The group III mGlu receptor agonist ACPT-I exerts anxiolytic-like but not antidepressant-like effects, mediated by the serotonergic and GABA-ergic systems.

Our earlier studies have demonstrated that (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid ACPT-I, a group III mGlu receptor agonist, produced anxiolytic-like and antidepressant-like actions after central administration. Here we describe the anxiolytic-like effects of ACPT-I after intraperitoneal administration in the stress-induced hyperthermia (SIH), elevated plus-maze (PMT) tests in mice and in the Vogel test in rats. However, the compound did not produce antidepressant-like effects in the tail suspension test (TST) or in the forced swim test (FST) in mice. The potential anxiolytic effect of ACPT-I (20 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (given i.p., 10 mg/kg), and by a 5-HT(1A) receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635) (0.1 mg/kg s.c.). At the same time, ritanserin (0.5 mg/kg i.p.), the 5-HT2A/C receptor antagonist, did not change the anxiolytic-like effects of ACPT-I. The results of these studies indicate that the GABA-ergic and serotonergic systems are involved in the potential anxiolytic action of ACPT-I.

Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents.

Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. Previous behavioral studies have indicated that metabotropic glutamate (mGlu) receptors may be useful targets for the treatment of psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential antipsychotic effects in behavioral models of schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and neurodegenerative disorders. However, despite encouraging data in animal models, most ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood-brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of psychosis or hallucinations. The results of the present study show that ACPT-I, given at doses of 10 or 30mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100mg/kg decreased amphetamine-induced hyperlocomotion in rats. Furthermore, ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of schizophrenia.

Effects of a selective 5-HT1B receptor agonist and antagonists in animal models of anxiety and depression.

The purpose of the present study was to investigate the effects of the selective 5-HT1B receptor agonist CP 94253, the selective 5-HT1B receptor antagonist SB 216641, and the 5-HT1B/1D receptor antagonist GR 127935 in behavioral tests commonly used to predict anxiolytic- and antidepressant-like activity. Diazepam and imipramine were used as reference drugs. In the Vogel conflict drinking test, CP 94253 (1.25-5 mg/kg), SB 216641 (2.5-5 mg/kg) and GR 127935 (5-10 mg/kg) showed anxiolytic-like effects comparable to that of diazepam (2.5-5 mg/kg). In the elevated plus-maze test, antianxiety-like activity of all the compounds tested was also observed: the effects of CP 94253 (2.5 mg/kg) and SB 216641 (5 mg/kg) were similar to that of diazepam (5 mg/kg), while GR 127935 (up to 40 mg/kg) was less active. In the four-plate test, the compounds tested (5-10 mg/kg) produced anxiolytic-like effects which were weaker than that of diazepam (2.5-5 mg/kg). In the forced swimming test, CP 94253 (5-10 mg/kg), like imipramine (30 mg/kg), showed anti-immobility action, whereas SB 216641 (2.5-10 mg/kg) and GR 127935 (20-40 mg/kg) did not affect the immobility time in mice. The results indicate that the selective agonist (CP 94253) and antagonists (SB 216641 and GR 127935) of 5-HT1B receptors produce effects that are characteristic of anxiolytics, in the preclinical models used; however, CP 94253 also behaves like an antidepressant drug.

The anxiolytic-like activity of AIDA (1-aminoindan-1,5-dicarboxylic acid), an mGLu 1 receptor antagonist.

In the present study we examined the effects of 1-aminoindan-1,5-dicarboxylic acid (AIDA), regarded as a selective and competitive mGluR1 antagonist, in animal models of anxiety. Diazepam (1-10 mg/kg) was used as a reference drug. After intraperitoneal administration, AIDA (0.5-2 mg/kg) produced anxiolytic-like effects in the conflict drinking test and the elevated plus-maze test in rats; however, in doses up to 8 mg/kg, it was inactive in the four-plate test in mice. AIDA tested at the effective doses in the conflict drinking test changed neither the treshold current nor water intake in rats compared to vehicle treatment. AIDA (in a dose of 4 mg/kg, but not lower) increased the exploratory locomotor activity of rats measured in the open-field test, but it did not disturb rat motor coordination in the rota-rod test. The above results indicate that selective mGluR1 antagonist AIDA induces antianxiety-like effects at a low risk of acute side effects characteristic of benzodiazepines. Further studies are required to identify the sites and the mechanism of action of AIDA.

Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats.

Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic and antidepressant drugs. The involvement of group I mGlu receptors in anxiety and depression has also been proposed. In view of the recent discovery of anxiolytic- or antidepressant-like effects of acute injections of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective and brain penetrable mGlu5 receptor antagonist, we designed the present study to examine anxiolytic- and/or antidepressant-like effects of multiple administrations of this drug. The anxiolytic-like effects of MPEP were evaluated in rats using the conflict drinking test. The antidepressant-like effect was estimated using the rat olfactory bulbectomy model of depression. Seven subsequent injections of MPEP (1 mg/kg) significantly (by 320%) increased the number of shocks accepted during the experimental session in the Vogel test. MPEP given once daily at a dose of 10 mg/kg, restored the learning deficit of bulbectomized rats after 14 days of treatment, remaining without any effect in the sham-operated animals. N-methyl-D-aspartic acid (NMDA)-induced convulsions in mice were not affected by a single injection of MPEP (30 mg/kg) indicating that at this dose MPEP did not block NMDA receptors. The results indicate that the prolonged blockade of mGlu5 receptors exerts anxiolytic- and antidepressant-like effects in rats. No tolerance to anxiolytic-like action occurs. The previously mentioned results further indicate that antagonists of group I mGlu receptors may play a role in the therapy of both anxiety and depression.

The antianxiety-like effects of antagonists of group I and agonists of group II and III metabotropic glutamate receptors after intrahippocampal administration.

RATIONALE: Substances acting as agonists of group II mGlu receptors with joint group I mGlu receptor antagonist effects, or group II mGlu receptors agonists, were shown to induce antianxiety-like effect in rats after intrahippocampal administration. OBJECTIVE: The present study was undertaken to establish whether a more selective group I, II, III mGlu receptors agonists/antagonists induce anxiolytic-like effects after injection to the hippocampus. METHODS: (S)-4-Carboxyphenylglycine [(S)-4CPG] and 7-(hydroxyimino)cyclopropan[b]chromen-1alpha-carboxylic ethyl ester (CPCCOEt), selective antagonists at group I mGlu receptors, or (+)1S, 2S, 5R, 6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and (2S, 1'S, 2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), two selective agonists of group II mGlu receptors, as well as (1S, 2S, 4S, 5S)-2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I (ABHxD-I), an agonist at all three groups of mGlu receptors and L-serine-O-phosphate (L-SOP), an agonist at group III mGlu receptors, were used. All compounds were administered into the CA1 region of the dorsal hippocampus. The conflict drinking Vogel test in rats was used to estimate the anxiolytic-like effects of all the compounds. RESULTS: After intrahippocampal administration, both selective group I mGlu receptors antagonists (S)-4CPG and CPCCOEt, as well as the selective agonists of group II mGlu receptors LY 354740 and L-CCG-I, and an agonist of group III mGlu receptors, L-SOP, induced anticonflict effects. CONCLUSION: Selective antagonists of group I mGlu receptors and agonists of group II and group III mGlu receptors exhibit anxiolytic-like activity in the conflict drinking test. It seems that the hippocampus may be one of the brain structures involved in the anticonflict effect of mGlu receptor agonists/antagonists.

Influence of the terminal amide fragment geometry in some 3-arylideneindolin-2(1H)-ones on their 5-HT1A/5-HT2A receptor activity.

Several 1,4-disubstituted arylpiperazine derivatives of 3-arylideneindolin-2(1H)-one (Z and E isomers) were tested for their 5-HT1A and 5-HT2A receptor activity in vitro and in vivo. It was shown that introduction of 3-arylidene substituents to indolin-2(1H)-one moiety allowed to change the mixed 5-HT1A/5-HT2A receptor ligands to 5-HT2A ones with antagonistic in vivo activity.

Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist.

1. Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic and/or antidepressant drugs. The involvement of group I mGlu receptors in anxiety and depression has also been proposed. Given the recent discovery of a selective and brain penetrable mGlu5 receptor antagonists, the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), i.e. the most potent compound described, was evaluated in established models of anxiety and depression. 2. Experiments were performed on male Wistar rats or male Albino Swiss or C57BL/6J mice. The anxiolytic-like effects of MPEP was tested in the conflict drinking test and the elevated plus-maze test in rats as well as in the four-plate test in mice. The antidepressant-like effect was estimated using the tail suspension test in mice and the behavioural despair test in rats. 3. MPEP (1 - 30 mg kg(-1)) induced anxiolytic-like effects in the conflict drinking test and the elevated plus-maze test in rats as well as in the four-plate test in mice. MPEP had no effect on locomotor activity or motor coordination. MPEP (1 - 20 mg kg(-1)) did shorten the immobility time in a tail suspension test in mice, however it was inactive in the behavioural despair test in rats. 4. These data suggest that selective mGlu5 receptor antagonists may play a role in the therapy of anxiety and/or depression, further studies are required to identify the sites and the mechanism of action of MPEP.

Glutamate receptor ligands as anxiolytics.

The glutamatergic system has received considerable attention over recent years as a potential target for anxiolytic drugs. In spite of the pronounced anxiolytic-like effects of competitive and non-competitive antagonists of NMDA receptors in animal models of anxiety, these substances can not be regarded as potential anxiolytic drugs, mainly due to their side-effect profiles (eg, ataxia, myorelaxation, impairment of learning and memory processes and psychotomimetic effects). Antagonists and partial agonists of the glycine, receptor inhibit function of the NMDA receptor complex and evoke in animals an anxiolytic-like response. Although data concerning anti-anxiety-like effects of glycine, receptor antagonists are not very promising, studies are underway to develop new, brain-penetrating agents devoid of side effects. Further developments are necessary to more fully elucidate the possible involvement of AMPA/kainate receptors in anxiety. The recent discovery of metabotropic glutamate receptors, which modulate the function of the glutamatergic system, offers new hope for discovery of a new generation of anxiolytics. MPEP, a highly selective, brain penetrable, noncompetitive mGlu5 receptor antagonist, evokes anxiolytic-like effects in several animal models of anxiety, remaining remarkably free of side effects. LY-354740, a selective brain-penetrable group II mGlu receptor agonist, evokes marked anxiolytic-like effects in animal models of anxiety. LY-354740 causes mild sedation in mice, does not disturb motor coordination and has no potential to cause dependence. Therefore mGlu receptor ligands may become the anxiolytics of the future, free from the side effects characteristic of benzodiazepines.

2-H- and 2-acyl-9- [omega-[4-(2-methoxyphenyl)piperazinyl]-alkyl]-1,2,3,4-tetrahydro-beta-carbolines as ligands of 5-HT1A and 5-HT2A receptors.

Three series of new unsubstituted or 2-acyl 1,2,3,4-tetrahydro-beta-carbolines (THBC), connected to 1-(o-methoxyphenyl)piperazine by 2-, 3- or 4-membered alkylene spacer (3, 4 or 5, respectively) in position 9, were synthesized and their 5-HT1A/5-HT2A receptor affinities and functional in vivo activities were investigated. Radioligand binding studies showed that unsubstituted (a) and acyl (b-f) derivatives with prop-1,3-ylene (4) and particularly with but-1,4-ylene (5) spacer had a high 5-HT1A receptor affinity (Ki = 30-110 nM), whereas the 5-HT1A affinity of derivatives with ethylene spacer (3) was low. All those compounds (except 5c, Ki = 44 nM) did not distinctly bind to 5-HT2A receptors. The obtained results indicated that the length of an alkylene chain was a crucial parameter for determining 5-HT1A receptor affinities of the tested compounds, while acyl substituents in position 2 of THBC were not important for their 5-HTIA/5-HT2A activities. It was also demonstrated that the few selected compounds (4d, 5a-c and 5e) with the highest affinity (Ki up to 50 nM) for 5-HT1A receptors, administered at doses of 10-20 mg/kg, behaved like antagonists of postsynaptic 5-HT1A receptors, as they reduced the 8-OH-DPAT (5-HT1A agonist)-induced lower lip retraction and behavioral syndrome in rats. Moreover, 4d seemed to be an agonist of presynaptic 5-HT1A receptors, since the hypothermia induced by its administration was attenuated by WAY 100635 (5-HT1A antagonist). Compound 5c, 5-HT2A receptor ligand, demonstrated an antagonistic activity, as it inhibited the (+/-)DOI (5-HT2A agonist)-induced head twitches in mice. The obtained results of in vivo studies suggest that introduction of different acyl substituents in position 2 of THBC with propylene or butylene spacer between tricyclous and arylpiperazine moiety is insignificant for the postsynaptic 5-HTIA receptor activity of the compounds tested in vivo. On the other hand, only compound 5c with an acryloyl group and a butylene chain behaved like a 5-HT1A/5-HT2A antagonist.

