Antagonistic effects of caffeine and yohimbine in animal tests of anxiety

The effect of a combination of caffeine and yohimbine was investigated in the social interaction, elevated plus-maze and punished-drinking tests of anxiety. Caffeine (40 mg/kg i.p.) had anxiogenic-like effects in the social interaction and plus-maze tests. Yohimbine (2.5 mg/kg i.p.) was anxiogenic-like in the plus-maze and displayed anticonflict activity. Unexpectedly, caffeine and yohimbine antagonized each others' effects in the social interaction and elevated plus-maze tests.     

Tolerance to nicotine's effects in the elevated plus-maze and increased anxiety during withdrawal

In the elevated plus-maze test of anxiety, nicotine (0.1 mg/kg sc; 30 min after injection) had a significant anxiogenic effect, shown by specific decreases in the percentage of time spent on the open arms and in the percentage of open-arm entries. Tolerance developed to this anxiogenic effect after 7 days of nicotine treatment (0.1 mg/kg/day). Five minutes after an acute injection, nicotine (0.1 mg/kg) was ineffective, but after 7 days of treatment a significant anxiolytic effect, shown by specific increases in the percentage of time spent on the open arms and in the percentage of open-arm entries, emerged. After 14 days of nicotine treatment, tolerance developed to this anxiolytic effect. There was a complete dissociation between the effects of nicotine on the measures of anxiety, and on the locomotor activity as measured by closed-arm entries. No changes in closed-arm entries were found after acute administration of nicotine, but rats tested 30 min after their 7th injection made significantly fewer, and those tested 5 min after their 14th injection made significantly more, entries than their respective controls. Rats that were tested after 24 h withdrawal from six daily nicotine injections showed a significant anxiogenic effect. A low dose of nicotine (5 ng) injected into the dorsal hippocampus was without effect in vehicle pretreated rats, but it was able to reverse the anxiogenic effect found after 24 h of withdrawal from 6 days of nicotine treatment.     

The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard

In addition to possessing anti-anxiety activity in man, triazolobenzodiazepines have been reported to have antidepressant and antipanic properties. In this they differ from classical 1,4-benzodiazepines that have only anti-anxiety activity. The purpose of the present study was to examine the effects of the triazolobenzodiazepines in two animal tests of anxiety and in the holeboard, to see whether clear differences could be observed between them and the 1,4-benzodiazepines. After acute administration, U-43,465 (16 mg kg-1) had a significant anxiolytic effect in the social interaction test. Neither adinazolam (1-3.5 mg kg-1) nor alprazolam (0.125-2 mg kg-1) had a significant effect. It is suggested that this is because, with adinazolam and alprazolam, doses at which anxiolytic effects can be observed are close to those at which sedative effects can be observed. U-43,465 (8-16 mg kg-1) and alprazolam (1-2 mg kg-1) had significant anxiolytic effects in the elevated plus-maze test of anxiety. U-43,465 (8-32 mg kg-1), adinazolam (0.5-5 mg kg-1) and alprazolam (0.2-2.0 mg kg-1) caused dose-related reductions in exploratory head-dipping, locomotor activity and rearing in the holeboard. In general the results seen in the three tests with the triazolobenzodiazepines alprazolam and adinazolam were similar to those seen with classical 1,4-benzodiazepines. With U-43,465, however, an anxiolytic effect was observed in the social interaction test after acute treatment; chronic treatment is required to see an effect with classical 1,4-benzodiazepines. In this U-43,465 resembles the effects of several novel non-benzodiazepine putative anxiolytic compounds that are believed to have less sedative potential than the benzodiazepines.     

