RO15-4513 antagonizes the anxiolytic effects of ethanol in a nonshock conflict task at doses devoid of anxiogenic activity.

RO15-4513 is a partial benzodiazepine inverse agonist that has been reported to antagonize some of the biochemical and neurobehavioral actions of ethanol. However, whether this antagonistic action of RO15-4513 is dependent on the drug exerting its intrinsic (inverse agonist) properties is unclear at present. The purpose of the present study was to examine whether RO15-4513 was capable of antagonizing the anxiolytic effects of ethanol in a nonshock conflict task at doses that, by themselves, do not reveal the compound's intrinsic anxiogenic properties. The consummatory conflict task employed (negative contrast) involves quantifying how animals respond to an abrupt, unexpected reduction in reward (sucrose solution), and is particularly sensitive to the effects of anxiolytic agents, including ethanol. As previously demonstrated, depressed consummatory behavior engendered by reward reduction was significantly alleviated by ethanol (0.75 g/kg). This anxiolytic effect of ethanol, however, was antagonized dose dependently by RO15-4513 (0.1875-3.0 mg/kg). Only the highest dose of RO15-4513 (3.0 mg/kg) showed evidence of further response suppression. Lower doses of RO15-4513 tested did not exert an anxiogenic effect when given alone. Thus the antagonism of EtOH's anxiolytic (contrast-reducing) effects occurred at doses of RO15-4513 (0.375-1.5 mg/kg) that did not exhibit any intrinsic anxiogenic activity. As such, these results suggest that RO15-4513 interacts with the anxiolytic effects of ethanol in a nonadditive fashion in this test situation.     

Effects of valproate on hyponeophagia in rats: Competitive antagonism with picrotoxin and non-competitive antagonism with RO 15-1788

The effects of valproate (30–500 mg/kg), alone and in combination with picrotoxin (1.5 mg/kg) or RO 15-1788 (10 mg/kg) were studied in two experiments on hyponeophagia in rats. Valproate reduced eating latency and incrased eating time and amount eaten of novel food, except at 500 mg/kg which reduced feeding. Picrotoxin induced generally opposite actions alone and shifted valproate dose/response curves to the right. RO 15-1788 had no detectable intrinsic action, but prevented both the behavioural facilitation and inhibition produced by valproate. These findings are discussed in the context of the GABA hypothesis of benzodiazepine action, with the conclusions that they provide behavioural support for the hypothesis of a receptor complex with GABA and benzodiazepine binding sites, and that an optimal and submaximal level of activity at the benzodiazepine site is a necessary condition for anxiolytic actions of valproate.     

Bay K 8644 potentiates the anxiolytic effect of ethanol.

The possible role of voltage-sensitive calcium channels (VSCCs) in the anxiolytic effect of ethanol was investigated using three different doses of ethanol (0.5, 1.0 and 2.0 g/kg) with calcium agonist Bay K 8644 (0.5 mg/kg) and calcium antagonist nifedipine (5 mg/kg) in rats. Ethanol produced an anxiolytic effect in a dose-dependent manner. The Bay K 8644-potentiated anxiolytic effect of ethanol, however, Bay K 8644 did not alter anxiety when used alone. Nifedipine itself showed an anxiolytic effect but did not change the ethanol-induced anxiolytic effect. This finding may lead to the consideration of the neurochemical mechanisms of the anxiolytic effects of ethanol and nifedipine as they vary from each other.     

Picrotoxin blocks the anxiolytic- and panicolytic-like effects of sodium valproate in the rat elevated T-maze

The effect of acute sodium valproate administration, an anxiolytic and putative panicolytic drug, was evaluated in rats tested in the elevated T-maze, an animal model that measures two defensive reactions: avoidance (inhibitory avoidance), related to generalized anxiety, and escape (escape from open arms), related to panic. Additionally, the involvement of gamma-aminobutyric acid (GABA) neurotransmission in sodium valproate effects was studied by picrotoxin co-administration. Sodium valproate (300 mg/kg, intraperitoneally, 30 min before the test) impaired both avoidance latency (time to leave the closed arm) and one-way escape (latency to enter the closed arm) indicating anxiolytic and panicolytic effects, respectively. Pre-treatment with picrotoxin (0.5 mg/kg, intraperitoneally, 5 min before sodium valproate administration) blocked the effects of sodium valproate on inhibitory avoidance and one-way escape. No locomotor effect was seen in the open-field. These data suggest that sodium valproate exerts anxiolytic-like and panicolytic-like effects in the elevated T-maze and that these effects were mediated by picrotoxin-sensitive GABA type A receptors.     

