Benzodiazepine Chlordiazepoxide Research Articles

Burrowing as an index of inflammatory pain in male vs. female rats.

The study objective was to determine whether burrowing behavior is useful as a functional index of pain in both male and female rats, and whether a 'no-training' protocol can be used to increase testing efficiency. Adult Sprague-Dawley rats were injected in one or both hindpaws with oil vehicle or complete Freund's adjuvant (CFA); starting the next day, the amount of gravel each rat burrowed out of a tube in 1 h was measured daily for ≤7 days. Without preliminary training on the burrowing procedure, CFA reliably suppressed burrowing for 2-3 days compared to controls, in both sexes. However, whereas unilateral CFA completely suppressed burrowing 1-day post-CFA in nearly all males, bilateral CFA was required to do so in females. When administered 30 min before testing, once daily for 5 days post-CFA, the nonsteroidal anti-inflammatory drug ketoprofen (0.01-3.2 mg/kg) and the opioid morphine (0.1-3.2 mg/kg) significantly increased CFA-suppressed burrowing, whereas the purported cannabinoid analgesic Δ 9 -tetrahydrocannabinol (0.01-2.0 mg/kg) did not. The benzodiazepine chlordiazepoxide (1.25-10 mg/kg), included as a 'true negative' control, also did not restore CFA-suppressed burrowing in either sex. However, in CFA-treated males only, chlordiazepoxide decreased burrowing, suggesting that anxiety may contribute to burrowing in males but not females that are in pain. Overall these results suggest that burrowing is a valid, functional index of inflammatory pain in both sexes, and training on the burrowing procedure is not necessary. However, females are more avid burrowers than males, which should be considered when both sexes are used in inflammatory pain testing.

Partial reinforcement in rat autoshaping with a long CS: Effects of pramipexole and chlordiazepoxide on sign and goal tracking

Abstract In Pavlovian autoshaping, sign-tracking responses (lever pressing) to a conditioned stimulus (CS) are usually invigorated under partial reinforcement (PR) compared to continuous reinforcement (CR). This effect, called the PR acquisition effect (PRAE), can be interpreted in terms of increased incentive hope or frustration-induced drive derived from PR training. Incentive hope and frustration have been related to dopaminergic and GABAergic activity, respectively. We examined the within-trial dynamics of sign and goal tracking in rats exposed to 20-s-long lever presentations during autoshaping acquisition under PR vs. CR conditions under the effects of drugs tapping on dopamine and GABA activity. There was no evidence of the PRAE in these results, both groups showing high, stable sign-tracking response rates. However, the pharmacological treatments affected behavior as revealed in within-trial changes. The dopamine D2 receptor agonist pramipexole (0.4 mg/kg) suppressed lever pressing and magazine entries relative to saline controls in a within-subject design, but only in PR animals. The allosteric benzodiazepine chlordiazepoxide (5 mg/kg) failed to affect either sign or goal tracking in either CR or PR animals. These results emphasize the roles of dopamine and GABA receptors in autoshaping performance, but remain inconclusive with respect to incentive hope and frustration theories. Some aspects of within-trial changes in sign and goal tracking are consistent with a mixture of reward timing and response competition.

Pharmacological and behavioral characterization of the novel CRF1 antagonist BMS-763534

BMS-763534 is a potent (CRF1 IC50 = 0.4 nM) and selective (>1000-fold selectivity vs. all other sites tested) CRF1 receptor antagonist (pA2 = 9.47 vs. CRF1-mediated cAMP production in Y79 cells). BMS-763534 accelerated the dissociation of 125I-o-CRF from rat frontal cortex membrane CRF1 receptors consistent with a negative allosteric modulation of CRF binding. BMS-763534 produced dose-dependent increases in CRF1 receptor occupancy and anxiolytic efficacy; lowest effective anxiolytic dose = 0.56 mg/kg, PO, which was associated with 71 ± 5% CRF1 receptor occupancy of frontoparietal CRF1 receptors. Sedative/ataxic effects of BMS-763534 were only observed at high dose multiples (54–179×) relative to the lowest dose required for anxiolytic efficacy. At doses of 5- to 18-fold higher than the lowest efficacious dose in the anxiety assay, BMS-763534 shared subjective effects with the benzodiazepine chlordiazepoxide. Interestingly BMS-790318, the O-demethylated metabolite of BMS-763534, showed weak affinity for the TBOB site of the GABAA receptor (67% inhibition at 10 μM) and augmented GABA evoked currents (EC50 = 1.6 μM). Thus, the unanticipated signal in the drug discrimination assay may have resulted from an interaction of the metabolite BMS-790318 with the TBOB site on the GABAA channel where it appears to behave as an allosteric potentiator of GABA evoked currents.