Effects of GABAB receptor ligands in animal tests of depression and anxiety

Preclinical evidence strongly implicates GABA(B) receptors in the pathophysiology of several psychiatric disorders including anxiety and depression. In the present study, we investigated the effects of the selective GABA(B) receptor agonists baclofen and SKF 97541, the GABA(B) receptor positive allosteric modulator CGP7930 and the GABA(B) receptor antagonist SCH 50911 in the modified forced swimming test (FST) and in the elevated zero maze test (EZM), i.e. in animal models predictive of antidepressant and antianxiety activities, respectively. The classical antidepressant imipramine and the anxiolytic diazepam were employed as control drugs in the FST and in the EZM, respectively. In the FST, baclofen (0.25 mg/kg), SKF 97541 (0.01-0.05 mg/kg) or CGP 7930 (1-3 mg/kg) and SCH 50911 (1-3 mg/kg) showed antidepressant-like activity, significantly decreasing immobility time; these effects were not related to changes in locomotor activity. The antidepressant effects produced by the GABA(B) receptor ligands were compared with that of imipramine (30 mg/kg). In the EZM, CGP 7930 (1 mg/kg) and SCH 50911 (1-3 mg/kg) produced anxiolytic-like effects, significantly increasing time spent in the open areas of the maze; those effects were comparable with the effects of diazepam (1-2 mg/kg). Our results indicate that differential manipulation of GABA(B) receptors can modify behaviors relevant to depression and anxiety. The GABA(B) receptor positive allosteric modulator CGP 7930 and the antagonist SCH 50911 show both antidepressant and anxiolytic profile, while the GABA(B) receptor agonists (baclofen and SKF 97541) produce effects that are characteristic of antidepressant drugs.     

Anxiolytic effects of mecamylamine in two animal models of anxiety

Clinical and preclinical evidence suggests that mecamylamine, a nicotinic receptor antagonist, may have anxiolytic properties. The purpose of this study was to further investigate the anxiolytic properties of mecamylamine in rats as measured by the Elevated Plus Maze and the Social Interaction models of anxiety and to determine if manipulation of the testing environment (either brightly lit or dimly lit conditions) influenced the results. Results indicated that mecamylamine had significant anxiolytic effects in both the Elevated Plus Maze and Social Interaction Tests and that these effects were dependent on dose administered and the level of anxiety produced under different testing conditions. If confirmed by further clinical research, nicotinic receptor antagonists like mecamylamine may represent a novel class of anxiolytics.     

The effects of PK 11195, a ligand for benzodiazepine binding sites, in animal tests of anxiety and stress

PK 11195 (1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3-isoquinolinecarboxami de, a potent ligand for peripheral benzodiazepine binding sites, was unable to reverse the anxiogenic effects of Ro 5-4864 (chlorodiazepam) in the social interaction test or in the punished drinking test. However, at 90 mg/kg PK 11195 also reduced social interaction, indicating an anxiogenic effect. Both PK 11195 (30-120 mg/kg) and Ro 5-4864 (20-60 mg/kg) significantly increased the plasma corticosterone concentrations of rats left in their home cages after injection, and in those placed in novel apparatus. Because both drugs had effects in the same direction and because the doses were far higher than those needed to saturate the peripheral receptor, it is unlikely that these behavioural actions are mediated by peripheral benzodiazepine binding sites. It is suggested that the effect of PK 11195 could even be mediated by the classical CNS benzodiazepine binding sites.     

Lack of consistent behavioural effects of Maudsley reactive and non-reactive rats in a number of animal tests of anxiety and activity

RATIONALE: A number of previous studies have reported that the Maudsley reactive (MR/Har) and non-reactive (MNRA/Har) strains of rats show behavioural and physiological differences consistent with the hypothesis that these strains differ in emotionality and could therefore be considered a model of trait anxiety in humans. OBJECTIVES: We sought to confirm this observation by determining their behaviour in various animal models of conditioned and unconditioned fear. METHODS: Both strains were evaluated in the open field (OF), conditioned avoidance (CA), elevated plus maze (EPM) and fear-potentiated startle (FPS) tests. In the OF the behaviour of both strains was consistent with previous results showing that reactive rats had significantly higher levels of defecation and lower levels of activity than the non-reactive rats. However, there were no significant strain differences in CA responses or in the time spent on the open arms of the EPM. In addition, the full benzodiazepine receptor agonist, chlordiazepoxide, induced quantitatively similar effects in both strains of rats. In the FPS test, MNRA/Hars had a higher baseline level of startle and fear potentiation than the MR/Har rats. CONCLUSIONS: These data show that the behaviour of MR/Har and MNRA/Har rats in some models of conditioned and unconditioned fear is inconsistent with that predicted by their behaviour in the OF test, suggesting that they are not a model of trait fear.     

The role of physical activity in nicotine's effects on body weight

The present study examined the effects of chronic nicotine administration and cessation of nicotine administration on body weight and 24-hour physical activity of rats. There was a significant, inverse, dose-effect relationship between nicotine administration and body weight. Cessation of nicotine was accompanied by increased rates of body weight gain compared to controls. The changes in body weight during nicotine administration could not be explained by changes in physical activity. However, decreases in physical activity after cessation of nicotine appeared to contribute to post-drug body weight increases. These findings have implications for weight control after cessation of cigarette smoking.     

