Anxiogenic Compounds Research Articles

Withdrawal from chronic phencyclidine produces a pentylenetetrazol-like discriminative stimulus

Rats trained to discriminate the anxiogenic compound pentylenetetrazol (PTZ) from water were implanted with osmotic mini-pumps containing 7 mg/kg/day phencyclidine (PCP) or water. Rats were tested for generalization to PTZ 24 hours prior to pump removal, and 4 to 96 hours after pump removal. While the pumps were in place, rats did not generalize to PTZ. When the pumps were removed on day 10, rats in the water group did not generalize to PTZ, but 69% of the rats in the chronic PCP group responded on the PTZ lever at 4 and/or 24 hours after pump removal, suggesting that the PCP withdrawal state mimics the interoceptive cue produced by PTZ. This withdrawal phenomenon was repeatable, in that rats that generalized once to PTZ during PCP withdrawal, generalized a second time when the procedure was repeated. In addition, the phenomenon was dose-dependent, as rats that did not generalize to PTZ after 7 mg/kg/day PCP did generalize when the chronic dose of PCP was increased to 10 mg/kg/day. These findings suggest that there is an anxiogenic component of PCP withdrawal and that tolerance does not develop to this effect.

Are 5-HT 2 antagonists endowed with anxiolytic properties in rodents?

The precise role of serotonin (5-HT) in anxiety remains unclear. We report here on the effects of RP 62203, a new 5-HT 2 antagonist, and ritanserin in different animal models of anxiety. In the elevated plus-maze in mice, RP 62203 increased dose-dependently the percentage of entries onto, and time spent on open arms, over the dose range 0.25–4 mg·kg −1 p.o. By contrast, ritanserin was ineffective up to the dose of 4 mg·kg −1 p.o. In addition, both compounds were tested against the anxiogenic compound FG 7142 (20 mg·kg −1, i.p.) in the plus-maze test in mice and via electrocorticographic recordings (ECoG) in rats. The anxiolytic effect of RP 62203 is antagonized by FG 7142 at a dose devoid of anxiogenic properties. A similar interaction between RP 62203 and FG 7142 is observed in ECoG studies. In contrast, ritanserin seemed to potentiate the anxiogenic and awakening activities of FG 7142. These results demonstrate that RP 62203, a selective 5-HT 2 antagonist, possesses anxiolytic properties in rodents suggesting that 5-HT 2 receptors are involved in the control of anxiety.

Differential effects of anxiogenic central and peripheral benzodiazepine receptor ligands in tests of learning and memory.

Previous research has demonstrated that low doses of anxiogenic central benzodiazepine receptor (CBR) ligands, the beta-carbolines, improve performance in various learning and memory tests in animals if administered prior to training. The present experiments compared the effect of a beta-carboline (FG 7142) with that of a pharmacologically distinct anxiogenic compound, a peripheral benzodiazepine receptor (PBR) ligand, 4'-chlorodiazepam (Ro5-4864), in two tests of learning and memory in rats. As expected, FG 7142 significantly improved performance in a passive avoidance test. Ro5-4864 was without effect. In a shuttlebox escape test, Ro5-4864 significantly impaired performance while FG 7142 had no effect. The effect of Ro5-4864 was antagonized by the specific peripheral benzodiazepine receptor antagonist, PK 11195. These results indicate that the differential impact of CBR and PBR anxiogenic ligands on performance in aversively-motivated learning tests may be a reflection of their distinct pharmacologies.

The Role of the Temporal Lobe in Feline Aggression and Defense

Four lines of research are reviewed which investigated the role of the amygdala, ventromedial hypothalamus, bed nucleus of the stria terminalis, ventral hippocampus and the benzodiazepine receptor in predatory aggression and defense in the cat. The first two lines of research involved permanently increasing defensive response to threat either by repeatedly inducing subclinical seizure discharges in the ventral hippocampus and amygdala or by administering the benzodiazepine inverse agonist, anxiogenic compound FG-7142. In the third line of research, defensive response of cats was both transiently and lastingly reduced by high frequency stimulation of the basolateral amygdala. The fourth line of research examined the relationship between spontaneous cellular response to species-characteristic threat and individual differences in transmission of neural activity between the amygdala and ventromedial hypothalamus. Together, these studies point to the importance of the amygdalo-ventromedial hypothalamic pathway in defensive response to some, but not all conspecific threats. They also implicate other limbic pathways in the suppression of predatory aggressive responses. The amygdalo-bed nucleus of the stria terminalis pathway does not appear to be important in mediating defensive response to prey, but it is implicated in suppression of some types of predatory aggression. Neural inhibition and facilitation in particular cell fields of the ventral hippocampus seem to play a role in modulation of predatory aggression. Finally, the benzodiazepine receptor may be involved in modulating excitability in the amygdalo-VMH pathway, and it may also participate in a separate neural substrate which suppresses approach-attack behaviors.