MGluR5 antagonist MTEP and benzodiazepine chlordiazepoxide psychoactive interaction: A rat drug discrimination analysis

mGluR5 antagonist MTEP and benzodiazepine chlordiazepoxide psychoactive interaction: A rat drug discrimination analysis

Gabra5-gene haplotype block associated with behavioral properties of the full agonist benzodiazepine chlordiazepoxide

The gabra5 gene is associated with pharmacological properties (myorelaxant, amnesic, anxiolytic) of benzodiazepines. It is tightly located (0.5cM) close to the pink-eyed dilution (p) locus which encodes for fur color on mouse chromosome 7. We tested the putative role of the gabra5 gene in pharmacological properties of the full non specific agonist chlordiazepoxide (CDP), using behavioral and molecular approaches in mutated p/p mice and wild type F2 from crosses between two multiple markers inbred strain ABP/Le and C57BL/6By strain. From our results, using rotarod, light–dark box, elevated maze and radial arm maze tests, we demonstrate that p/p mice are more sensitive than WT to the sensory motor, anxiolytic and amnesic effect of CDP. This is associated with the presence of a haplotypic block on the murine chromosome 7 and with an up regulation of gabra5 mRNAs in hippocampi of p/p F2 mice.

Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal

Discovered in the late 1950s by Leo Sternbach, the first benzodiazepine (BZD) chlordiazepoxide was followed by several congeners, which rapidly constituted one of the largest and most widely prescribed classes of psychotropic compounds. After 50 years, BZDs are still routinely utilized not only in psychiatry but, more generally, in the whole of medicine. Despite their high therapeutic index which makes BZDs safer than other compounds like barbiturates, as well as their rapidity of onset, psychiatrists and family physicians are well aware about the controversy that surrounds the wide use – often not adequately based on scientific evidence – of BZDs in many psychiatric disorders. In this overview of international treatment guidelines, systematic reviews and randomized clinical trials, the aim was to provide a critical appraisal of the current use and role of BZDs in psychiatric disorders and their disadvantages, with specific emphasis on anxiety and affective disorders, sleep disorders, alcohol withdrawal, violent and aggressive behaviours in psychoses, and neuroleptic-induced disorders. In addition, specific emphasis has been given to the extent of usage of BZDs and its appropriateness through the assessment of available international surveys. Finally, the entire spectrum of BZD-related adverse effects including psychomotor effects, use in the elderly, paradoxical reactions, tolerance and rebound, teratologic risk, dependence, withdrawal and abuse issues was examined in detail.

P-212 - Factors influencing choice of treatment for Bipolar I/II disorder patients in the course of a major depressive episode

To investigate factors that may influence treatment choice for Bipolar I/II Disorder (BDI/BDII) patients experiencing a major depressive episode. The HARMONY study (NCT00888264) was a multi-centre, prospective, non-interventional Belgian study that enrolled BDI or BDII patients experiencing a major depressive episode. The study involved four visits (V): V1 (Baseline), V2 (after 6-weeks), V3 (3-months) and V4 (6-months). Data collection included psychiatric hospitalizations, effect of substance abuse or work/school situation on treatment. Safety and tolerability were not assessed. 152 patients aged 19–75 years (mean ± SD: 46.5 ± 11.0; 62.3% female) were recruited: 95 patients (63.3%) with BDI and 55 (36.7%) with BDII, diagnosis was missing for 2 patients. At enrolment, 138 patients were treated by atypical antipsychotics (AAPs) combined with other antipsychotic medications, 14 by AAP monotherapy. Depressive symptoms were treated with quetiapine (42.7%, 64/150), at least one other AAP (40.0%, 60/150; olanzapine, aripiprazole, risperidone or paliperidone), amisulpride (2%, 3/150) and the benzodiazepine chlordiazepoxide (0.67%, 1/150). Patients who first developed symptoms at ≤ 30-years-old were prescribed quetiapine less than patients who developed symptoms when older (34.2%, 27/79 vs. 53.6%, 37/69, p = 0.017). Males were prescribed quetiapine for depressive symptoms more than females (52.6% vs. 36.2%; p = 0.047), more females were prescribed other antipsychotics (42.6% vs. 35.1%). 56.7% (85/150) of patients were hospitalized ≥once for psychiatric symptoms (last 5-years): BDI-63.2% (60/95), BDII-45.5% (25/55). Current treatment choice was not influenced by prior AAP treatment or substance abuse. Age and gender were the main factors influencing treatment choice for BD patients experiencing a depressive episode.

