Journal - Journal of psychopharmacology (Oxford, England) (United States )

Abstract :

The effect of the anxiogenic ß-carboline, FG-7142, on defense and approach-attack behavior in the cat was investigated. FG-7142 (10 mg/kg) enhanced defensive responses to rats and mice when tested 10 and 20 min after injection. At the same time, FG-7142 suppressed approach and attack responses to prey. Behavioral effects of FG-7142 were blocked by the specific benzodiazepine receptor blocker RO-15-1788 (10 mg/kg). One or two administrations of FG-7142 were sufficient to produce a lasting (up to 105 days) enhancement of defensive response to rats but not to mice. Defensive response to conspecific threat vocalizations was also lastingly increased. Two injections of FG-7142 produced a lasting suppression of approach-attack on rats only, whereas one injection of FG-7142 did not. The lasting suppression of some measures of approach-attack was found to be independent of the fear-enhancing properties of FG-7142. Tests of the effects of RO-15-1788 on the lasting after-effects of FG-7142 revealed at least two mechanisms which mediate the lasting changes in behavior, one which is dependent upon the benzodiazepine receptor and one which is not. The implications of these findings for rodent models of anxiety which use response suppression to assess fearful 'anxiogenic' effects of drugs are discussed.

Journal - Journal of psychopharmacology (Oxford, England) (United States )

Abstract :

This selective review considers the contribution of recent investigations of corticotropin releasing factor (CRF) to our understanding of the link between stress and psychopathology associated with limbic epilepsy. Data are reviewed which clearly indicate that CRF does not play a simple modulatory role in behaviour. On the one hand, it is clear that CRF reproduces many of the central effects initiated by environmental stressors. One primary effect of limbic and locus coeruleus CRF systems, at least, seems to be to modulate neural circuitry involved in anxiety. On the other hand, its functioning as a modulator of animal anxiety can vary from anxiogenic, to neutral to anxiolytic, depending on the prior experience of the animal. Handling stress eliminates the anxiogenic action of CRF, and repeated limbic seizures change CRF into an anxiolytic. All of these findings suggest that CRF is an important link between stress and affective disturbance, but the nature of that link is complex and poorly understood. Chronic stress and epileptic disorders probably modify CRF functioning itself, as well as neurotransmitter systems with which CRF interacts. Nevertheless, the data suggest a novel hypothesis regarding the relationship between stress and mood in epileptics and the role of CRF in that relationship.

Journal - Journal of psychopharmacology (Oxford, England) (United States )

Abstract :

The effects on rodent anxiety of corticotrophin releasing factor (CRF), common experimental stressors and the CRF receptor blocker, a-helical CRF, were measured using the hole board and elevated plus-maze tests. Centrally administered (intracerebroventricular, i.c.v.) CRF increased anxiety in an anxioselective manner. a-Helical CRF (i.c.v) antagonized the effects of CRF, implicating central CRF receptors. Common experimental stressors, such as surgical implantation of cannulas and intraperitoneal injections of saline also selectively increased anxiety in the plus maze. Endogenous CRF binding to central CRF receptors probably mediates the anxiogenic effects of stressors, since a-helical CRF reversed the increased anxiety following surgery. Finally, repeated gentle handling seemed to blunt the anxiogenic effect of CRF. Handling also altered the effect of CRF on behavior, creating an apparently CRF-mediated suppression of rearing and exploration which was not present in rats not stressed with repeated handling. Together the data suggest a modifiable modulatory role of CRF in rodent anxiety. The findings also suggest that careful attention should be paid to stress history when examining the role of CRF in rodent behavior.