Effects of chlordiazepoxide and of valproate on hyponeophagia in rats. Evidence for a mutual antagonism between their anxiolytic properties

The effects of chlordiazepoxide (0,2.5 and 7.5 mg/kg), of valproate (0,100 and 300 mg/kg), and of combinations of these drugs, on hyponeophagia in rats, were studied using a food preference test. Chlordiazepoxide alone reduced the latency for eating, and also enhanced the time of eating and the amount of familiar food eaten at the smaller dose, and of novel food eaten at the larger dose. Valproate alone reduced the latency of eating and enhanced time of eating and the amount of novel food eaten, especially at 300 mg/kg. However, valproate antagonised the effects of chlordiazepoxide on all behavioural measures. These findings are discussed in the context of the GABA hypothesis of the actions of benzodiazepines, with the conclusion that valproate has an atypical pharmacological profile amongst putative GABA agonists, and may have partial agonist activity at the proposed benzodiazepine/GABA receptor complex.     

Effects of ethanol and GABAB drugs on working memory in C57BL/6J and DBA/2J mice

RATIONALE: It has been suggested that GABA(B) receptors may be part of a neural substrate mediating some of the effects of ethanol. OBJECTIVE: The purpose of this experiment was to investigate, in mice, the effects of ethanol on working memory in a delayed matching-to position (DMTP) task, and additionally to determine if these effects were modulated by GABA(B) receptors. METHODS: Female C57BL/6J and DBA/2J mice were trained in the DMTP task, and after asymptotic levels of performance accuracy were achieved, injections (IP) of ethanol, baclofen, or phaclofen were administered. Baclofen or phaclofen were then co-administered with ethanol. Each test was repeated twice. RESULTS: Ethanol caused deficits in working memory at 2.0 g/kg and higher. The highest dose (2.5 g/kg) produced additional non-specific effects, indicative of sedation. Baclofen increased performance accuracy (2.5 mg/kg), while decreasing the total number of trials completed. When combined with ethanol (1.5 g/kg), baclofen increased memory deficits at the highest dose (7.5 mg/kg). Phaclofen increased performance accuracy at 10 and 30 mg/kg but had no effect on the total number of trials completed. When combined with ethanol (2.5 g/kg), phaclofen did not significantly alter ethanol-induced deficits in performance. CONCLUSIONS: Analyses of performance accuracy, total trials completed and variables indexing bias and motor impairment indicated that GABA(B) drugs modulate working memory in a behaviorally specific manner. Overall, these receptors may be part of a neural substrate that modulates some of the effects of ethanol.     

Differential effects of GABA transaminase inhibitors on sexual behavior, locomotor activity, and motor execution in the male rat

The GABA transaminase inhibitors gamma-acetylen GABA (GAG) and sodium valproate were administered intraperitoneally and their effects on locomotor activity, motor execution and sexual behavior were analyzed. It was found that sodium valproate, administered 15 min before observation, reduced locomotor activity only at a dose of 200 mg/kg. Doses of 100 and 400 mg/kg had no effect. Motor execution was impaired in a dose-dependent way, the lowest effective dose being 200 mg/kg. Sexual behavior was also dose-dependently reduced. Sodium valproate, administered 60 min before observation, inhibited all behaviors. The lowest effective dose was 200 mg/kg for locomotor activity and 400 mg/kg for motor execution and sexual behavior. GAG also inhibited all behavior, in doses ranging from 25 mg/kg (locomotor activity) to 100 mg/kg (motor execution and sexual behavior). The data showed that there is no relation between effects on locomotor activity and the effects on sexual behavior, whereas sexual behavior is inhibited whenever motor execution is impaired. Moreover, there is no correlation between effects on locomotor activity and motor execution. It is suggested that GABA transaminase inhibitors effect sexual behavior only indirectly, via an impairment of motor execution. Therefore it is doubtful whether GABAergic mechanisms play any role in the normal regulation of sexual behavior.     