The amphetamine–chlordiazepoxide mixture, a pharmacological screen for mood stabilizers, does not enhance amphetamine-induced disruption of prepulse inhibition

In rodents, administration of a mixture of the psychostimulant d-amphetamine and the benzodiazepine chlordiazepoxide results in supra-additive hyperlocomotion, a phenomenon used to identify mood stabilizers. In an attempt to determine whether the d-amphetamine/chlordiazepoxide assay could extend to other behaviors that are affected in mania, we evaluated the effects of the mixture on prepulse inhibition. In addition, we combined chlordiazepoxide with the selective dopamine reuptake inhibitor GBR 12909 or the noradrenergic stimulant (−) ephedrine, and tested these alternative mixtures in locomotor activity and prepulse inhibition tests. Chlordiazepoxide (3 mg/kg) robustly potentiated amphetamine-induced hyperactivity, but did not change the amphetamine-induced disruption of prepulse inhibition. This indicates that the d-amphetamine-chlordiazepoxide-induced hyperlocomotion does not extend to other dopamine-driven behaviors. GBR 12909 (16 mg/kg) and (−) ephedrine (50 mg/kg) both enhanced locomotor activity and disrupted PPI, but combined treatment of either of these compounds with chlordiazepoxide had no significant additive effect on locomotor activity or prepulse inhibition. These findings suggest that the effect of the d-amphetamine/chlordiazepoxide mixture cannot be accounted for by the dopamine enhancing properties of amphetamine alone. Last, valproic acid (120–240 mg/kg) did not reduce the GBR-induced hyperactivity. Therefore, further pharmacological evaluation of GBR 12909-induced hyperactivity is warranted to determine its pharmacological potential to model mania-like behavior. Based on the current results, it is concluded that the utility of the pharmacological d-amphetamine/chlordiazepoxide assay as a tool to study brain mechanisms relevant to mania is limited.

Discriminative stimulus properties of GABAA receptor positive allosteric modulators TPA023, ocinaplon and NG2-73 in rats trained to discriminate chlordiazepoxide or zolpidem

There is increased understanding that distinct GABAA receptor subtypes mediate different effects of classical benzodiazepines. Here, we aimed to define the contributions of α1-containing subtypes of the subtype-selective GABAA receptor positive allosteric modulators TPA023, ocinaplon, and NG2-73 using drug discrimination. We characterized these compounds with defined subunit preferences in rats that were trained to discriminate either the non-selective benzodiazepine chlordiazepoxide (CDP, 5.0mg/kg) or the α1-selective drug zolpidem (1.5mg/kg). In short, CDP but not zolpidem generalized to the CDP cue. In contrast, zolpidem-trained rats showed opposite effects and generalized to zolpidem but not to CDP, while the response rate reducing effects of both ligands were comparable. Moreover, TPA023, lacking efficacy at the GABAA receptor α1 subunit, occasioned dose-dependent CDP-appropriate responding but generalized only to around 10% to zolpidem. Both ocinaplon and NG2-73 completely generalized to both the CDP and zolpidem cue. Overall, our data confirm and extend the previous findings in rats that compounds that lack efficacy at α1-containing GABAA receptors generalize to CDP, whereas the opposite holds true for α1-preferential compounds, which generalize to the α1-selective positive allosteric modulator zolpidem. Also, our data support the hypothesis that subtle in vitro differences in α subunit efficacy and/or affinity may eventually have large consequences in vivo. Together, our data demonstrate a reliable in vivo method to determine the contribution of the subtype-selective mechanism(s) of action for novel and subtype-selective GABAA receptor positive allosteric modulators, suggesting that a complex activation of multiple α subunits accounts for drug discrimination between non-selective and selective GABAA receptor ligands.

