Efficacy of pregabalin in depressive symptoms associated with generalized anxiety disorder: A pooled analysis of 6 studies

Epidemiological evidence supports comorbidity of generalized anxiety disorder (GAD) and major depressive disorder (MDD) or dysthymia, and its association with significant disability. As pregabalin, a new ₂-δ anxiolytic treatment for GAD, unlike most other licensed treatments for GAD has not undergone investigation in patients with MDD, we examined its efficacy in depressive symptoms associated with GAD, through a post-hoc analysis of the existing clinical trial database. The results provide consistent evidence that in patients with GAD pregabalin reduced associated symptoms of depression. This was seen in the 150 mg/day, 300–450 mg/day and 600 mg/day dosing groups. Even in subjects with more prominent depressive symptoms, pregabalin remained effective for both sub-syndromal depression and GAD symptoms, with pregabalin 300–450 mg/day demonstrating the most beneficial response. In conclusion, pregabalin, an alternative treatment option for GAD with a novel mechanism of action, also demonstrated efficacy in treating depressive symptoms typically encountered in GAD patients.     

Hemangiosarcoma in mice administered pregabalin: analysis of genotoxicity, tumor incidence, and tumor genetics

Pregabalin, (S)-3-(aminomethyl)-5-methylhexanoic acid, binds with high affinity to the α(2)δ subunit of voltage-gated calcium channels and exerts analgesic, anxiolytic, and antiseizure activities. Two-year carcinogenicity studies were completed in B6C3F1 and CD-1 mice and two separate studies in Wistar rats. Doses in mice were 200, 1000, and 5000 mg/kg/day, with systemic exposures (AUC(0-24 h)) up to 31 times the mean exposure in humans, given the maximum recommended clinical dose. In rats, doses were 50, 150, and 450 mg/kg/day in males and 100, 300, and 900 mg/kg/day in females; systemic exposures up to 24 times were achieved in clinical trials. In both strains of mice, pregabalin treatment was associated with an increased incidence of hemangiosarcoma primarily in liver, spleen, and bone marrow. The incidence of hemangiosarcoma was higher in B6C3F1 mice than in CD-1 mice, consistent with its spontaneous incidence. Pregabalin did not increase the incidence of any other tumor type in rats and was not genotoxic, based on an extensive battery of in vivo and in vitro tests in bacterial and mammalian systems. Thus, pregabalin is a single-species, single tumor-type, nongenotoxic mouse carcinogen. Hemangiosarcomas occurring in mice treated with pregabalin were genotypically distinct from hemangiosarcomas induced by genotoxic carcinogens in humans with respect to ras and p53 mutation patterns and were similar to spontaneous tumors. Furthermore, there was a strong association between pregabalin treatment and bone marrow changes in these studies in mice, suggesting a possible link between the effects observed in bone marrow and the increase in tumor incidence in pregabalin-treated mice.     

Cost-effectiveness analysis of a lidocaine 5% medicated plaster compared with gabapentin and pregabalin for treating postherpetic neuralgia: a german perspective