The effects of p-chlorophenylalanine and ethanolamine-O-sulphate in an animal test of anxiety

p-Chlorophenylalanine, which produces a depletion of brain 5-HT concentration, had effects qualitatively similar to those previously found with chronic chlordiazepoxide and with acute ethanol in the social interaction test of anxiety. This result is compatible with the idea that a reduced turnover of 5-HT is important in anxiety reduction. On the same test, ethanol-amine-O-sulphate, which raises brain γ-aminobutyric acid, was without effect, suggesting raised concentrations of this acid are not essential for anxiety reduction.     

The effects of chronic antidepressant treatment in an animal model of anxiety

We have examined the anxiolytic activity of acute and chronic antidepressant treatment in an animal model of anxiety involving novelty-suppressed feeding. Rats were food deprived for 48 h, placed into a novel environment containing food, and the latency to begin eating was recorded. Chronic (21 days), but not acute injections of desipramine (DMI; 10 mg/kg) and amitriptyline (AMI; 10 mg/kg) significantly reduced the latency to begin eating compared to controls, but the percentage decrease was not as great as that seen with either acute or chronic treatment with diazepam (2 mg/kg) or adinazolam (20 mg/kg). A time course study indicated that at least 2 weeks of treatment was necessary to observe a significant anxiolytic effect of antidepressants. The anxiolytic effect of the antidepressants was specific to the novel environment, as 2 weeks of treatment with either diazepam or DMI did not influence the latency to begin eating in the home cage. Finally, a single dose of the central benzodiazepine receptor antagonist, Ro15-1788 (20 mg/kg), given 15 min prior to testing, did not block the anxiolytic effects of chronic DMI, while it completely eliminated the effect of chronic diazepam treatment. These data suggest that antidepressants acquire anxiolytic properties following chronic administration and that this effect appears to be independent of the benzodiazepine receptor system.     

Comparison of anti-conflict drug effects in three experimental animal models of anxiety

A novel form of experimentally-induced conflict behavior based on the conditioned suppression of drinking (CSD) is described and compared with two conventional animal models of human anxiety — a modified Geller-Seifter and an Estes-Skinner (Conditioned Emotional Response) procedure. The CSD procedure offered significant advantages over the two operant procudures in that the session duration was short (10 min) and the acquisition of stable behavioral baselines was rapid (approximately 2 weeks). Like the more conventional procedures, the CSD paradigm permitted the simultaneous determination of drug effects on shock-suppressed and nonsuppressed responding as estimates of antianxiety and sedative properties, respectively. With the CSD procedure, the anticonflict profiles for the benzodiazepines were highly correlated with their relative clinical antianxiety potency. Therefore, the CSD procedure appears to be a valuable tool in screening for possible antianxiety agents as well as in the behavioral testing of mechanism of action hypotheses regarding such agents.     

The effects of angelica essential oil in three murine tests of anxiety

The effects of angelica essential oil in three assays predictive of anxiolytic activity in male mice were studied, with diazepam as a positive anxiolytic control. In the elevated plus-maze test, compared to the positive control diazepam, angelica essential oil (30.0 mg/kg, PO) had a modest anxiolytic-like effect (increased the percentage of open-arm time and reduced the percent protected head dips). In the light/dark test, angelica essential oil (30.0 mg/kg) prolonged the time spent in the light area without altering the locomotor activity of the animals. In the stress-induced hyperthermia test, 60 and 70 min after drug administration, rectal temperature was measured twice, angelica essential oil at the dose of 30.0 mg/kg inhibited stress-induced hyperthermia. Thus, these findings indicate that angelica essential oil, as does diazepam, exhibits an anxiolytic-like effect. Further studies will be required to assess the generality of the present findings to other species and behavioural paradigms.     

The effects of p-chlorophenylalanine and ethanolamine-O-sulphate in an animal test of anxiety.

p-Chlorophenylalanine, which produces a depletion of brain 5-HT concentration, had effects qualitatively similar to those previously found with chronic chlordiazepoxide and with acute ethanol in the social interaction test of anxiety. This result is compatible with the idea that a reduced turnover of 5-HT is important in anxiety reduction. On the same test, ethanolamine-O-sulphate, which raises brain gamma-aminobutyric acid, was without effect, suggesting raised concentrations of this acid are not essential for anxiety reduction.     