Phasic and Sustained Fear are Pharmacologically Dissociable in Rats

Previous findings suggest differences in the neuroanatomical substrates of short- (seconds) vs longer-duration (minutes) fear responses. We now report that phasic and sustained fear can also be differentiated pharmacologically, based on their response to several treatments that either are or are not clinically effective anxiolytics. For these experiments, short- or long-duration clicker stimuli were paired with footshock. Acoustic startle amplitude was later measured in the absence of the clicker, or within seconds (phasic fear) or minutes (sustained fear) of its onset. Before testing, rats received a single injection of vehicle, the benzodiazepine chlordiazepoxide, the 5HT(1A) agonist and dopamine D2 antagonist buspirone, the selective serotonin reuptake inhibitor fluoxetine, or a 3-week treatment with either vehicle or fluoxetine. Chlordiazepoxide blocked sustained, but not phasic startle increases. Acute buspirone, which is not anxiolytic in human beings, did not affect sustained startle increases, but did disrupt phasic increases. Chronic fluoxetine blocked sustained startle increases and unreliably reduced phasic increases; acute fluoxetine affected neither. The results indicate that phasic and sustained fear responses can be pharmacologically dissociated, further validating this distinction, and suggest that sustained startle increases may be especially useful as anxiety models and anxiolytic screens.

Comparison of the predictive validity of the mirror chamber and elevated plus maze tests in mice

The mirror chamber (MC) is a putative test of anxiety-like behavior in mice, and is increasingly popular. Nonetheless, it is unclear whether the observed behaviors rely on the presence of mirrored panels. If so, it is unclear whether the behaviors are sensitive to clinically effective anxiolytics, and how the test compares to the elevated plus maze (EPM) in terms of predictive validity. The present studies assessed anxiety-like behaviors in different mouse strains in the MC using mirrored and non-mirrored panels, under variable lighting conditions. We also assessed the pharmacological validity of the MC and EPM tests, and the locomotor properties of active test compounds. Seven mouse strains exhibited different levels of anxiety-like behaviors in the MC, and differential sensitivity to panel and light conditions. DBA/2J mice appeared most sensitive to the mirrored, versus black or white, panels and were therefore used in pharmacological MC studies. The mGlu5 receptor antagonist MPEP significantly decreased anxiety-like behaviors, similar to an intermediate dose of the benzodiazepine diazepam. The benzodiazepines chlordiazepoxide and alprazolam and the 5HT1A partial agonist buspirone had no effects on anxiety-like behaviors in the MC. None of the MC effects of active test compounds were attributable to non-specific/locomotor effects. The antidepressants fluoxetine and venlafaxine increased anxiety-like behaviors in the MC. By contrast, the anxiolytic-like effects of chlordiazepoxide, diazepam and MPEP were revealed in the EPM in C57Bl6/J mice. In conclusion, the EPM test exhibits superior predictive validity compared to the MC test, despite the sensitivity of the MC to mouse strain differences.

The rapid hydrolysis of chlordiazepoxide to demoxepam may affect the outcome of chronic osmotic minipump studies

BackgroundIn chronic studies, the classical benzodiazepine chlordiazepoxide (CDP) is often the preferred drug because, unlike other benzodiazepines, it is soluble in water. However, rapid CDP hydrolysis in solution has been described. This would diminish plasma levels in chronic minipump studies and introduce the corelease of active compounds.MethodsTherefore, the present study aimed to explore the putative hydrolysis of CDP in aqueous solution over time and to identify the hydrolysis products. Moreover, we aimed to characterize the hydrolysis products for their in vitro (3H-flunitrazepam binding and oocyte electrophysiology) and in vivo (stress-induced hyperthermia paradigm) GABAA receptor potency.ResultsCDP in solution hydrolyzed to the ketone structure demoxepam which was confirmed using mass spectrometry. The hydrolysis was concentration dependent (first-order kinetics) and temperature dependent. CDP exerted greater potency compared to demoxepam in vitro (increased activity at GABAA receptors containing α1 subunits) and in vivo (stress-induced hyperthermia), although 3H-flunitrazepam binding was comparable.ConclusionsThe classical benzodiazepine CDP is rapidly hydrolyzed in solution to the active compound demoxepam which possesses a reduced activity at the GABAA receptor. Chronic studies that use CDP in aqueous solution should thus be interpreted with caution. It is therefore important to consider drug stability in chronic minipump applications.

