or s.c.). The time spent in social interaction was scored during 10 min. PCP (1 mg/kg) decreased social interaction time by about 35%. This effect was fully antagonized by pre-treatment with SSR181507 (1 mg/kg). In contrast, neither haloperidol (0.05 and 0.1 mg/kg) nor clozapine (0.3 and 1 mg/kg) antagonized this PCP-induced deficit. The selective 5-HT1A receptor agonist 8-OH-DPAT (0.025 and 0.05 mg/kg s.c.), but not the anxiolytic diazepam (0.75 and 1.5 mg/kg), also improved social interaction impairment in PCP-treated rats: this would indicate that the 5-HT1A receptor agonist properties of SSR181507 are responsible for the reversal of PCP-induced social deficit. These data suggest that, in addition to its atypical antipsychotic profile and antidepressant/anxiolytic activities, SSR181507 has a potential therapeutic activity in another key feature of schizophrenia poorly controlled by current antipsychotics, namely deterioration in social functioning.

Further evidence that the mouse defense test battery is useful for screening anxiolytic and panicolytic drugs: effects of acute and chronic treatment with alprazolam.

The Mouse Defense Test Battery (MDTB) has been designed to investigate defensive responses of Swiss-Webster mice confronted with a natural predator, a rat. These behaviors include flight, avoidance, defensive threat/attack responses, and risk assessment activities. Previous studies with the MDTB have suggested that this model may have some utility for the investigation of panicogenic and antipanic compounds. In the present study the MDTB was used to investigate the effects of acute (0.05-1 mg/kg, i.p., 30 min) or chronic (0.5-2 mg/kg, one daily i.p. injection during 10 days) treatment with the benzodiazepine receptor (BZPR) full agonist and panicolytic agent alprazolam. At non motor-impairing doses (0.05-0.5 mg/kg), acute alprazolam failed to alter the avoidance distance between the subject and the predator, the number of avoidances when the rat is approaching, predator assessment activities, defensive threat/attack responses when contact is forced between the subject and the predator or contextual escape attempts after the predator was removed. This was in contrast to chronic treatment which decreased both avoidance variables at 0.5 and 1 mg/kg, defensive threat/attack responses at all doses, and predator assessment responses at 0.5 mg/kg. In addition, the latter treatment reduced post-predator potentiation of escape attempts at 2 mg/kg. These results (1) confirm previous findings with the BZPR full agonist chlordiazepoxide, indicating that these compounds generally attenuate antipredator defensive responses in Swiss-Webster mice; (2) support recent data indicating that panic-altering drugs modulate flight/escape reactions, and suggest that the primary mechanism of action of drugs with efficacy against panic disorder may involve neural systems controlling flight; (3) confirm that the MDTB may be useful for the investigation of panicolytic as well as anxiolytic agents.

Effects of SR48968, a selective non-peptide NK2 receptor antagonist on emotional processes in rodents.

RATIONALE: It has been suggested that tachykinin NK(2) receptor antagonists may have therapeutic utility in anxiety and/or depressive disorders. OBJECTIVE: The present study investigated the modulatory action of the NK(2) receptor antagonist SR48968 on emotional processes in rodents. METHODS: The tests used include classical models of anxiety (punished lever pressing and punished drinking conflict tests, elevated plus-maze in rats), a model based on defensive behaviors of mice confronted with a natural threat (a rat), and two tests based on exposure of rats or mice to a natural predator (a cat) followed by subsequent exposure to a cat odor cue. The prototypical anxiolytic diazepam was used throughout as a positive control, the antidepressant imipramine was tested in the mouse defense test battery and in both models of predatory exposure, and the selective CRF1 receptor antagonist antalarmin was used in the cat-exposure test in rats. RESULTS: Unlike diazepam, SR48968 failed to increase rates of responding suppressed by punishment in both conflict procedures. By contrast, in the elevated plus-maze test, the NK(2) receptor antagonist (3 mg/kg, IP) elicited positive effects on traditional and ethologically derived measures of anxiety. In the mouse defense test battery, SR48968 (0.03-1 mg/kg, IP) decreased flight reactions, risk assessment behavior, defensive biting and escape attempts. While the magnitude of the effects on flight, risk assessment and escape attempts of the NK(2) receptor antagonist was less than that of diazepam, SR48968 appeared to be as effective as the BZ on defensive biting. In rats previously exposed to a cat, SR48968 (3 mg/kg, IP), antalarmin (1 mg/kg, IP), imipramine (30 mg/kg, IP), but not diazepam, reduced subsequent high levels of avoidance responses when subjects are exposed to a cat odor-saturated cue 1 h later. Similar effects of SR48968 (0.1-0.3 mg/kg, IP) were observed in mice following repeated administration (twice a day/5 days/IP). Importantly, the positive effects of the NK(2) receptor antagonist were evident at doses that did not impair general activity, unlike imipramine which displayed mainly sedative action. Moreover, the (R)-enantiomer of SR48968, SR48965, which was tested in the elevated plus-maze, the mouse defense test battery and the cat exposure tests, was much less active than its racemate, indicating a stereoselective action of SR48968. CONCLUSION: These data show that while SR48968 has limited or no efficacy in models or behavioral measures mainly sensitive to BZs, it shows good activity in reducing anxiety-like behaviors following traumatic stress or upon forced and unavoidable contact with a threatening stimulus. This suggests that NK(2) receptor antagonists may have a potential in the treatment of some forms of anxiety disorders.