Synthesis, 5-HT1A and 5-HT2A receptor activity of new 1-phenylpiperazinylpropyl derivatives with arylalkyl substituents in position 7 of purine-2,6-dione.

A series of new 1,3-dimethyl-7-phenylalkyl-8-[3-(4-phenyl-1-piperazinyl)propylamino]-purine-2,6-dione derivatives (10-16) was synthesized and their 5-HTIA and 5-HT2A receptor affinities were determined. It was found that compounds with the phenylpropyl substituent in position 7 of purine-2,6-dione (12, 14 and 16), or with phenylmethyl in position 7 and 2-OCH3 in the phenylpiperazine part (13) showed a distinct affinity for 5-HTIA receptors (Ki = 8-50 nM). No structural modifications resulted in 5-HT2A ligands, since the affinity of 10-16 for those receptors was insignificant (Ki = 115-550 nM). The new 5-HT1A receptor ligands (12-14, 16) were investigated in vivo to determine their functional activity at those receptors. In behavioral studies, 12-14 and 16 behaved like postsynaptic 5-HTIA receptor antagonists, since they reduced lower lip retraction and the behavioral syndrome induced by 8-OH-DPAT (5-HT1A receptor agonist) in rats. When given alone, none of the compounds investigated in vivo, mimicked 8-OH-DPAT activity in those tests. Derivative 12 did not affect the body temperature in mice, whereas 13, 14 and 16 decreased it. Furthermore, 12 did not change the hypothermia induced by 8-OH-DPAT, and the decrease in body temperature in mice induced by 13, 14 or 16 was not antagonized by WAY 100635 (5-HT1A receptor antagonist); hence in that model neither 12, 13, 14 nor 16 acted as antagonists or agonists, respectively, at presynaptic 5-HT1A receptors.

Anticonflict effect of the glycineB receptor partial agonist, D-cycloserine, in rats. Pharmacological analysis.

RATIONALE: Several studies have provided evidence that antagonists and partial agonists of glycine(B) receptors exhibit an anxiolytic-like activity in different animal models. OBJECTIVE: Using the conflict-drinking Vogel test in rats as a model, in the present study we examined the anxiolytic-like activity of D-cycloserine (DCS), a partial agonist of the glycine(B) site of the N-methyl-D-aspartate (NMDA) receptor complex. Diazepam was used as a reference drug. RESULTS: DCS (200 and 300 mg/kg) and diazepam (5 mg/kg) produced an anxiolytic-like effect in rats by increasing the number of shocks accepted. We also demonstrated that NMDA (15 mg/kg) reduced the anxiolytic-like activity of DCS (200 mg/kg), whereas glycine (800 mg/kg) and flumazenil (10 mg/kg) did not affect the anticonflict effect of DCS (200 mg/kg). The anticonflict effect of diazepam (5 mg/kg) was totally blocked by flumazenil (10 mg/kg). CONCLUSION: The obtained results have shown that DCS exhibits an anxiolytic-like activity which depends on NMDA receptors rather than on glycine(B) or benzodiazepine sites.

Influence of the aliphatic spacer length on the 5-HT1A receptor activity of new arylpiperazines with an indazole system.