OBJECTIVE: This study set out to assess the cost effectiveness of using a 5% lidocaine (lignocaine) medicated plaster for the treatment of postherpetic neuralgia (PHN) compared with gabapentin, pregabalin 300 mg/day or 600 mg/day in German primary care. The analysis took the perspective of the Statutory Health Insurance scheme (GKV). METHODS: A Markov model was used to calculate the costs (2007) and benefits of the lidocaine plaster, gabapentin 1800 mg/day and pregabalin 300 or 600 mg/day over a 6-month time horizon in elderly patients with PHN who experienced insufficient pain relief with standard analgesics and could not tolerate or had contraindications to tricyclic antidepressants. The model calculated the cost per quality-adjusted life-year (QALY) gained and the cost per additional month without symptoms or intolerable adverse effects. The majority of transition probabilities were obtained from randomized controlled trials identified from a systematic literature review. Further model inputs, including resource use, concomitant medication and long-term efficacy/adherence data, were obtained from a Delphi panel. Utility values were taken from a previous study and age adjusted. Cost data were obtained from official price tariffs. Mortality, indirect costs and costs associated with inpatient treatment were not considered in the present analysis due to the perspective and time horizon employed. RESULTS: Over the 6-month period modelled, the mean total therapy cost per patient treated with the lidocaine plaster was euro911, compared with euro728 for gabapentin, euro875 for pregabalin 300 mg/day and euro977 for pregabalin 600 mg/day. Treatment with the lidocaine plaster was related to greater numbers of QALYs and more months without symptoms or intolerable adverse effects (mean 0.300 QALYs and 4.06 months per patient) than with gabapentin (mean 0.247 QALYs and 2.72 months), pregabalin 300 mg/day (mean 0.253 QALYs and 3.02 months) or pregabalin 600 mg/day (mean 0.256 QALYs and 3.22 months). The lidocaine plaster cost euro3453/QALY gained and euro137 per additional month without adverse effects or symptoms relative to gabapentin and euro766/QALY and euro35 per month without adverse effects or symptoms relative to pregabalin 300 mg/day. The lidocaine plaster dominated pregabalin 600 mg/day, being less costly and more effective. Probabilistic sensitivity analysis indicated that there is a 99.36% chance that the lidocaine plaster is the most clinically effective treatment considered in the analysis and a 99.09% chance that the lidocaine plaster is the most cost-effective treatment of the four therapies considered in the analysis if the GKV is willing to pay at least euro20 000/QALY gained. Extensive deterministic sensitivity analyses demonstrated that the findings are robust. CONCLUSIONS: The 5% lidocaine-medicated plaster is a cost-effective treatment option for the management of PHN in Germany compared with gabapentin and both 300 and 600 mg/day of pregabalin.     

Anxiolytic-Like Effect of baicalin and its additivity with other anxiolytics

Baicalin, a naturally occurring flavonoid, was previously reported to exert anxiolytic-like effects in the Vogel conflict test. In the present study, the anxiolytic effects of baicalin alone and in combination with other anxiolytics were tested in mice using the elevated plus-maze (EPM). Baicalin treatment (7.5 - 30 mg/kg) significantly increased entries into and time spent in open arms, indicative of an anxiolytic-like effect. Motor-depressive and myorelaxant side effects commonly associated with anxiolytics were not observed with baicalin at effective anxiolytic doses in the hole-board and horizontal wire tests, respectively. Co-administration of baicalin (3.75 mg/kg) with dl-tetrahydropalmatine ( dl-THP; 0.25 mg/kg), an anxiolytic-hypnotic alkaloid, both at sub-effective doses, induced an additive effect resulting in considerable anxiolysis. Similarly, an additive anxiolytic-like effect was observed with baicalin (3.75 mg/kg) and diazepam (DZ; 0.5 mg/kg). Results obtained from this study demonstrate the potential of baicalin as a candidate anxiolytic and its possible application in multidrug therapy. Abbreviations. BZS:benzodiazepine-binding site EPM:elevated plus-maze DZ:diazepam GABA (A):type A gamma-aminobutyric acid dl-THP: dl-tetrahydropalmatine.     

The dorsal raphé nucleus is a crucial structure mediating nicotine's anxiolytic effects and the development of tolerance and withdrawal responses