Journal - Journal of psychopharmacology (Oxford, England) (United States )

Abstract :

The effect of the anxiogenic ß-carboline, FG-7142, on behavior and limbic physiology was investigated. A single systemic injection of FG-7142 (10 mg/kg) changed behavior for at least 43 days. Two days after drug administration, defensive response to rats was increased. In addition, predatory attack was suppressed in some, but not all, animals. Cats that were more predatory (killers, n=2) before drug administration showed suppression of predatory attack after FG-7142. The attack of less predatory cats (non-killers, n=3) was unaffected by FG-7142. Suppression of attack was not correlated with changes in defense. This finding suggests FG-7142 acts on separate substrates of defense and attack suppression to change these behaviors lastingly. FG-7142 produced long-term potentiation (LTP) in two of three limbic pathways investigated. LTP was observed in the amygdalo-ventromedial hypothalamic (AM-VMH) pathway. AM-VMH LTP depended on changes within the amygdala and not in the efferent synapses or in the VMH. LTP lasted 6 days, returning to baseline by 21 days after FG-7142. The only behavioral change correlated with AM-VMH LTP was defensive response at 2 days after FG-7142. Increased defense from 6 to 43 days after the drug was not correlated with AM-VMH LTP. Therefore, AM-VMH LTP may be necessary for the initiation, but not maintenance, of increased defensive response. LTP of the population spike of the perforant path-CA3 (PP-CA3) field potential in the ventral hippocampus was also seen. LTP appeared 6 days after drug administration, after cats had been exposed to rats. Before the appearance of PP-CA3 LTP, there was a transient failure of recurrent inhibition in area CA3. It is likely that exposure to a rat during the period of failed inhibition facilitated the PP-CA3 LTP. In addition, following FG-7142, facilitation in area CA3 increased lastingly, consistent with a lasting increase in the duration of excitatory neurotransmitter release. Changes in hippocampal inhibition and facilitation correlated with changes in attack behavior, but not with changes in defensive response. Systemic flumazenil (10 mg/kg) partially reversed the lasting changes in defense and approach-attack in a drug-dependent manner. Limbic physiology was unchanged by flumazenil. Flumazenil probably did not affect AM-VMH transmission in the present study because AM-VMH LTP had returned to baseline when flumazenil was given. These findings suggest flumazenil only acts on potentiated AM-VMH transmission.

Journal - Journal of psychopharmacology (Oxford, England) (UNITED STATES )

Abstract :

The findings of this study support the hypothesis that N-methyl-D-aspartate (NMDA) receptors mediate the initiation of long-term potentiation (LTP) and behavioral changes induced by the anxiogenic beta-carboline, FG-7142. Unlike previous work, this study examined the effects of FG-7142 on LTP of amygdala efferents in both hemispheres. 7-amino-phosphono-heptanoic acid (AP7), a competitive NMDA receptor blocker, given prior to administration of FG-7142, prevented LTP in amygdala efferent transmission to the medial hypothalamus and periacqueductal gray (PAG). When given FG-7142 alone, cats showed lasting behavioral changes accompanied by LTP in all pathways studied. Duration of LTP, and its relationship to behavioral change, depended on the pathway and the hemisphere of the pathway. Correlation and covariance analyses indicate that LTP in the left amygdalo-ventromedial hypothalamic pathway mediates initiation, but not maintenance, of increased defensiveness. This finding replicates previous work. A new finding is that increased local excitability in the right basal amygdala (reduced threshold for evoked response), and LTP in the right amygdalo-PAG pathway, may be important for maintenance of increases in defensive behavior. Furthermore, the effects of flumazenil, a benzodiazepine receptor antagonist, on behavior and physiology single out the importance of right amygdalo-PAG LTP as a critical mediator of increased defensiveness. Flumazenil reversed the increase in defensiveness produced by FG-7142 in a drug-dependent manner as described in Adamec (1998a). Moreover, flumazenil reversed LTP only in the right amygdalo-PAG pathway. The findings of the present study suggest that response to FG-7142 may be a useful model of the effects of traumatic stressors on limbic system function in anxiety, especially in view of the recent data in humans implicating right hemispheric function in persisting negative affective states.