Nitric oxide-mediated anxiolytic-like and antidepressant-like effects in animal models of anxiety and depression

The effects of microinjection of the nitric oxide (NO) precursor l-arginine (l-Arg), the NO synthase (NOS) inhibitors N-methyl-l-arginine (l-NAME) and 7-nitroindazole (7-NI), and the cyclic guanosine 3',5'-monophosphate (cGMP) analog 8-Br-cGMP into the dorsal raphe nucleus (DRN) were assessed in rats using the elevated plus maze (EPM) and the forced swim test (FST). l-Arg (100 and 200 nmol) produced an anxiolytic-like effect in the EPM. 8-Br-cGMP (25 and 50 nmol) dose-dependently increased locomotor activity. In the FST, antidepressant-like effects were produced by l-Arg (50 and 100 nmol) and 8-Br-cGMP (12.5 and 25 nmol). Dual effects were observed with NOS inhibitors l-NAME and 7-NI in both the EPM and FST. While low doses of l-NAME (25 nmol) or 7-NI (1 nmol) induced a selective increase in EPM open arm exploration and a decrease in immobility time in the FST, high doses (l-NAME 400 nmol, 7-NI 10 nmol) decreased locomotor activity. These results show that interference with NO-mediated neurotransmission in the DRN induced significant and complex motor and emotional effects. Further studies are needed to elucidate the mechanisms involved in these effects.     

Sex differences in nicotine's effects on consummatory behavior and body weight in rats

Nicotine administration and cessation have greater effects on body weight and eating behavior in female than in male rats. These generalizations are based on studies of body weight and eating behavior for 2–3 week periods before, during, and after nicotine administration. Therefore, the sex differences may reflect differences in sensitivity to nicotine or simply differences in the time course of nicotine's effects. The present research was designed to replicate these previous studies and to examine long-term effects of nicotine cessation on body weight. Nicotine or saline was administered SC to female and male Sprague-Dawley rats for 16 days. Body weight, food consumption, and water consumption were measured before, during, and after nicotine administration. In addition, body weight was measured for 4 months after cessation of nicotine. There was an inverse relationship between nicotine and body weight. Also, there was an inverse relationship between nicotine and general consummatory behavior for females but not for males. The body weight of females that had received nicotine were indistinguishable from controls up to 4 months after cessation of nicotine. The body weight of males that had received 12 mg nicotine per kg per day remained lower than controls.This work was supported by the USUHS Protocol No. C07223. The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences     

Adolescent and adult male rats differ in sensitivity to nicotine's activity effects

More than 90% of cigarette smokers begin smoking during adolescence, suggesting that adolescents may be particularly vulnerable to nicotine's effects. This experiment examined: (1) nicotine's acute effects on locomotion in adolescent and adult male Sprague-Dawley rats (Drug Phase I); (2) the effects of age of initial nicotine exposure on locomotion when nicotine was not administered (Interim Phase); and (3) the effects of age of initial nicotine exposure on later responses to nicotine (Drug Phase II). In Drug Phase I, animals were administered 0, 0.01, 0.10, 0.50, or 1.0 mg/kg nicotine sc for 12 days and horizontal activity was measured daily. During the Interim Phase, activity was measured but nicotine was not administered. During Drug Phase II, animals were administered the same nicotine dosages as in Drug Phase I for 12 days, and activity was measured daily. Drug Phase I revealed dose-response differences between adolescents and adults such that adolescents exhibited peak activity at both the 0.50- and 1.0-mg/kg dosages, but adults exhibited peak activity at the 0.50-mg/kg dosage. Initial nicotine exposure in adolescence (0.50 and 1.0 mg/kg), but not in adulthood, resulted in hyperactivity in adulthood in the absence of nicotine (Interim Phase). Reexposure to nicotine when all animals were adults (Drug Phase II) revealed that initial nicotine exposure in adolescence compared to adulthood resulted in dose-response differences in adulthood similar to those in Drug Phase I. In addition, animals initially exposed in adolescence exhibited sensitization to nicotine's activity-increasing effects in adulthood. These findings suggest that there are age differences in nicotine sensitivity that could predispose individuals initially exposed to nicotine in adolescence to long-term smoking.     