Novel arylpiperazines (1a, 1c, 2a and 2c), containing a terminal 1- or 2-indazolyl fragment and a di- or tetramethylene aliphatic spacer, were synthesized and their 5-HT1A and 5-HT2A receptor affinities were determined. All those compounds showed a potent affinity for 5-HT1A receptors (Ki = 5-16 nM) and were evaluated for an intrinsic activity at those receptors. In order to determine a 5-HT1A agonistic effect of the investigated compounds, their ability to induce a lower lip retraction in rats and a behavioral syndrome (flat body posture and forepaw treading) in reserpinized rats were tested, whereas their 5-HT1A antagonistic activity was assessed via inhibition of those symptoms produced by 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT). The effect of spacer length on the 5-HT1A activity of the tested compounds was discussed in comparison with that of the three-methylene analogs (1b and 2b) described earlier. Both dimethylene derivatives (la and 2a) were characterized as weak postsynaptic 5-HT1A receptor antagonists. Compounds 1c (1-indazolyl analog) and 2c (2-indazolyl analog) with a tetramethylene aliphatic chain were classified as a postsynaptic 5-HT1A antagonist and a partial 5-HT1A agonist, respectively. Furthermore, the latter showed a moderate anxiolytic-like effect (conflict drinking Vogel's test in rats) and a weak antidepressant-like activity (forced swimming Porsolt's test in rats).

Synthesis and pharmacological characteristics of novel (Z)-3-arylidene-indolin-2(1H)-ones: preliminary results.

New amide derivatives of 1-(m-chlorophenyl)piperazine, the 5-HT2A antagonists 3-6, with moderate in vitro and in vivo activity were obtained by enlargement of the indolin-2(1H)-one core with 3-arylidene substituents.

Roles of group II metabotropic glutamate receptors in modulation of seizure activity.

Evidence suggests that metabotropic glutamate receptors (mGluR) are involved in mediating seizures and epileptogenesis. In the present experiments, the selective, group II mGluR agonist (+)-2-aminobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid (LY354740, 0.1-1.0 microM) inhibited spontaneous epileptiform discharges which developed in rat cortical slices in Mg2+-free medium. LY354740 (4-16 mg/kg) administered prior to an injection of pentylenetetrazol (80 mg/kg) or picrotoxin (3.2 mg/kg) produced a dose-dependent decrease in the number of mice exhibiting clonic convulsions, but had no effect on N-methyl-D-aspartate (NMDA, 150 mg/kg)-induced convulsions. LY354740 (4-16 mg/kg) did not affect lethality induced in mice by pentylenetetrazol, picrotoxin or NMDA. LY354740 potentiated the anticonvulsant activity of the conventional antiepileptic drug diazepam, significantly decreasing the ED50 for that drug's effect on pentylenetetrazol-induced convulsions by 30%, but had no influence on anticonvulsant activity of ethosuximide and valproic acid. A pharmacokinetic interaction between LY354740 and diazepam, leading to the lowering of the plasma level of free diazepam, was also demonstrated. Our data suggest that the group II mGluR agonist LY354740 possesses anti-seizure activity and may modify the effects of some conventional antiepileptic drugs.

Anxiolytic-like effect of nafadotride and PNU 99194A, dopamine D3 receptor antagonists in animal models.

The obtained results indicate that dopamine D3 receptor antagonists, nafadotride and PNU 99194A, produced anxiolytic-like effect in animal models, which suggests a putative role of these drugs in the therapy of anxiety.

Anxiolytic-like effects of group I metabotropic glutamate antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in rats.

We examined the anxiolytic-like activity of2-methyl-6-(phenylethynyl)-pyridine (MPEP) using the conflict drinking Vogel test in rats as a model. MPEP is a selective and brain-penetrable mGlu5 receptor antagonist, the most potent compound described so far. The results indicate that MPEP produced a dose-dependent anticonflict effect in rats. These data suggest that selective mGlu5 receptor antagonists may become a new class of anxiolytics.