Behavioral effects of the inhibitors of phenylethanolamine-N-methyltransferase,LY 78335 and LY 134046, and their interactions with ethanol

The centrally active inhibitors of phenylethanolamine-N-methyltransferase (PNMT), LY 78335 and LY 134046, were investigated both alone and in combination with ethanol (2 g/kg) in a holeboard test of directed exploration and locomotor activity. Both PNMT inhibitors showed dose-related reductions in exploratory head-dipping but were without effect on locomotor activity. In combination with ethanol both PNMT inhibitors tended to attenuate the ethanol-induced reductions in exploratory head-dipping but did not effect ethanol's locomotor stimulant properties. LY 134046 showed neither an anxiolytic nor an anxiogenic profile in the plusmaze test of anxiety, nor did it alter the anxiolytic effects of either 1.2 g/kg or 2 g/kg ethanol. LY 134046 did, however, attenuate the ataxic effects of a 2.4 g/kg dose of ethanol. These results may suggest a role for adrenaline synthesis in some, but not all, of the behavioral effects of ethanol.     

Time course of ethanol's effects on locomotor activity,exploration and anxiety in mice

The time course of the effects of two doses of ethanol on exploration, locomotor activity and anxiety were investigated using the holeboard and plus-maze tests. In an 8 min holeboard test the lower (1.2 g/kg) dose increased both exploration and locomotor activity 0.5 h after ethanol administration whereas the higher (2.4 g/kg) dose decreased exploration but caused an even greater increase in locomotor activity. This activity increase was also seen 1 h postadministration. In the plus-maze test both doses showed an increased number of arm-entries 0.5 h and 1 h after administration but only the 2.4 g/kg dose caused anxiolytic effects persisting for over 2 h. The results add further support to the notion that the behavioral effects of ethanol vary with dose, time of administration and the behavioral measure taken.     

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.     

Effects of ethanol on cocaine discrimination in rats

Ethanol and cocaine are frequently abused in combination, but little is known about how the subjective effects of the two drugs interact. The ability of ethanol and other GABA(A)-active compounds to alter the discriminative stimulus effects of cocaine was tested. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg ip) from saline using either single- or cumulative-dosing methods. In single-dose testing, ethanol (0.1-0.5 g/kg) dose-dependently decreased cocaine-appropriate responding following the training dose of cocaine. Ethanol (0.5 g/kg) produced a rightward shift in the cocaine cumulative dose-effect curve. Ethanol (0.1-1.0 g/kg) failed to substitute for the discriminative stimulus effects of cocaine and the higher doses (1-2 g/kg) completely suppressed responding. Indirect GABA(A) agonists diazepam (benzodiazepine site) and pentobarbital (barbiturate site) did not block the discriminative stimulus effects of cumulative doses of cocaine. The GABA(A) antagonist pentylenetetrazol (PTZ) (10-40 mg/kg) did not substitute for cocaine. These findings suggest that ethanol can modulate the discriminative stimulus effects of cocaine, and that these effects may not be mediated by the actions of ethanol at the GABA(A) receptor.     

Increased specificity of ethanol's discriminative stimulus effects in an ethanol-pentobarbital-water discrimination in rats.