RATIONALE: Smokers frequently report that they obtain anxiety-reducing (anxiolytic) effects from smoking, and this may be one factor which contributes to nicotine dependence. OBJECTIVE: The aim of this study was to investigate the role of the dorsal raphé nucleus (DRN) in mediating the acute anxiolytic effect of nicotine, the development of tolerance to this effect and the anxiogenic response observed on withdrawal from chronic nicotine. METHODS: The social interaction test of anxiety was used to investigate the effects of a range of doses of (-)-nicotine (2.5-4000 ng) following DRN infusion, and whether co-administration of the specific 5-HT1A receptor antagonist WAY 100635 could antagonise the anxiolytic action of nicotine. We then examined the effects of intra-DRN nicotine (2.5-7 ng) following six daily injections of subcutaneous (s.c.) (-)-nicotine (0.1 mg/kg). Finally, we examined whether s.c. or intra-DRN (-)-nicotine could antagonise the anxiogenic response seen 72 h after the termination of 7 days of nicotine treatment. RESULTS: Acute nicotine administration into the DRN produced dose-related effects: low doses (2.5-10 ng) induced an anxiolytic effect, intermediate doses were behaviourally silent (100-1000 ng), and an anxiogenic effect was seen following administration of a high dose (4 micrograms). The anxiolytic effect of (-)-nicotine (5 ng) was reversed by co-administration of a behaviourally inactive dose of WAY 100635 (200 ng). Following 6 days of treatment with s.c. 0.1 mg/kg per day (-)-nicotine, tolerance developed to its anxiolytic action in the DRN. Rats withdrawn for 72 h following this chronic treatment showed an anxiogenic response which was reversed by (-)-nicotine injected s.c. (0.1 mg/kg) or into the DRN (5 ng). CONCLUSIONS: The present findings therefore suggest that the DRN plays an important role in mediating the acute effects of nicotine on anxiety, as measured in the social interaction test, and that the anxiolytic effect is mediated by activation of somatodendritic 5-HT1A autoreceptors. The DRN is also concerned with mediating the development of tolerance to nicotine's anxiolytic effects and because there is an anxiogenic response 72 h after withdrawal from chronic nicotine, this suggests that an oppositional, compensatory mechanism is mediating the tolerance.     

Pregabalin: in the treatment of generalised anxiety disorder

Pregabalin, the pharmacologically active S-enantiomer of 3-aminomethyl-5-methyl-hexanoic acid, is a structural analogue of GABA, although it is not active at GABA receptors, nor does it acutely alter GABA uptake or degradation.black triangle Pregabalin binds with high affinity to the alpha2-delta subunit protein of voltage-gated calcium channels in CNS tissues and acts as a presynaptic modulator of the excessive release, in hyperexcited neurons, of various excitatory neurotransmitters. Binding of pregabalin to the alpha2-delta subunit appears necessary for its demonstrable anxiolytic, analgesic and anticonvulsant activities in animal models.black triangle Oral pregabalin, typically at dosages of 300-600 mg/day, was superior to placebo and similar to lorazepam 6 mg/day, alprazolam 1.5 mg/day and venlafaxine 75 mg/day in improving anxiety and depressive symptoms in patients with moderate-to-severe generalised anxiety disorder (GAD). Pregabalin had a rapid onset of anxiolytic activity relative to alprazolam and venlafaxine, which was evident after 1 week. Additionally, pregabalin (initial dosage 450 mg/day) was effective for the prevention of relapse of GAD over 34 weeks. Pregabalin was well tolerated during dosage escalation to fixed dosages (maximum 600 mg/day) over 7 days. Dizziness and somnolence, usually of mild to moderate severity, were the most common adverse events.black triangle The drug was not associated with a clinically significant medication withdrawal syndrome during a 1-week taper following 4 or 6 weeks' double-blind treatment.     

Comparison of acute and repeated treatment with the 5-HT1A receptor ligands 8-OH-DPAT and ipsapirone in animal models of anxiety and depression

The present study compared the 5-HT_1A receptor ligands 8-OH-DPAT and ipsapirone with diazpepam and imipramine in the shock induced ultrasonic vocalization anxiety test and the forced swimming depression test in the rat. Acutely, 8-OH-DPAT induced anxiolytic and antidepressive effects (ED₅₀: 0.12 and 1.4 mg/kg, i.p., respectively), whereas ipsapirone induced anxiolytic (ED₅₀: 0.6 mg/kg) and moderate antidepressive effects (33% at 3-10 mg/kg). Virtually no tolerance developed for the anxiolytic effects after 2 weeks of treatment with 0.03-1 mg/kg 8-OH-DPAT or 0.1-10 mg/kg ipsapirone (i.p., b.i.d.), with 10 mg/kg/day ipsapirone (s.c., mini-pumps), or with 1.5 μg/rat/hr 8-OH-DPAT (local infusion in the dorsal raphe nucleus, mini-pumps). However, some tolerance developed for the antidepressive effects of 8-OH-DPAT (ED₅₀: 0.6, 1.4, 2.5 and >3 mg/kg, after 2 weeks of pretreatment with vehicle, 0.3, 1, and 3 mg/kg 8-OH-DPAT, respectively, i.p., b.i.d.). In the case of ipsapirone, the dose-effect curve in the forced swimming test was shifted to the left after 2 weeks of pretreatment with ipsapirone (0.3-10 mg/kg, i.p., b.i.d.). Acutely, diazepam induced an anxiolytic effect (ED₅₀: 3.6 mg/kg, i.p.), but failed to induce an antidepressive effect; whereas imipramine induced an antidepressive effect (ED₅₀: 20.5 mg/kg) and a moderate anxiolytic effect (max. efficacy: 47% at 30 mg/kg). Upon repeated administration (2 weeks), diazepam (5 mg/kg) showed t0olerance for its anxiolytic effects and weak antidepressive effects emerged, whereas imipramine (20 mg/kg) showed weak sensitization for both effects. It is concluded that (a) with all compounds, tolerance, as well as sensitization can be observed, depending on the behavioral test, the dose and the type of compound; and (b) compared with the other compounds tested, relatively low doses of 5-HT_1A drugs offer the most attractive profile of mixed anxiolytic/antidepressive activity. © 1993 wiley-Liss, Inc.     