Journal - International review of neurobiology (United States )

Journal - Neuroscience and biobehavioral reviews (UNITED STATES )

Abstract :

Exposure of rats to cats (predator stress) lastingly increases rodent anxiety-like behavior (ALB) in the elevated plus-maze. Previous work shows that lasting changes in ALB following predator stress depend on NMDA and CCKB receptors. In this paper we describe the effects of differing degrees of predator exposure on behavior. Effects depend on the behavioral measure. In general, exposure to predator odor is less provocative of lasting change in ALB than is unprotected exposure to a cat. In addition, we examine the development of effects of unprotected predator exposure over time. Lasting effects on ALB begin at 30 min to 1 h after predator stress and persist for at least 3 weeks. We also report a complex pattern of effects of predator stress on neuroendocrine and stress peptide (bombesin, CRF and AVP) levels in a variety of brain areas. Not surprisingly, predator exposure increases plasma levels of corticosterone and ACTH. Central changes in peptide content in the hypothalamo-pituitary axis, related hypothalamic nuclei, limbic and brain stem areas are also noted. Finally, path analysis demonstrates a replicable relationship between cat behavior, rat defensive behavior and degree of increase in ALB one week later. It is proposed that behavioral changes following predator stress may model anxiety associated with PTSD.

Journal - Journal of psychopharmacology (Oxford, England) (UNITED STATES )

Abstract :

The anxiogenic beta-carboline, FG-7142, produces intense anxiety in humans and anxiety-like behavior in animals. FG-7142 also mimics the effects of exogenous stressors. In cats, FG-7142 lastingly changes defensive and aggressive behavior. Long-term potentiation (LTP) of neural transmission between limbic structures known to modulate feline defensive response to threat accompany behavioral changes. A series of three reports describes experiments designed to test the hypothesis that behavioral changes depend upon an N-methyl-D-aspartate (NMDA) receptor-based LTP of efferent transmission from the amygdala. This first study characterizes the dose and time effects of injection of the NMDA receptor blocker 7-amino-phosphono-heptanoic acid (AP7) on efferent transmission from the cat amygdala to the ventromedial hypothalamus (VMH). Effects of doses of 0.5-10mg/kg (i.v.) of AP7 on potentials evoked in the VMH by single pulse stimulation of the basal amygdala were examined. In order to localize the action of the drug, concurrent measurements were taken of potentials evoked in the VMH by stimulation of the efferent fibers from the amygdala to the VMH (ventral amygdalofugal pathway, VAF). There was a dose-dependent reduction in the amygdalo-VMH evoked potential. The greatest reduction occurred at 5 mg/kg. Effects peaked at 10 min, and persisted for at least 1 h after injection. In contrast, AP7 increased the VAF-VMH-evoked potential at 10 min after injection, with a maximal increase at 5mg/kg. The data suggest that NMDA receptors intrinsic to the amygdala modulate excitatory efferent transmission from amygdala to VMH in the cat. It is speculated that a glutamatergic projection to gamma-aminobutyric acid tonic inhibitory systems in the VMH accounts for the VAF-VMH results.

Journal - Journal of psychopharmacology (Oxford, England) (UNITED STATES )

Abstract :

The hypothesis that N-methyl-D-aspartate (NMDA) receptors mediate initiation of lasting behavioral changes induced by the anxiogenic beta-carboline, FG-7142, was supported in this study. Behavioral changes normally induced by FG-7142 were blocked when the competitive NMDA receptor blocker, 7-amino-phosphono-heptanoic acid, was given prior to administration of FG-7142. When cats were subsequently given FG-7142 alone, the drug produced lasting behavioral changes like those reported previously. Flumazenil, a benzodiazepine receptor antagonist, reversed an increase in defensiveness produced by FG-7142 alone, replicating previous findings. The data are consistent with the hypothesis that NMDA-dependent long-term potentiation in limbic pathways subserving defensive response to threat mediates lasting increases in defensiveness produced by FG-7142.