Ethanol's modulation of a number of receptor systems results in a heterogeneous discriminative stimulus complex. A previous study found that these heterogeneous discriminative stimulus effects were seemingly diminished when rats were trained to discriminate ethanol (2.0 g/kg) from pentobarbital (10.0 mg/kg). The present experiment was designed to extend these findings by using a lower training dose of ethanol (1.0 g/kg). Adult male Long-Evans rats (n = 7) discriminated pentobarbital (10.0 mg/kg; intragastric (i.g.)) from ethanol (1.0 g/kg; i.g.) from water (2.3 ml; i.g.) in a 3 lever, food-reinforced task. Substitution tests were conducted following intraperitoneal (i.p.) administration of GABA(A) positive modulators, noncompetitive NMDA antagonists, 5-HT1 agonists and isopropanol. The GABA(A) positive modulators diazepam, midazolam and allopregnanolone completely substituted for pentobarbital. Isopropanol completely substituted for ethanol, while the NMDA antagonists dizocilpine and phencyclidine partially substituted for ethanol. The 5-HT agonists RU 24969 and CGS 12066B did not result in complete substitution for ethanol or pentobarbital, although RU 24969 resulted in partial pentobarbital substitution. These data replicate and extend the previous findings that discriminating ethanol from pentobarbital attenuates the ethanol-like effects of GABA(A) positive modulators, NMDA antagonists and 5-HT1 agonists and results in a more specific ethanol cue. The outcome appears to be a conditional basis for the ethanol discrimination, where a full ethanol-like effect is produced only by drugs with pharmacological activity similar to the heterogenous effects of ethanol (e.g. other alcohols).     

Evidence for GABA-BZ receptor modulation in short-term memory passive avoidance task paradigm in mice

The possible involvement of gamma-aminobutyric acid/benzodiazepine (GABA-BZ) receptor modulation in scopolamine-induced short-term memory deficit was investigated in mice. Passive avoidance step-down task behavior was observed. Latency of mice to reach shock-free zone (SFZ) and number of mistakes the animal made in 15 min were used as separate parameters for acquisition and memory retention, respectively. Scopolamine (0.3 mg/kg) caused a delay in reaching SFZ and an increased number of mistakes. Physostigmine reversed the scopolamine-induced increase in number of mistakes; however, it caused a delay in the time to reach SFZ. Subeffective dose of GABA, when combined with physostigmine, further delayed the latency to reach SFZ, but reduced the number of mistakes very significantly. GABA (50, 75 and 100 mg/kg, i.p.) and GABA agonists sodium valproate (30 and 60 mg/kg, i.p.), fengabine (5 and 10 mg/kg, i.p.), (+/-)baclofen (0.25, 0.5 and 1.0 mg/kg, i.p.) and (-)baclofen (0.25 and 0.5 mg/kg i.p.) reversed the scopolamine-induced effect; however, sodium valproate at higher dose delayed time to reach SFZ. Combined administration of lower dose (+/-)baclofen and subeffective dose of GABA showed significant decrease in latency and number of mistakes in scopolamine-treated animals. The specific benzodiazepine antagonist flumazenil (Ro-15-1788) (5 and 10 mg/kg, i.p.) and inverse agonist FG-7142 (10 mg/kg, i.p.) very significantly reversed scopolamine-induced increase in number of mistakes, but Ro-15-1788 failed to show any effect on latency per se and in scopolamine-treated experiments, as well.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anxiolytic effects of ethanol and phenobarbital are abolished in test-experienced rats submitted to the elevated plus maze

Prior test experience compromises the anxiolytic efficacy of benzodiazepines (BZs) either in rats or mice, a phenomenon not exclusive to the elevated plus-maze (EPM) animal model of anxiety, which is referred to as "one-trial tolerance." However, it remains to be determined whether a similar event occurs when testing other drugs that also possess binding-sites on the GABA(A) receptor, such as ethanol and barbiturates. In the present study, we have addressed this issue using maze-naive and maze-experienced (free exploration of the EPM 48 h earlier for 5 min) rats pretreated with ethanol (1.0-1.4 g/kg) or phenobarbital (20-60 mg/kg) and submitted to the EPM. The results confirmed the anxiolytic profile of both drugs, represented by increased open arm exploration and decreased risk assessment behavior, in maze-naive rats. However, in maze-experienced rats, neither ethanol nor phenobarbital anxiolytic effects were observed, suggesting that prior maze experience compromised the drugs' anxiolytic activity. Thus, the "one-trial tolerance" phenomenon might also be extended to other drugs that bind to the GABA(A) receptor complex.     