The anxiogenic-like effects of pentylenetetrazole in mice treated chronically with carbamazepine or valproate.

The chronic effects of carbamazepine administration (5, 10, 20 mg/kg i.p. daily for 14 days) on the anxiogenic response to pentylenetetrazole were studied in the light/dark aversion test. In mice, these effects were compared with those of sodium valproate (100, 200 and 300 mg/kg i.p.), a putative anxiolytic drug, and lorazepam (0.025, 0.05 and 0.10 mg/kg i.p.), a well-established anxiolytic drug. The results showed that the anxiogenic-like behavior induced by subconvulsant doses of pentylenetetrazole (15 mg/kg i.p.) was antagonized by the chronic administration of lorazepam as well as sodium valproate, a GABA agonist. In fact, the increased aversion of mice for the light compartment of the light/dark box was reduced. Carbamazepine failed to significantly alter the anxiogenic-like behavior of mice. These findings provide further evidence for the absence of anxiolytic properties of carbamazepine and for a behavioral anxiolytic profile of valproate similar to that of benzodiazepines.     

Synergistic interaction of pregabalin with the synthetic cannabinoid WIN 55,212-2 mesylate in the hot-plate test in mice: an isobolographic analysis

BackgroundThe aim of the study was to determine the type of interaction between pregabalin (a 3^rd-generation antiepileptic drug) and WIN 55,212-2 mesylate (WIN – a highly potent non-selective cannabinoid CB1 and CB2 receptor agonist) administered in combination at a fixed ratio of 1:1, in the acute thermal pain model (hot-plate test) in mice.MethodsLinear regression analysis was used to evaluate the dose-response relationships between logarithms of drug doses and their resultant maximum possible antinociceptive effects in the mouse hot-plate test. From linear equations, doses were calculated that increased the antinociceptive effect by 30% (ED₃₀ values) for pregabalin, WIN, and their combination. The type of interaction between pregabalin and WIN was assessed using the isobolographic analysis.ResultsResults indicated that both compounds produced a definite antinociceptive effect, and the experimentally-derived ED₃₀ values for pregabalin and WIN, when applied alone, were 29.4 mg/kg and 10.5 mg/kg, respectively. With isobolography, the experimentally derived ED_{30 mix} value for the fixed ratio combination of 1:1 was 5.7 mg/kg, and differed significantly from the theoretically calculated ED_{30 add} value of 19.95 mg/kg (p < 0.01), indicating synergistic interaction between pregabalin and WIN in the hot-plate test in mice.ConclusionsIsobolographic analysis demonstrated that the combination of WIN with pregabalin at a fixed ratio of 1:1 exerted synergistic interaction in the mouse model of acute thermal pain. If the results from this study could be adapted to clinical settings, the combination of WIN with pregabalin might be beneficial for pain relief in humans.     