Journal - Behavioral neuroscience (UNITED STATES )

Abstract :

Lasting increases in anxiety-like behavior (ALB) in rodents in the elevated plus maze have been reported to follow brief (5 min) exposures to a cat. This study examined the role of CCK(A) and CCK(B) receptors in lasting increases in ALB following exposure to a cat. Block of CCK(B) receptors 30 min before and after cat exposure prevented increases in ALB assessed 1 week later in the elevated plus maze. Blocks of CCK(A) receptors either before or after cat exposure were without effect on increases in ALB measured 1 week later. Changes in activity or exploration could not account for the results. Effects of cat exposure on ALB, startle, and corticosteroid levels have been proposed as a model of affective disorder in posttraumatic stress disorder (PTSD). Implications of these findings for mechanisms of initiation of anxiety in PTSD and posttrauma pharmacological prophylaxis in PTSD are discussed.

Journal - Toxicology and industrial health (UNITED STATES )

Abstract :

The effects of kindling and inverse benzodiazepine receptor agonist beta-carbolines on animal models of anxiety are briefly reviewed in relation to affective disorder associated with chemical exposure. Recent experimental results are described. In the present study, cats were given the inverse benzodiazepine receptor agonist, FG-7142, a powerful anxiogenic compound in humans and animals. Neural transmission in pathways involved in defensive behavior in the cat was monitored using evoked potential techniques. Change in these pathways was related to behavioral changes induced by the drug. It was found that a single dose of FG-7142 lastingly increased defensive response to rodents for at least 40 days after drug administration. Behavioral change was specific to defensive response, since approach-attack behavior remained unchanged, replicating previous studies. The benzodiazepine receptor antagonist, Flumazenil, reversed the increase in defensiveness in a drug-dependent manner, replicating previous findings. Increased defensiveness was paralleled by a delayed onset potentiation of neural transmission between the amygdala and the medial hypothalamus of the left hemisphere. Potentiation in the left hemisphere was transient, decaying between 6 and 12 days after the drug. There was a longer lasting potentiation (LTP) of activity evoked in the left and right amygdalo-periacqueductal gray pathways and in the right amygdalo-medial hypothalamic pathway. Potentiation in these pathways appeared at the time of behavioral change. Potentiation of the right amygdalo-periacqueductal gray and right amygdalo-medial hypothalamic pathways persisted until the end of the experiment. In contrast, potentiation of the left amygdalo-periacqueductal gray pathway faded by 40 days after the drug. Flumazenil decreased potentiation ony in the right amygdalo-periacqueductal gray pathway. These data strongly suggest that lasting affective change is mediated by lasting changes in particular efferents of the amygdala of the right hemisphere. Behavioral and physiological effects of FG-7142 were blocked by the N-methyl-D-Aspartate (NMDA) receptor blocker, AP7. The data suggest that failure of neural inhibition induced by FG-7142 engages NMDA receptor processes to produce lasting potentiation of transmission in neural circuits that mediate defensive response with behavioral consequences. Since FG-7142 interferes with GABA mediated neural inhibition and is proconvulsant, its action might mimic the action of other environmental chemicals with similar properties, such as chlorinated hydrocarbon insecticides. The relationship of the present data to the literature on the neural and behavioral effects of insecticide exposure is discussed. The significance of these findings for multiple chemical sensitivity disorder is also briefly discussed.

Journal - Physiology & behavior (UNITED STATES )

Abstract :

The effects on rodent anxiety of kindling in the medial or basolateral amygdaloid nuclei in each hemisphere were examined. Anxiety was measured using the hole board and elevated plus maze tests. The animals were kindled in medial or basolateral amygdalas, of either the left or right hemisphere. Controls had electrodes implanted in comparable areas, but were not kindled. Analysis of electrode location showed that some animals were kindled in amygdaloid nuclei other than medial or basolateral amygdala. These animals were labelled outliers. Kindling of the medial/basolateral amygdala in the left hemisphere decreased anxiety for at least 1 week after the last kindled seizure. Right hemisphere medial/basolateral kindling tended to increase anxiety. Outlier-kindled rats were less anxious than their controls regardless of hemisphere 1 week after their last kindled seizure. Clear anxiogenic effects were not likely seen in the right hemisphere in this study because of the electrode locations. The degree of anxiety following kindling was correlated with electrode location in the anterior-posterior plane. More anterior foci in the amygdala were associated with more anxiety. More posterior amygdala foci were associated with less anxiety. These findings point to the importance of kindled focus in the amygdala for behavioral effect. Future research should carefully control the location of kindled foci when investigating effects of amygdala kindling on anxiety and other behaviors.