Bromocriptine and quinpirole,but not 7-OH-DPAT or SKF 38393, potentiate the inhibitory effect of L-NAME on ethanol-induced locomotor activity in mice

The effects of N(G)-nitro- l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, SKF 38393, bromocriptine (BRM), quinpirole (QPR) and 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), dopamine receptor agonists, and combinations of the dopamine agonists and L-NAME on ethanol-induced locomotor activity in adult male Swiss-Webster mice were investigated. The mice were given ethanol (0.5-2 g/kg), L-NAME (15-60 mg/kg), SKF 38393 (5-20 mg/kg), BRM (2.5 and 5 mg/kg), QPR (0.25 and 0.5 mg/kg), 7-OH-DPAT (0.5 and 1.0 mg/kg), a combination of l-arginine (1 g/kg) and L-NAME (60 mg/kg), combinations of SKF 38393, BRM, QPR or 7-OH-DPAT with L-NAME (60 mg/kg) or ethanol (0.5 g/kg) and saline or vehicle by i.p. injection. Triple combinations (dopaminergic agonist, 60 mg/kg L-NAME and 0.5 g/kg ethanol) were also given. Locomotor activity was measured for 30 min immediately following ethanol injections. Ethanol (0.5 g/kg) significantly increased locomotor activity. L-NAME, BRM, QPR and 7-OH-DPAT blocked the ethanol (0.5 g/kg)-induced locomotor hyperactivity dose dependently and at doses that did not affect locomotor activity in naive mice when administered alone. The inhibitory effects of L-NAME (60 mg/kg) were not prevented by pretreatment with l-arginine. BRM and QPR, but not 7-OH-DPAT, significantly and dose-dependently potentiated the inhibitory effect of L-NAME. Our results suggest that L-NAME inhibits ethanol-induced locomotor hyperactivity in mice by a mechanism not involving NO. The inhibitory effect of L-NAME may be related to the activation of presynaptic dopamine D(2) receptors rather than dopamine D(3) receptors.     

Sodium valproate decreases exploratory behaviour in mice: development of tolerance and cross-tolerance with chlordiazepoxide

Sodium valproate (400 mg/kg) significantly reduced exploratory head-dipping in mice, without significant reductions in locomotor activity or rearing. After 5 daily injections of sodium valproate (50 or 400 mg/kg) there was tolerance to the effects of a test dose of 400 mg/kg. Pretreatment for 5 days with chlordiazepoxide (5 mg/kg) did not change the effects of sodium valproate (400 mg/kg), but 5 days pretreatment with chlordiazepoxide (20 mg/kg) did produce cross-tolerance. Sodium valproate (50 mg/kg) was without significant effect acutely, or after 5 days of pretreatment with sodium valproate (50 or 400 mg/kg) or chlordiazepoxide (5 or 20 mg/kg). Daily injections of the benzodiazepine antagonist, flumazenil (10 mg/kg), immediately after the daily injection of sodium valproate (400 mg/kg) or chlordiazepoxide (20 mg/kg) did not prevent the development of tolerance or cross-tolerance. This suggests that benzodiazepine receptors may not mediate these phenomena; possible roles of GABA and 5-HT are also discussed.     

Effects of agonists and antagonists at the GABA/benzodiazepine receptor on conditioned suppression in rats

Certain drugs generally regarded as GABA agonists, such as valproate and combinations of muscimol and baclofen, have been reported to produce apparent anxiolytic effects in various animal behavioral tests. The present paper reports two experiments on the effects of these agents on conditioned suppression in rats. In the first study, muscimol (0, 1.25 micrograms/kg or 1 mg/kg), baclofen (0, 1 mg/kg) and combinations of these treatments failed to alleviate conditioned suppression. Experiment Two showed that valproate (200 mg/kg) did attenuate conditioned suppression, and that its effects were antagonised by picrotoxin (1.5 mg/kg), but not by bicuculline (1.5 mg/kg), Ro 15-1788 (10 mg/kg) or by delta-amino-n-valeric acid (10 mg/kg). The findings are discussed in the context of the proposed GABA/benzodiazepine receptor complex, with the conclusion that there is little evidence for a mediating role of GABAa or GABAb receptors in such drug actions, and that the site of valproate action is probably the chloride ion channel associated with the receptor complex.     