Structure-activity relationship studies of CNS agents. Part 38. Novel 1,4-benzoxazin-3(4H)-one, 1,2-benzoxazolin-3-one and 1,3-benzoxazolin-2,4-dione arylpiperazine derivatives with different 5-HT1A and antagonistic 5-HT2A activities.

New 1-arylpiperazine (series d-f) and 1,2,3,4-tetrahydroisoquinoline (series g) derivatives of 1,4-benzoxazin-3(4H)-one 1, 1,2-benzoxazolin-3-one 2, and 1,3-benzoxazolin-2,4-dione 3 with an n-butyl chain were synthesized in order to explore the effect of spacer elongation on their binding affinity and in vivo functional activity at 5-HT1A and 5-HT2A receptors in comparison with trimethylene analogues (a, bc). 5-HT1A receptor binding constants of derivatives 1d-g, 2d-f, and 3d-f were very high (Ki = 1.25-54 nM), and 5-HT2A affinities were maintained at a similar, high level (Ki = 27-85 nM) for series d and e, and moderate (Ki = 246-495 nM) for series f. In respect of a spacer, the obtained results showed either no effect or a slight increase in the 5-HT1A/5-HT2A affinity in case of derivatives of 1 and 2, respectively. A striking effect was observed for derivatives 3d and 3f, whose 5-HT1A affinity was reinforced by two orders of magnitude with a simultaneous decrease in 5-HT2A binding constants in comparison with trimethylene analogues. As shown by X-ray crystallography, this phenomenon may be attributed to the position of non-carbonyl oxygen atom in the amide moiety. In vivo studies demonstrated that compounds 1e-g, 2d-f, and 3f behaved like typical postsynaptic 5-HT1A receptor antagonists, whereas 3d and 3e might be qualified as their potential partial agonists. Moreover, 1e, 2e, and 3e demonstrated 5-HT2A receptor antagonistic properties. Of the tested compounds, two derivatives showed some very outstanding properties: 3e may be regarded as a potential anxiolytic and/or antidepressant agent, while 3f as a new potent 5-HT1A antagonist.

Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models.

Despite there being a lot of biochemical data about metabotropic glutamate (mGlu) receptors, our knowledge of the behavioural effects of mGlu receptor agonists/antagonists is still inadequate. LY 354740 is a systemically active agonist of group II mGlu receptors. After peripheral administration, LY 354740 produced anxiolytic-like effects in the conflict drinking test in rats and a four-plate test in mice. It was also found that LY 354740 decreased spontaneous locomotor activity in mice, but did not disturb motor coordination. In behavioural models of depression including the despair test and a tail suspension test, LY 354740 did not produce antidepressant-like effects. LY 354740 inhibited the naloxone-induced symptoms of morphine withdrawal in morphine-dependent mice. The above results indicate that agonists of group II mGlu receptors may play a role in the therapy of anxiety and/or drug-dependence states. The brain sites of action of LY 354740 need to be identified and the mechanism of both the above described effects remains to be elucidated.

Tolerance to anxiolytic- and antidepressant-like effects of a partial agonist of glycineB receptors.

The present study examined effects of acute and repeated administration of 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist of glycineB receptors, in the conflict drinking test and the forced swim test in rats. Diazepam and imipramine were used, respectively, as reference drugs in those tests. In the conflict drinking test, acute administration of ACPC (200 mg/kg) increased fivefold the number of punished licks. A three- and fivefold increase in the number of punished licks was observed in rats treated repeatedly with ACPC (200 mg/kg daily; 14 days) and challenged with the same dose of the drug 24 h or 4 days later, respectively. A single injection of ACPC (400 mg/kg) reduced by 40% the immobility time in the forced swim test. In rats treated repeatedly with ACPC (400 mg/kg daily; 14 days) and challenged with the same dose 24 h or 4 days later, the drug either produced no significant effect or reduced the immobility time by 50%, respectively. On the other hand, no changes in anxiolytic- and antidepressant-like effects of chronically administered diazepam (10 mg/kg daily; 14 days) and imipramine (30 mg/kg daily; 14 days), respectively, were observed. The above results indicate that tolerance develops to the anxiolytic- and, particularly, to the antidepressant-like activity of ACPC.