Effects of Different Psychotropic Agents on the Central Nerve Growth Factor Protein

Objective(s) Psychotropic medications produce their effects, in part, through increasing neurotrophin levels in the brain. Since studies concerning nerve growth factor (NGF) analysis have been limited in scope, in the current experiments we investigated the effects of diverse psychotropic agents on NGF protein levels in various brain regions of rat. Materials and Methods Male Wistar rats received acute and chronic administration of drugs and electroconvulsive shock (ECS). Twenty four hr after the last treatment, NGF quantification was performed using sandwich ELISA kit. Results Acute administration of desipramine, phenelzine, fluoxetin, chlordiazepoxide (10 mg/kg, each), haloperidol (1 mg/kg), or clozapine (20 mg/kg) failed to alter NGF protein in any brain structure investigated. However, a single ECS treatment significantly elevated NGF protein in the hippocampus. Chronic administration (21 days) of desipramine, fluoxetine, phenelzine, haloperidol and clozapine led to a reliable enhancement of NGF protein in the frontal cortex. In addition desipramine, fluoxetine, phenelzine, and clozapine significantly increased NGF protein in the hippocampus. In the olfactory bulb, chronic injections of desipramine and fluoxetine elevated NGF level, however, phenelzine and haloperidol decreased NGF. Repeated applications of ECS (10 days) led to a remarkable augmentation of NGF protein in the frontal cortex, hippocampus, amygdala, and olfactory bulb. Neither acute nor chronic treatment with the benzodiazepine chlordiazepoxide altered NGF level in the examined brain regions. Conclusion These findings suggest that diverse psychotropic treatments may regulate NGF protein level in a brain region-specific fashion which may be indicative of their therapeutic properties.

Hormonal and cognitive factors associated with the exploratory behavior of rats submitted to repeated sessions of the elevated plus-maze.

rats submitted to the elevated plus-maze (EPM) display a characteristic increase in open arm exploration and reduced risk assessment behaviors (RABs) after the administration of anxiolytic drugs. Upon re-exposure to the maze, however, the traditional measures of the EPM become resistant to these drugs. This intriguing phenomenon was initially observed for the benzodiazepine chlordiazepoxide and referred as one-trial tolerance (OTT). In this review, we summarized hormonal, cognitive and neuroanatomical data obtained from rats submitted to the test/retest protocol in the EPM. The re-exposure to the EPM is characterized by more prominent RABs and a distinct Fos protein distribution in the brain, particularly in limbic structures involved with the cognitive aspects of fear, such as the ventral regions of the medial prefrontal cortex (mPFC) and amygdala. Interestingly, naive rats treated with midazolam had a significant decrease in the number of Fos-positive neurons in the anterior cingulate cortex, area 1 (Cg1), anterior and dorsal premammillary nuclei of hypothalamus. On the other hand, midazolam caused a significant decrease in the number of Fos-positive neurons in the mPFC, amygdala, dorsomedial nucleus of hypothalamus and raphe nuclei in maze-experienced rats. Cg1 was the only structure targeted by the benzodiazepine in both sessions. Systemically administered midazolam before test or retest sessions reduced the RABs and plasma corticosterone levels in rats submitted to both sessions. Similar behavioral results were obtained with intra-Cg1 infusions of midazolam. The results reviewed here support the view of the crucial role of the RABs in the development of the OTT and point to this mPFC area as an important locus for the anxiolytic-like action of benzodiazepines in rodents. Keywords: elevated plus-maze, retest session, benzodiazepines, corticosterone, Fos expression, anterior cingulate cortex.