Pharmacological and anatomical evidence for an interaction between mGluR5- and GABA(A) alpha1-containing receptors in the discriminative stimulus effects of ethanol.

The discriminative stimulus properties of ethanol are mediated in part by positive modulation of GABA(A) receptors. Recent evidence indicates that metabotropic glutamate receptor subtype 5 (mGluR5) activity can influence GABA(A) receptor function. Therefore, the purpose of this work was to examine the potential involvement of mGluR5 in the discriminative stimulus effects of ethanol. In rats trained to discriminate ethanol (1 g/kg, intragastric gavage (i.g.)) from water, 2-methyl-6-(phenylethyl)-pyridine (MPEP) (1-50 mg/kg, i.p.) a selective noncompetitive antagonist of the mGlu5 receptor did not produce ethanol-like stimulus properties. However, pretreatment with MPEP (30 mg/kg) reduced the stimulus properties of ethanol as indicated by significant reductions in ethanol-appropriate responding, specifically at 0.5 and 1 g/kg ethanol, and a failure of ethanol test doses (1 and 2 g/kg) to fully substitute for the ethanol training dose. To test whether mGluR5 antagonism altered the GABA(A) receptor component of the ethanol stimulus, the ability of MPEP to modulate pentobarbital and diazepam substitution for ethanol was assessed. Pentobarbital substitution (1-10 mg/kg, i.p.) for ethanol was not altered by MPEP pretreatment. However, MPEP pretreatment inhibited the ethanol-like stimulus properties of diazepam (5 mg/kg, i.p.). To examine a potential anatomical basis for these pharmacological findings, expression patterns of mGluR5- and benzodiazepine-sensitive GABA(A) alpha1-containing receptors were examined by dual-label fluorescent immunohistochemistry with visualization by confocal microscopy. Results indicated that mGluR5- and GABA(A) alpha1-containing receptors were both coexpressed in limbic brain regions and colocalized on the same cells in specific brain regions including the amygdala, hippocampus, globus pallidus, and ventral pallidum. Together, these findings suggest an interaction between mGluR5- and benzodiazepine-sensitive GABA(A) receptors in mediating ethanol discrimination.     

Discriminative stimulus effects of pentobarbital in pigeons

Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0–17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6–17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3–3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.     

On the mechanism of anti-hyperthermic effects of LY379268 and LY487379, group II mGlu receptors activators, in the stress-induced hyperthermia in singly housed mice

Earlier studies have demonstrated that the agonists of the mGlu(2/3) receptors produced anxiolytic actions after peripheral administration. However, the mechanism of their action is still not clear. Therefore the aim of the present study was to specify the role of the GABAergic and serotonergic system in the mechanism of the anxiolytic activity of group II mGlu receptor activators by using the stress induced hyperthermia test (SIH) in singly housed mice. We used an orthosteric mGlu(2/3) receptor agonist, LY379268, which induced anti-hyperthermic efficacy in the doses of 1-5mg/kg (73% of inhibition after a highest dose). The effect of the second ligand used, a mGlu(2) receptor positive modulator (PAM), LY487379, was observed in a dose range of 0.5-5mg/kg and reached 53% of the inhibition. The blockade of GABAergic system by GABA(A) receptor antagonist flumazenil (10mg/kg) or GABA(B) receptor antagonist CGP55845 (10mg/kg), and the blockade of serotonergic system by 5-HT(1A) receptor antagonist WAY100635 (0.1 and 1mg/kg) or 5-HT(2A/2C) receptor antagonist ritanserin (0.5mg/kg) had no influence on the anti-hyperthermic effect induced by effective dose of LY379268. However, the action of the effective dose of LY487379 was enhanced when co-administered with flumazenil, WAY100635 (0.1mg/kg) and ritanserin. Similar results were observed for the subeffective dose of LY379268 (0.5mg/kg). WAY100635 in a dose of 1mg/kg did not induce any enhancing effect on the activity of compounds. Therefore, it seems that the antagonism towards GABA(A) receptors, presynaptic 5-HT(1A) and postsynaptic 5-HT(2A/2C) receptors is responsible for the phenomenon. This article is part of a Special Issue entitled 'Anxiety and Depression'.