Resident-Intruder Paradigms and Antiaggressive Drugs: Some Further Data

Treatment with a number of phenylpiperazine drugs induces a selective inhibition of attack behavior during resident-intruder encounters which has been interpreted as reflecting a drug-induced “serenic” state. Treatment with two well-characterized anxiogenic compounds (yohimbine, FG 7142), however, also closely mimicked the effects of phenylpiperazines on such attack. In addition, studies with two of the serenics revealed that they increased avoidance induced by novel stimuli (fluprazine) and/or nonaggressive conspecifics (fluprazine and eltoprazine). These data not only suggest that phenylpiperazines may be more properly characterized as anxiogenic, but the data also bring into question the usefulness of behavioral profiles derived exclusively from resident-intruder tests to infer anxiolytic or anxiogenic drug actions. Novelty-induced tearfulness is suggested to provide a useful instrument for the detection of generalized anxiolytic or anxiogenic effects whereas nonagonistic social interactions reveal more specific drug effects on reactivity to conspecifics. In addition, the fact that the attack-suppressing effects of fluprazine and yohimbine are also accompanied by increased sniffing behavior and altered conspecific odor preferences strongly suggests the need for a careful examination of olfactory function in the assessment of any putative antiaggressive drug.

Effects of 8-OH-DPAT, buspirone and ICS 205-930 on feeding in a novel environment: comparisons with chlordiazepoxide and FG 7142

Previously, the 5-hydroxytryptamine (5-HT)1A receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone and the 5-HT3 receptor antagonist ICS 205-930 have been shown to exert anxiolytic-like effects in several animal models. In the experiments reported here the effects of these compounds on feeding behaviour and food preference in a novel environment were examined, and compared with the effects of the anxiolytic drug chlordiazepoxide and the anxiogenic compound FG 7142. Chlordiazepoxide significantly reduced the latency to begin eating and prolonged the total time spent eating; chlordiazepoxide also abolished food neophobia, by significantly increasing the time spent eating novel food items. In contrast, FG 7142 significantly increased eating latency and reduced eating duration. Both 8-OH-DPAT and buspirone significantly enhanced eating duration, but unlike chlordiazepoxide eating was directed only towards the familiar food. In addition buspirone, but not 8-OH-DPAT, reduced eating latency. ICS 205-930 significantly increased eating latency and reduced eating duration; however, these effects were observed only at the lowest dose tested. All of these behavioural effects were observed only when animals were unfamiliar with the testing situation, and cannot be accounted for in terms of changes in mechanisms controlling hunger. The behavioural paradigm used in these experiments may induce a competition between the drives to explore a novel environment and to eat. It is suggested that the tendency of buspirone and 8-OH-DPAT to suppress exploratory activity may thus result in enhanced feeding duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of yohimbine on novel open field exploration of mice

The effects of the anxiogenic compound yohimbine on exploration of a novel open field was investigated. The drug had no effect on latency to enter the open field but produced a marginally significant increase in number of open field entries. The results suggest that yohimbine may have behavioral stimulant and/or anticonflict properties under some testing conditions. Such effects may limit its usefulness as a research tool for the study of anxiety.

Central effects of corticotropin releasing factor (CRF): evidence for similar interactions with environmental novelty and with caffeine

Centrally administered rat/human corticotropin-releasing factor (rCRF) increases low levels of locomotor activity by rats tested in a familiar environment but suppresses the higher levels of activity associated with exposure of the animals to a novel environment. These opposing responses do not appear to be manifestations of a simple rate-dependent effect, since ICV-administered rCRF did not lower the higher levels of locomotor activity associated with the dark (active) phase of the animal's activity cycle. Caffeine, which has anxiogenic effects in man, produces effects in rats which are similar to those of rCRF. That is, both compounds elevate activity in a familiar environment but lower activity in a novel environment. Furthermore, caffeine appears to substitute for novelty in determining the direction of the locomotor effect of rCRF. Animals made hyperactive by caffeine show decreased activity when co-administered rCRF. These findings are consistent with the view that CRF acts through pathways which also subserve the responsiveness to novelty and to the anxiogenic compound caffeine.