Journal - Physiology & behavior (UNITED STATES )

Abstract :

The effects on anxiety and risk assessment of exposure to a cat were tested in hooded rats. Anxiety and risk assessment were measured in an elevated plus maze and hole board in a room different from the cat-exposure room. Behavior was tested either 1, 2, 7, 14, or 21 days after cat exposure in different groups of rats. A single exposure to a cat increased anxiety over controls in the plus maze from 1 to 21 days after exposure to a cat. The effects on anxiety were independent of activity or exploratory tendency. Severity of anxiety produced was predicted by the approach, but not the attack, behavior of the cat. Analogous correlations between traumatic stimuli and anxiety are seen in humans suffering from posttraumatic stress disorder (PTSD). Risk assessment in the plus maze was reduced over the same period in rats exposed to cats. Risk assessment was weakly correlated with anxiety. The findings are discussed with respect to the potential of this phenomenon as a model of generalized anxiety disorder found in PTSD.

Journal - Physiology & behavior (UNITED STATES )

Abstract :

Wistar rats were kindled electrically in the anterior or posterior medial amygdala of the right hemisphere. One week after the fourth stage 5 seizure, anxiety was assessed in the elevated plus maze test. Anxiety levels of rats kindled in posterior medial amygdala were reduced relative to implanted controls, but not relative to unoperated controls. Kindling of the anterior medial amygdala increased anxiety relative to implanted and unoperated controls. The different effects of kindling on behavior were unrelated to any parameter of kindling. The stress of an ICV injection of saline increased anxiety in unkindled controls but reduced anxiety in anterior medial amygdala-kindled rats. Injection stress effects on behavior were blocked by 50 micrograms of alpha-helical CRF (the CRF receptor blocker). These findings suggest that CRF released by the stress of the injection procedure mediates the behavioral effects in both kindled and control rats. In contrast, injection of CRF (2 micrograms, ICV) has no greater effect than ICV saline in anterior medial amygdala kindled rats, whereas it was anxiogenic in unkindled rats. ICV vehicle and CRF reduce kindling-induced anxiety equally. These findings suggest that CRF released during the injection procedure saturates available CRF receptors. Finally, kindling did not alter basal plasma corticosterone levels. These and other findings suggest that the anxiety-modulating actions of CRF are at central CRF receptors.

Journal - Physiology & behavior (UNITED STATES )

Abstract :

This study examined the interictal consequences of partial kindling of the ventral perforant path on attack and defensive behavior in the domestic cat. Partial kindling produced a lasting increase in defense response of cats to both rats and conspecific threat howls. In addition, there was a lasting suppression of approach-attack behaviors directed toward rats. The suppression of some components of approach-attack were shown to be independent of the increases in defensive response. The effects of partial kindling of the ventral perforant path on spread of seizure activity into the amygdala, and on the output of the amygdala to both the ventromedial hypothalamus (VMH) and bed nucleus of the stria terminalis (BNST) were also examined. In addition, the effects of repeated hippocampal seizures on recurrent inhibition in the trisynaptic circuit (areas CA1 and CA3) were investigated. Growth of seizure activity in the amygdala and VMH as partial kindling progressed was essential for behavioral change. In addition, interictal long-term potentiation of potentials evoked in the VMH and in the BNST by pulsed stimulation of the amygdala followed partial kindling or afterdischarge threshold determination in the ventral perforant path. A lasting interictal increase in inhibition in area CA3 and a lasting interictal failure of inhibition in area CA1 of the ventral hippocampus also followed partial kindling. These changes in limbic physiology were related to the behavioral changes produced by partial kindling. The analysis revealed the importance of the amygdalo-VMH pathway in increased defensive response to rats. The amygdalo-BNST pathway is not important in mediating defensive response to prey, but it is implicated in suppression of some types of predatory aggression. Finally, changes in neural inhibition in the ventral hippocampus in areas CA1 and CA3 are associated with changes in both defensiveness and predatory aggression.