Adolescent and adult female rats differ in sensitivity to nicotine's activity effects

More than 90% of cigarette smokers begin smoking during adolescence. This between-subjects repeated-measures experiment examined: (1) nicotine's acute effects on activity in adolescent and adult female Sprague–Dawley rats (Drug Phase I); (2) the effects of age of initial nicotine exposure on activity when nicotine was not administered (Interim Phase); and (3) the effects of age of initial nicotine exposure on later responses to nicotine (Drug Phase II). The experiment consisted of three separate phases. In Drug Phase I, animals were administered either 0 (saline), 0.01, 0.10, 0.50, or 1.0 mg/kg nicotine via subcutaneous injections for 12 days and horizontal activity was measured daily. During the Interim Phase (no drug phase), activity was measured but nicotine was not administered. During Drug Phase II, the same animals were administered the same nicotine dosages as in Drug Phase I for 12 days and activity was measured daily. Drug Phase I revealed dose–response differences between adolescent and adult female rats. In addition, animals initially exposed to nicotine in adolescence exhibited greater sensitivity to nicotine's activity-increasing effects than did females initially exposed to nicotine in adulthood (i.e., Drug Phase II).     

The effects of gabapentin in two animal models of co-morbid anxiety and visceral hypersensitivity

Maslinic acid (2-α, 3-β-dihydroxyolean-12-en-28-oic acid) is a natural triterpenoid compound from Olea europaea. This compound prevents oxidative stress and pro-inflammatory cytokine generation in vitro. This study was planned to investigate the anti-inflammatory effects of maslinic acid in central nervous system by using rat astrocyte cultures stimulated with lipopolysaccharide (LPS). We evaluated different proteins implicated in the nuclear factor kappa B (NF-κB) signal transducer pathway employing Western blot and quantitative real time PCR techniques. Results demonstrated that maslinic acid treatment exerted potent anti-inflammatory action by inhibiting the production of Nitric Oxide and tumor necrosis factor alpha (TNF-α). Western blot analysis showed that maslinic acid treatment attenuated LPS-induced translocation of NF-κB p65 subunit to the nucleus and prevented LPS-induced IκBα phosphorylation in a concentration-dependent manner, Moreover, maslinic acid significantly suppressed the expression of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) at protein and mRNA levels. These results suggest that maslinic acid can potentially reduce neuroinflammation by inhibiting NF-κB signal transducer pathway in cultured cortical astrocytes.     

Mild social stress abolishes the effects of isolation on anxiety and chlordiazepoxide reactivity

  Rationale: Social isolation is anxiogenic and may change the effects of anxiolytic drugs. These effects are generally attributed to ”isolation stress”. However, isolation does not affect basal corticosterone levels; thus, it cannot be considered stressful. On the contrary, isolation deprives animals of mild daily stressors that are inherent to social life. Since mild stressors were shown to be anxiolytic in rats, it was postulated that short-term, repeated stressors may abolish the effects of isolation. Objectives: The aim of the present study was to investigate whether short-term, repeated, mild social stress can abolish the consequences of isolation on anxiety and on the effects of chlordiazepoxide. Methods: Rats were housed in groups or in individual cages for 5 days (isolates). Half of isolates were daily submitted to the attacks of a resident rat for 30 min per day, on 4 consecutive days (stressed isolates). On day 5, rats were treated either with vehicle or with chlordiazepoxide and submitted to the elevated plus-maze test. Endocrinological consequences of experimental manipulations were assessed in a different set of rats. Results: Plasma ACTH and corticosterone levels were similar in the three groups. Weight gain was higher, while plasma growth hormone was lower in stressed isolates, both effects being consistent with a mild stress. Isolation had a clear anxiogenic effect. This effect was completely abolished by the daily experience of social stress. Chlordiazepoxide had a significant anxiolytic effect in all three groups. Its effects on classical plus-maze variables did not differentiate the three groups. However, chlordiazepoxide decreased risk assessment activity only in isolates. Conclusions: The lack of appropriate endocrinological changes challenges the concept of ”isolation stress”. However, isolation was anxiogenic in our study and it also induced subtle changes in the effects of chlordiazepoxide. It appears that mild daily stressors have a protective effect against the effects of isolation. Received: 23 May 1998 / Final version: 3 December 1998