Behavioral effects of propentofylline (HWA 285) on ambulatory activity, discrete avoidance response and passive avoidance response in mice

Behavioral effects of propentofylline (HWA 285) were investigated by means of ambulatory activity, discrete lever-press avoidance and step-through type passive avoidance response in mice. Single administration of HWA 285 produced no marked change in the bodily condition and also produced no changes in ambulatory activity at 1.25-20 mg/kg, s.c.; the discrete avoidance response at 2.5-40 mg/kg, s.c.; and the passive avoidance response at 10-30 mg/kg, s.c. However, 5-20 mg/kg of HWA 285 attenuated the ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) and scopolamine (0.5 mg/kg, s.c.). HWA 285 tended to attenuate the avoidance-suppressing effect of chlorpromazine (2 mg/kg, s.c.) and physostigmine (0.1 mg/kg, s.c.) at 2.5 mg/kg, while it enhanced the effect of chlorpromazine at 10-40 mg/kg. The mice treated with HWA 285 (10-30 mg/kg) at 30 min before or immediately after the acquisition trial did not show a marked change in the passive avoidance response when the retention trial was done 24 hr after the acquisition trial. The treatment with scopolamine (2 mg/kg, s.c.) at 30 min before the acquisition trial suppressed the passive avoidance response, eliciting a marked shortening of the step-through latency and decrease in % of mice to the 300 sec criterion of latency. The effect of scopolamine was attenuated by combined administration of HWA 285 (30 mg/kg) and treatment with HWA 285 (30 mg/kg) after the end of the acquisition trial. The present results suggest that HWA 285 demonstrates complex behavioral effects which vary dependently on the doses and types of behaviors.     

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work in naive rats showed that 5-HT₄ receptor agonists had rapid effects on depression-related behaviors and on hippocampal neurogenesis. We decided to investigate whether 5-HT₄ receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression, and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT₄ receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety- and depression-related behaviors, as well as on hippocampal neurogenesis in comparison with chronic fluoxetine treatment (18 mg/kg/day). Then, using our anxiety/depression model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7 days) or chronic (28 days) RS67333 treatment. We also assessed whether a 5-HT₄ receptor antagonist ({"type":"entrez-nucleotide","attrs":{"text":"GR125487","term_id":"238373281","term_text":"GR125487"}}GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis, specifically facilitating maturation of newborn neurons. However, unlike fluoxetine, anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with {"type":"entrez-nucleotide","attrs":{"text":"GR125487","term_id":"238373281","term_text":"GR125487"}}GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT₄ receptor activation is necessary for these effects of SSRIs. 5-HT₄ receptor stimulation could represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.     

Efficacy of pregabalin in generalized social anxiety disorder: results of a double-blind, placebo-controlled, fixed-dose study

The objective of this study was to evaluate the efficacy and tolerability of pregabalin for the treatment of generalized social anxiety disorder (SAD). Patients with generalized SAD, who met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) criteria (total N=329), were randomly assigned to 11 weeks of double-blind treatment with fixed daily doses of either pregabalin (300, 450, and 600(mg) or placebo. The treatment with pregabalin (600(mg) was associated with a significantly greater mean reduction in the Liebowitz Social Anxiety Scale total score, from baseline to endpoint, compared with placebo (-29.8 vs. -19.7; P= 0.0099), whereas reduction on pregabalin (300(mg, -20.2) and pregabalin (450(mg, -25.5) was not significant Treatment with pregabalin (600(mg) was also associated with a significantly greater improvement than placebo on the fear and avoidance subscales of the Liebowitz Social Anxiety Scale, as well as the majority of other secondary measures. Onset of improvement occurred by week 1 in the pregabalin 600-mg dose group. The most common adverse events on all three doses of pregabalin were somnolence and dizziness. Consistent with a previous study, the results of this study suggest that the 600-mg dose of pregabalin per day may be efficacious in the treatment of SAD.     