Journal - Physiology & behavior (UNITED STATES )

Abstract :

In Experiment I, neurosensory responses from three limbic areas in the cat brain were recorded when cats of differing defensive temperamental traits were exposed to species characteristic threat. The cats investigated were more or less defensive in response to rats and conspecific threat howls. The behavioral disposition of these cats was stable over retest periods of more than one year. It was found that during visual inspection of rats, more defensive cats displayed greater neural activity in the amygdala and the ventromedial hypothalamus than less defensive cats, who showed no change over baseline. Neurosensory response of the amygdala to conspecific threat howls was also found to be greater in more defensive cats. In contrast, there was no neural response to threat howls in the hypothalamus. Neurosensory response to mice was different from the response to rats and threat howls. Visual inspection of the mouse was associated with a decrease in activity in the amygdalas of more defensive cats. Finally, response of the ventral hippocampus was unspecific, appearing to signal only a change in the stimulus environment. The increase in hypothalamic neural activity in response to rats in more defensive cats appeared to be driven by a potentiated output from the amygdala, since the ratio of hypothalamic to amygdala neurosensory response to rats was greater than one in more defensive cats, but equal to one in less defensive cats. Output of the amygdala was directly investigated using evoked potential techniques in Experiment II. Potentials evoked in the hypothalamus by amygdala stimulation were larger in more defensive cats. Size of the hypothalamic potential was highly correlated with the ratio of hypothalamic to amygdala neurosensory response (ratio response) to rats. Removing the effects of size of the hypothalamic evoked potential from the ratio response by analysis of covariance eliminated the difference between more and less defensive cats in ratio response to rats. The significance of these findings for the physiological bases of defensive response to threat and of temperamental traits are discussed.

Journal - Neuroreport (ENGLAND )

Abstract :

In humans, limbic epilepsy seems to predispose to anxiety. Attempts to model this phenomenon have shown that limbic kindling increases anxiety in domestic cats. No comparable data exist in rodents. The present study was done to investigate the effects of unilateral medial amygdala kindling in Wistar rats on behaviour in the 'elevated plus maze' test of anxiety. It was found that kindling to stage 5 seizures increased anxious response in the plus maze for at least a week following the last seizure. There were equally long lasting decreases in exploratory motivation in the hole board test, which were unrelated to the change in anxiety in the plus maze. The relevance of these findings to epilepsy, stress and anxiety are discussed.

Journal - Progress in neuro-psychopharmacology & biological psychiatry (ENGLAND )

Abstract :

1. The effects of intravenous injections of procaine HCl on population cellular activity in limbic tissue and overlying cortex, and on transmission of evoked activity between limbic structures was investigated in awake cats. Clear dose-related increases in cellular activity were seen in amygdala and ventral hippocampus. Changes in cellular activity in the nucleus accumbens and temporal neocortex were also dose-related, but in a complex time-dependent manner. Changes in ventromedial hypothalamus only appeared at the second highest dose of procaine. 2. Procaine facilitated transmission of evoked excitatory activity from the amygdala to the ventromedial hypothalamus, but only after a considerable delay from the time of injection. On the other hand, procaine had no effect on activity evoked in the ventral hippocampus, nucleus accumbens or temporal cortex by amygdala stimulation. 3. It was concluded that intravenous procaine functions as an excitant of limbic system cells, and that procaine alters synaptic transmission in some, but not all, output pathways from the amygdala. The neuroexcitant effects of procaine appear to be idiosyncratic, however, varying over dose with limbic and cortical area examined.