The supra-additive hyperactivity caused by an amphetamine–chlordiazepoxide mixture exhibits an inverted-U dose response: Negative implications for the use of a model in screening for mood stabilizers

One of the few preclinical models used to identify mood stabilizers is an assay in which amphetamine-induced hyperactivity (AMPH) is potentiated by the benzodiazepine chlordiazepoxide (CDP), an effect purportedly blocked by mood stabilizers. Our data here challenge this standard interpretation of the AMPH–CDP model. We show that the potentiating effects of AMPH–CDP are not explained by a pharmacokinetic interaction as both drugs have similar brain and plasma exposures whether administered alone or in combination. Of concern, however, we find that combining CDP (1–12 mg/kg) with AMPH (3 mg/kg) results in an inverted-U dose response in outbred CD-1 as well as inbred C57Bl/6N and 129S6 mice (peak hyperactivity at 3 mg/kg CDP + 3 mg/kg AMPH). Such an inverted-U dose response complicates interpreting whether a reduction in hyperactivity produced by a mood stabilizer reflects a “blockade” or a “potentiation” of the mixture. In fact, we show that the prototypical mood stabilizer valproic acid augments the effects of CDP on hypolocomotion and anxiolytic-like behavior (increases punished crossings by Swiss–Webster mice in the four-plate test). We argue that these data, in addition to other practical and theoretical concerns surrounding the model, limit the utility of the AMPH–CDP mixture model in drug discovery.

Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats

Since the discovery of endogenous cannabinoid signaling, the number of studies exploring its role in health and disease has increased exponentially. Fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid anandamide, has emerged as a promising target for anxiety-related disorders. FAAH inhibitors (e.g., URB597) increase brain levels of anandamide and induce anxiolytic-like effects in rodents. Recent findings, however, questioned the efficacy of URB597 as an anxiolytic. We tested here the hypothesis that conflicting findings are due to variations in the stressfulness of experimental conditions employed in various studies. We found that URB597 (0.1-0.3 mg/kg) did not produce anxiolytic effects when the aversiveness of testing procedures was minimized by handling rats daily before experimentation, by habituating them to the experimental room, or by employing low illumination during testing. In contrast, URB597 had robust anxiolytic effects when the aversiveness of the testing environment was increased by eliminating habituation to the experimental room or by employing bright lighting conditions. Unlike URB597, the benzodiazepine chlordiazepoxide (5 mg/kg) had anxiolytic effects under all testing conditions. The anxiolytic effects of URB597 were abolished by the cannabinoid CB1-receptor antagonist AM251, showing that they were mediated by CB1 receptors. Close inspection of experimental conditions employed in earlier reports suggests that conflicting findings with URB597 can be explained by different testing conditions, such as those manipulated in the present study. Our findings show that FAAH inhibition does not affect anxiety under mildly stressful circumstances but protects against the anxiogenic effects of aversive stimuli.

Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments

Antidepressant treatments have been proposed to produce their therapeutic effects, in part, through increasing neurotrophin levels in the brain. The current experiments investigated the effects of acute and chronic treatment with different pharmacologic and somatic antidepressant treatments on protein levels of BDNF in several brain regions associated with depression in the rat. Repeated applications (10 days) of electroconvulsive shock (ECS), but not a single treatment (1 day), produced 40–100% increases of BDNF protein in the hippocampus, frontal cortex, amygdala, and brainstem. Chronic (21 days), but not acute (1 day), treatment with the tricyclic antidepressant (TCA) desipramine (10 mg/kg), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10 mg/kg), and the monoamine oxidase inhibitor (MAOI) phenelzine (10 mg/kg) increased BDNF protein levels in the frontal cortex (10–30%), but not in the hippocampus, amygdala, olfactory bulb, and brain stem. To determine whether the regulation of BDNF was unique to antidepressant treatments, drugs used to treat schizophrenia and anxiety were also studied. Chronic administration of the typical antipsychotic haloperidol (1 mg/kg) and the atypical antipsychotic clozapine (20 mg/kg) increased BDNF levels by only 8–10% in the frontal cortex. Haloperidol also elevated BDNF levels in the amygdala, while clozapine decreased BDNF in the olfactory bulb. Acute or chronic treatment with the benzodiazepine chlordiazepoxide (10 mg/kg) did not alter BDNF levels. These results suggest that diverse pharmacologic and somatic antidepressant treatments, as well as antipsychotics, increase levels of BDNF protein in the frontal cortex, even though they have different mechanisms of action at neurotransmitter systems.