Effects of buspirone and chlordiazepoxide on plasma catecholamine and corticosterone levels in stressed and nonstressed rats

The effects of intragastric administration of the prototypical benzodiazepine (BDZ) anxiolytic drug chlordiazepoxide (CDP) and the non-BDZ anxiolytic agent buspirone (BUSP) on basal and stress-elevated plasma noradrenaline (NA), adrenaline (A) and corticosterone (CS) contents were investigated. Acute dosing of CDP (1-27 mg/kg) produced dose-related increases in basal CS secretion but was without effect on basal NA levels. The high dose of CDP caused a slight short-term A increase. Dose-dependent increases in plasma A, NA and CS contents were observed after acute treatment with BUSP (2 and 20 mg/kg). A medium dose of CDP (9 mg/kg) attenuated the stress-induced CS and A elevations. High doses of CDP that elevated basal CS release prevented a further increase of CS by stress and inhibited the NA and A response to stress. BUSP (2 and 20 mg/kg) was not effective in decreasing the stress-elicited rise of CS, NA or A. Conversely, the 20 mg/kg dose of BUSP enhanced the stress-induced A response. Repeated administration of CDP (9 mg/kg/day for six days) produced tolerance to the elevation of basal CS triggered by acute CDP treatment, but increased the efficacy of the drug's CS and A attenuating action in stressed rats. Repeated administration of BUSP (2 mg/kg/day for six days) also produced tolerance to the acute BUSP-induced effect on basal CS release, but did not affect the stress-induced CS, NA and A responses. It is concluded that the clinically effective anxiolytic BUSP does not have the BDZ-like property to inhibit stress-induced elevations in CS, NA and A. Furthermore, the present data support other evidence that activation of 5-HT1A receptor mechanisms increases plasma catecholamine and corticosterone concentrations.     

Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats

RATIONALE: D(1) dopamine receptor antagonists and agonists attenuate cocaine reinstatement of cocaine-seeking behavior (i.e., responding in the absence of cocaine reinforcement). OBJECTIVES: The present study investigated the effects of a D(1) antagonist (SCH-23390), partial agonist (SKF-38393), and full agonist (SKF-81297) on reinstatement of cocaine-seeking behavior elicited by presentation of cocaine-paired cues. METHODS: Rats that had been trained to self-administer cocaine with a light/tone stimulus complex paired with each infusion underwent extinction across days. After responding diminished, rats were given response-contingent access to the cocaine-paired stimulus complex. The effects of SCH-23390 (0-10.0 microg/kg), SKF-38393 (0-3.0 mg/kg), and SKF-81297 (0-3.0 mg/kg) on cue reinstatement of cocaine-seeking behavior were examined. The ability of the two D(1) agonists to independently reinstate cocaine-seeking behavior and the effects of SKF-81297 on cocaine reinstatement were also examined. To investigate the possibility of behavioral interference, the effects of SKF-38393 and SKF-81297 on grooming and stereotypy were assessed. RESULTS: SCH-23390 and SKF-81297, but not SKF-38393, attenuated cue reinstatement. However, while SKF-81297 dose-dependently increased response latency, SCH-23390 did not. SKF-81297 also independently reinstated responding at the two lowest doses tested while SKF-38393 had no effect. Furthermore, SKF-81297 decreased cocaine reinstatement and increased response latency only at the highest dose. Finally, stereotypy was observed at all doses of SKF-81297 that also decreased responding, although the patterns of changes in these behaviors did not completely correspond. CONCLUSIONS: While the antagonist and full agonist produced similar effects on cocaine-seeking behavior, only the agonist increased response latency, suggesting that different processes mediate the effects of these drugs.     

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.     

Evaluation of anxiolytic effect and withdrawal anxiety in chronic intermittent diazepam treatment in rats

This study evaluated the effect of intermittent administration in the development of dependence to diazepam in chronic use of the drug. Gabapentin was used to provide an anxiolytic effect on drug-free days. During a 28-day treatment schedule, rats were given diazepam (15 mg/kg) once daily continuously, or intermittently with saline or gabapentin (50 mg/kg) on days 5, 10, 15, 20, and 25. Anxiety-like behavior was assessed on days 10 and 30 using the elevated plus-maze test and novelty-induced grooming test. Contrary to continuous administration, intermittent diazepam did not provide anxiolytic-like activity on day 10; instead, it prevented withdrawal anxiety on day 30. Gabapentin produced anxiolytic-like effects during the withdrawal period, but not on day 10. These results suggest that intermittent administration of diazepam (given either alone or alternatively with a drug possessing anxiolytic activity) may be of value in preventing the development of physical dependence during the chronic use of the drug. However, further studies are needed to demonstrate that this protocol could effectively produce anxiolytic activity on diazepam-free days.     