Interactions between RO 15-4513 and ethanol on brain self-stimulation and locomotor activity in rats

Experiments were conducted to elucidate the behavioral effects of RO 15-4513, a putative alcohol antagonist, when administered alone or in combination with alcohol. Two groups of animals were trained to lever-press for brain self-stimulation (ICSS) on either a fixed ratio:15 or a fixed interval:15 second schedule of reinforcement. RO 15-4513 (0.1–3.0 mg/kg) reduced the rate of lever-pressing for ICSS in both groups. RO 15-4513 (1.0 mg/kg) further reduced rates when combined with alcohol (0.1–1.7 g/kg), and this effect was especially marked in the fixed ratio paradigm. Other groups of animals were tested in a locomotor activity apparatus. In contrast to the depression of lever-pressing in the ICSS experiments, RO 15-4513 produced a graded increase in locomotor activity. When combined with alcohol (0.1–1.7 g/kg), 1.0 mg/kg RO 15-4513 also increased locomotor activity. Thus, the depression in schedule-controlled behavior was not associated with a generalized behavioral depression. These results demonstrated that RO 15-4513 has potent behavioral effects of its owm that are consistent with its classification as an anxiogenic compound.

Effect of 5-HT 1A agonists on stress-induced deficit in open field locomotor activity of rats: Evidence that this model identifies anxiolytic-like activity

Deficits in locomotion and exploratory behaviour in an open field were induced in rats by restraint for 2 hr, 23 hr before testing. Diazepam, 0.62 and 1.25 mg/kg, intraperitoneally (i.p.), 15 min before testing, reversed the stress-induced reduction in locomotion; 1.25 mg/kg also attenuated the effect of stress on exploration (rearing and object exploring). Diazepam did not affect the activity of controls. A putative anxiogenic compound, pyrazoloquinoline (CGS 8216, 10 mg/kg administered 30min before testing), also markedly reduced locomotion and exploration and the effect was reversed by 2.5 mg/kg diazepam, 15min before testing. Buspirone, 0.1 mg/kg subcutaneously (s.c.) 15 min before testing, significantly attenuated the effect of stress on locomotion and exploration but had no effect in controls. Larger doses (0.5 and 1.0 mg/kg) markedly reduced the behavioural measures in controls and did not modify or enhance the effect of stress. 8-Hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), 0.25 and 0.5 mg/kg (s.c.), 1 hr before testing, significantly attenuated the reduction in locomotion without affecting rearing and object-exploring in stressed rats. At doses from 0.125 to 0.5 mg/kg, 8-OH-DPAT reduced exploration in control rats. Two hr after restraint (corresponding to 21 hr before testing in the open field) 8-OH-DPAT, 0.125 to 2 mg/kg (s.c.), did not modify the open field deficits, caused by stress. In these treatment conditions, 0.5 and 2 mg/kg 8-OH-DPAT reduced locomotion and exploration in control rats. Desipramine (10 mg/kg i.p.), given by an acute (1 hr before testing) or chronic (once daily for 14 days, last injection 1 hr before testing) treatment schedule, did not modify the effect of stress on locomotion and exploration in the open field, whereas a single dose of 10 mg/kg of desipramine reduced these measures in control rats. The results suggest that the stress-induced deficit in locomotor activity of rats in the open field offers a model for identifying anxiolytic-like activity ofserotonuiiA receptor agonists, in addition to diazepam.

Chronic treatment with imipramine does not reverse the effects of 3 anxiogenic compounds in a test of anxiety in the rat.

The ability of chronic treatment with imipramine (an antidepressant with anti-panic activity) to antagonise the anxiogenic effects of 3 different compounds was investigated in the elevated plus-maze. The compounds chosen are likely to produce anxiety by activity at different sites in the central nervous system: yohimbine, by blocking the alpha 2-adrenoceptor; FG 7142, by action at the beta-carboline site on the GABA-benzodiazepine receptor complex and pentylenetetrazole, by acting at the picrotoxinin site on this complex. Administration of imipramine following 21 days pre-treatment did not produce a significant consistent anxiolytic effect alone and was unable to reverse the anxiety produced by any of the 3 anxiogenic compounds. Our results are discussed in terms of the nature of the anxiety produced by the anxiogenic drugs and the sensitivity of tests of anxiety to anti-panic agents.

Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat.

The current studies further investigated the effects, in animal models of anxiety, of novel putative anxiolytic and anxiogenic compounds believed to induce their effects by actions at the GABA-benzodiazepine receptor complex. It was expected that the results would also provide further validation for a novel test of anxiety based on the ratio of open to closed arm entries in an elevated plus maze in the rat. The novel putative anxiolytics CL 218,872 (10-20 mg/kg) and tracazolate (5 mg/kg) significantly elevated the percentage of time spent on the open arms of an elevated plus-maze, consistent with their anxiolytic activity in several other animal tests. Also consistent with results from other animal tests, no anxiolytic activity was observed for the phenylquinoline PK 8165 (10-25 mg/kg), the 3,4-benzodiazepine tofisopam (25-50 mg/kg), or buspirone (0.5-20 mg/kg). The benzodiazepine receptor inverse agonists FG 7142 (1-5 mg/kg) and CGS 8216 (3-10 mg/kg) had anxiogenic activity in this test, as did the atypical benzodiazepine Ro 5-4864 (1-5 mg/kg). Interestingly, however, the benzodiazepine receptor antagonists Ro 15-1788 (10-20 mg/kg) and ZK 93426 (5-10 mg/kg) had no anxiogenic activity in this test.

The effects of putative anxiogenic compounds (FG 7142, CGS 8216 and Ro 15-1788) on the rat corticosterone response

The effects of FG 7142, CGS 8216 and Ro 15-1788, three compounds that are believed to produce anxiety by an action at benzodiazepine receptors in the CNS, are investigated on the plasma corticosterone concentrations in the rat both in the home cage and after exposure to novelty stress. FG 7142 (5 mg/kg) and CGS 8216 (10 mg/kg), but not Ro 15-1788 (4 or 10 mg/kg) increased basal corticosterone levels in the home cage, and all three compounds potentiated the increase in corticosterone concentrations observed after exposure to a novel environment. The relationship between the effects of drugs on corticosterone concentrations and on anxiety is considered in the light of these results.

Can drug effects on anxiety and convulsions be separated?

The effects of benzodiazepines, barbiturates, a series of novel putative anxiolytic compounds and anxiogenic compounds are reviewed in animal tests of anxiety and on experimentally-induced seizures. It is clear from the data that drug effects on anxiety and convulsions are not always in the same direction; certain compounds are apparently both anxiolytic and proconvulsant, others are anxiogenic and anticonvulsant, others have varied effects depending on the test situation. It is suggested that this work necessitates considerable revision of our traditional concepts of an “anticonvulsant”. The extent to which drug-induced anxiety is correlated with weak epileptiform activity in the brain is discussed. Finally, the Discussion considers a number of possible mechanisms that could underlie the separation of drug effects on anxiety and convulsions that is observed.

Exploratory behavior models of anxiety in mice

Parameters of exploratory behaviors responsive to anti-anxiety drugs are reviewed with respect to their sensitivity and specificity for anxiolytics in mice. Mouse models appear to rest on a disinhibition of natural exploratory tendencies by anxiolytic treatments. Analysis of agonists of the brain benzodiazepine binding site, such as chlordiazepoxide and diazepam, significantly increase exploration of a hole-board, of a two-chambered light dark apparatus, increase social interaction under high levels of illumination, increase consumption of a novel food in an unfamiliar environment, and increase punished crossings in a footshock conflict paradigm. These tests detect anxiolytic responses at doses of benzodiazepines well within the clinically effective range. Pharmacological specificity was established for the hole-board and light dark transition tests, showing that non-anxiolytic categories of psychoactive drugs did not produce false positives. Open field behaviors and isolation-induced aggression were reduced by anxiolytics, at doses which may be within the sedative-hypnotic range. Analysis of antagonists of the brain benzodiazepine binding site did not show active antagonist properties in the light dark transitions model, although the antagonist Ro-15-1788 appeared to have partial agonist properties in the open field test, suggesting that rat models may be more sensitive to anxiogenic compounds than are mouse models. The wide separation between anxiolytic and sedative doses in mouse models recommend these exploration paradigms as good predictive screens for the testing of novel anxiolytic compounds.