Assessing the relationship between latent inhibition and the partial reinforcement extinction effect in autoshaping with rats

Results from a variety of independently run experiments suggest that latent inhibition (LI) and the partial reinforcement extinction effect (PREE) share underlying mechanisms. Experiment 1 tested this LI = PREE hypothesis by training the same set of rats in situations involving both nonreinforced preexposure to the conditioned stimulus (LI stage) and partial reinforcement training (PREE stage). Control groups were also included to assess both LI and the PREE. The results demonstrated a significant, but negative correlation between the size of the LI effect and that of the PREE. Experiment 2 extended this analysis to the effects on LI and the PREE of the anxiolytic benzodiazepine chlordiazepoxide (5 mg/kg, i.p.). Whereas chlordiazepoxide had no effect on LI, it delayed the onset of the PREE. No evidence in support of the LI = PREE hypothesis was obtained when these two learning phenomena were compared within the same experiment and under the same general conditions of training.

Strain- and model-dependent effects of chlordiazepoxide, L-838,417 and zolpidem on anxiety-like behaviours in laboratory mice

The promise of subtype-selective GABA A receptor drugs with anxiolytic properties but with a much reduced side-effect burden (compared to benzodiazepines) is an attainable goal. However, its achievement necessitates the availability of in vivo preclinical assays capable of demonstrating differences as well as similarities between subtype-selective agents and non-selective benzodiazepines. In this study, we have compared three mouse strains (NMRI, C57BL/6J and DBA/2) in four models of anxiety-like behaviour (plus-maze, zero-maze, light–dark, and Vogel conflict). Furthermore, in each model, we have contrasted in detail the behavioural responses of each strain to the non-selective benzodiazepine chlordiazepoxide (CDP; 5–20 mg/kg), and the subtype-selective agents L-838,417 (GABA A-α 2/3/5; 3–30 mg/kg) and zolpidem (GABA A-α1; 0.3–3.0 mg/kg). The data show a complex mouse strain × model × pharmacological agent interaction. Most importantly, not all mouse strain × model test systems showed a positive response to CDP or predicted the response to L-838,417. This dissociation between CDP and L-838,417 opens up opportunities for preclinical test systems that differentiate subtype-selective and non-selective GABA A receptor agents, an attribute that might well be important in providing the necessary confidence for further drug development. Present findings suggest the need for a much greater focus on defining test systems appropriate for screening novel chemical entities, rather than self-selection of models or genotypes based on responses to known pharmacological agents. For example, if current data with L-838,417 are confirmed with compounds showing similar selectivity profiles, such agents may in future be best identified and characterised using test systems comprising NMRI mice in the zero-maze and/or C57 mice in the Vogel conflict and/or light–dark tests.

Evaluation of the anxiolytic-like profile of the GABA B receptor positive modulator CGP7930 in rodents

There is a growing body of data to support the notion that GABA B receptors may be a therapeutic target for anxiety disorders. However, the application of GABA B receptor agonists in anxiety research and psychiatry is hampered by side effects that include motor in-coordination and hypothermia. Recently the GABA B receptor positive modulator GS39783 was shown to be anxiolytic in rodent models, but was devoid of accompanying side effects characteristic of full agonists. However, it is important to test whether such anxiolytic effects generalise to another chemical class of GABA B receptor positive modulators. We therefore aimed to investigate the anxiolytic and side-effect profile of CGP7930, the first-reported GABA B receptor positive modulator, in rodent models of anxiety, motor coordination and hypothermia. CGP7930 (3–300 mg/kg) showed a modest, compared to the benzodiazepine chlordiazepoxide (10 mg/kg), dose-dependent anxiolytic profile in the mouse stress-induced hyperthermia (100 mg/kg), staircase (100 and 300 mg/kg) and elevated zero maze tests (3–100 mg/kg), but did not have any anxiolytic effects in the rat elevated plus maze. Similar to GS39783, CGP7930 also demonstrated a greatly reduced side-effect profile in comparison to the GABA B receptor full agonist baclofen in the mouse rotarod and traction wire tests and did not induce hypothermia. Although the effects of CGP7930 were modest, these results represent a second, structurally distinct, class of GABA B positive modulators showing anxiolytic activity. As such, these data support the premise that GABA B receptor positive modulation represents a novel therapeutic strategy for the development of anxiolytic drugs with a superior side-effect profile. The generation of more potent compounds is now warranted.