Pregabalin may represent a novel class of anxiolytic agents with a broad spectrum of activity

The present study examines the effect of pregabalin (previously S-Isobutylgaba and CI-1008) in two distinct rat models of anxiety. Pregabalin binds with high affinity and selectivity to the alpha(2)delta subunit of voltage dependent calcium channels (VDCC). Its corresponding R-enantiomer (R-isobutylgaba) is approximately 10 fold weaker. Pregabalin dose-dependently induced anxiolytic-like effects in both the rat conflict test and elevated X-maze with respective minimum effective doses (MED) of 3 and 10 mg kg(-1). In contrast, R-isobutylgaba only showed activity at the highest dose of 100 mg kg(-1) in the conflict test. These data indicate that pregabalin may possess clinical utility as a novel anxiolytic agent and demonstrates the importance of the alpha(2)delta subunit of VDCC in the mediation of anxiety related behaviours.     

Effects of Hypericum perforatum and paroxetine on rat performance in the elevated T-maze.

Hypericum perforatum extract exhibits an antidepressant effect and since several antidepressant drugs are also effective on generalised anxiety disorder (GAD) and panic disorders (PD), H. perforatum may possess some anxiolytic/antipanic effect. Thus, the aim of the present study was to evaluate the putative antipanic/anxiolytic effect of standardised H. perforatum extract (LI 160) on rats tested in the elevated T-maze, an animal model of innate (panic) and learned (generalised) anxiety, at doses that exhibit antidepressant-like activity. H. perforatum (150, 300 and 500 mg/kg, administered orally 24, 18 and 1h before the test) decreased the immobility time in the forced swim test. Rats were treated orally with H. perforatum (150 or 300 mg/kg) or paroxetine (5mg/kg) 24, 18, and 1h before being tested in the elevated T-maze (subacute treatment). Immediately after this test, the animals were submitted to the open field to evaluate locomotor activity. Paroxetine was used as a positive control, since it was clinically effective in GAD and PD. Other groups of animals were submitted to the same drug treatment for 7 days (subchronic treatment). Paroxetine (5mg/kg) impaired inhibitory avoidance after subacute treatment, while subchronic administration increased one-way escape latency. Subacute treatment with H. perforatum (300 mg/kg) exerts a partial anxiolytic-like effect in the inhibitory avoidance task. Repeated administration of H. perforatum (300 mg/kg) induced an anxiolytic effect (decreased inhibitory avoidance) and an antipanic effect (increased one-way escape). No effect on locomotor activity was found with any treatment. Thus, the results suggest that H. perforatum extract could exert an anxiolytic and antipanic effect.     

Antidepressant properties of rotigotine in experimental models of depression

Limited clinical data are available on the use of dopamine agonists for the control of motor function and also for the treatment of depression. This study was performed to evaluate the potential effects of the dopamine receptor agonist rotigotine in rat models of anxiety and depression. After repeated administration at doses of 0.05, 0.5, 1, and 5 mg/kg, rotigotine increased spontaneous motor activity at the 5 mg/kg dose after 3-5 days of treatment. At lower doses, the drug had no effect on locomotor activity. After a single administration, rotigotine had no anxiolytic activity in rats during the elevated plus-maze test or the Geller-Seifter conflict test. In the behavioral despair test (also known as the forced swim test), the 5 mg/kg dose of rotigotine enhanced the mobility of rats. Rotigotine (0.5, 1, and 5 mg/kg/day for 5 days) reversed the active avoidance deficit of helpless rats in the learned helplessness test, as shown by a significant decrease in escape failures after 3 to 4 days (0.5 mg/kg/day), 5 days (1 mg/kg/day), and 3 to 5 days (5 mg/kg/day) of treatment. During open-field testing of rats subjected to olfactory bulbectomy and given a 14-day schedule of rotigotine (0.3 mg/kg every 2 days), hyperactivity reversed according to a U-shaped dose-response curve. These results suggest that rotigotine may have antidepressant properties at doses of 1 mg/kg and lower. Potential effects at doses of 5 mg/kg and higher may be masked by an effect of the compound whereby general locomotor activity is enhanced.