Cyclooxygenase-2 inhibition affects the expression of down syndrom cell adhesion molecule via interaction with metabotropic glutamate receptor 5.

Since we previously discovered that simultaneous inhibition of cyclooxygenase-2 (COX-2; a highly inducible enzyme, crucial for the conversion of arachidonic acid to prostaglandin G2, which plays a predominant role in the CNS) by NS398 and metabotropic glutamate receptor 5 (mGluR5) through the use of its antagonist [3-((2-methyl-4-thiazolyl)ethyl)pyridine; MTEP] alters mouse behavior (e.g., affects spatial learning, and induces/intensifies the antidepressant effect), our aim was to discover the mechanism responsible for these changes. Down syndrome cell adhesion molecule (DSCAM), a member of the immunoglobulin cell adhesion molecule (Ig-CAM) superfamily, is involved in developing the central and peripheral nervous system by influencing cell adhesion mechanisms necessary for synaptic activity and plasticity. Since COX-2 has been implicated in several neuropsychiatric diseases (e.g., major depressive disorder) resulting from neuroplasticity disorders, and on the other hand, its expression is regulated by synaptic activity, we hypothesized that cognitive changes after administration of COX-2 inhibitor and mGluR5 antagonist might be a consequence of impaired DSCAM expression. Importantly, DSCAM deficiency leads to dysregulation of glutamatergic transmission and plasticity. In previous studies, we have demonstrated glutamatergic changes after NS398 and MTEP administration, further supporting the validity of our hypothesis. Due to the different effects observed in behavioral tests, this study used the prefrontal cortex (PFC) and hippocampus (HC) of C57BL/6J mice, which received NS398 and MTEP alone, or in combination, for 7 or 14 days. Among many properties, we also previously investigated the antidepressant potential of these compounds, so we used imipramine (a tricyclic antidepressant) as the reference drug. DSCAM mRNA expression was determined by qRT-PCR. Our results indicate that DSCAM expression after administration of MTEP and NS398 and imipramine along with NS398 is structure- and time-dependent.

Herd-level versus animal-level variation in methane emission prediction in grazing dairy cattle.

In response to the increased concern over agriculture's contribution to greenhouse gas (GHG) emissions, more detailed assessments of current methane emissions and their variation, within and across individual dairy farms and cattle, are of interest for research and policy development. This assessment will provide insights into possible changes needed to reduce GHG emissions, the nature and direction of these changes, ways to influence farmer behavior and areas to maximize the adoption of emerging mitigation technologies. The objectives of this study were to (1) quantify the variation in enteric fermentation methane emissions within and among seasonal calving dairy farms with the majority of nutritional requirements met through grazed pasture; (2) use this variation to assess the potential of new individual animal emission monitoring technologies and their impact on mitigation policy. We used a large database of cow performance records for milk production and survival from 2 398 herds in New Zealand, and simulation to account for unobserved variation in feed efficiency and methane emissions per unit of feed. Results showed an average of 120 ± 31.4 kg predicted methane (CH4) per cow per year after accounting for replacement costs, ranging 8.9-323 kg CH4/cow per year. Whereas milk production, survival and predicted live weight were reasonably effective at predicting both individual and herd average levels of per cow feed intake, substantial within animal variation in emissions per unit of feed reduced the ability of these variables to predict variation in per animal methane output. Animal-level measurement technologies predicting only feed intake but not emissions per unit of feed are unlikely to be effective for advancing national policy goals of reducing dairy farming enteric methane output. This is because farmers seek to profitably utilize all farm feed resources available, so improvements in feed efficiency will not result in the reduction in feed utilization required to reduce methane emissions. At a herd level, average per cow milk production and live weight could form the basis of assigning a farm-level point of obligation for methane emissions. In conclusion, a comprehensive national database infrastructure that was tightly linked to animal identification and movement systems, and captured live weight data from existing farm-level recording systems, would be required to make this effective. Additional policy and incentivization mechanisms would still be required to encourage farmer uptake of mitigation interventions, such as novel feed supplements or vaccines that reduce methane emissions per unit of feed.

Genotype by environment interactions in fertility traits in New Zealand dairy cows.

New Zealand's seasonal dairy farming system entails a condensed calving pattern with cows required to conceive within approximately 12 wk of the planned start of calving. This has resulted in strong selection for fertility through culling of nonpregnant cows and relatively strong emphasis on fertility in Breeding Worth, the national breeding objective that drives sire selection. Despite this, average herd-level fertility is highly variable across New Zealand dairy farms. We studied genotype by environment interaction in fertility-related traits, with the goal of improving selection decisions in different fertility environments. We used data from the New Zealand national dairy database, which contains records on 3,743,862 animals. Herds were classified into high-, mid-, or low-fertility categories or environments based on herd average fertility performance, and data were analyzed in 2 different ways. First, we estimated genetic parameters when the fertility trait was defined specifically for each fertility environment to determine the extent to which genetic correlations between high- and low-fertility environments differed from 1 and the extent of changes in genetic variance across environments. Second, we used simple regression to evaluate the impact of ancestral genetic merit for fertility on cow fertility phenotypes to compare the effect of changes in genetic merit on phenotypic performance between fertility environments. The genetic standard deviations of fertility-related traits were 1.5 to 3.6 times higher in low-fertility herds than in high-fertility herds, and the genetic correlations between the same fertility-related traits between the high- and low-fertility environments were moderate to high, albeit with high standard errors. The high standard errors of the correlations reflected the low heritabilities of the traits and potential problems of culling bias, particularly for traits expressed in later parities. Regression analysis revealed that the bottom 30% of herds (in terms of fertility) could achieve more than twice the benefit from selection for fertility than the top 30% of herds. Although our analyses do not support separate genetic evaluations of fertility in the different environments, they indicate that low-fertility herds could benefit more from targeted selection of sires with higher fertility estimated breeding values than from selection based solely on the multitrait national index. Conversely, high-fertility herds could focus their sire selection on traits other than fertility, provided they avoid very low fertility sires.

Combining genetic and physiological data to identify predictors of lifetime reproductive success and the effect of selection on these predictors on underlying fertility traits.

Fertility of the dairy cow relies on complex interactions between genetics, physiology, and management. Mathematical modeling can combine a range of information sources to facilitate informed predictions of cow fertility in scenarios that are difficult to evaluate empirically. We have developed a stochastic model that incorporates genetic and physiological data from more than 70 published reports on a wide range of fertility-related traits in dairy cattle. The model simulates pedigree, random mating, genetically correlated traits (in the form of breeding values for traits such as hours in estrus, estrous cycle length, age at puberty, milk yield, and so on), and interacting environmental variables. This model was used to generate a large simulated data set (200,000 cows replicated 100 times) of herd records within a seasonal dairy production system (based on an average New Zealand system). Using these simulated data, we investigated the genetic component of lifetime reproductive success (LRS), which, in reality, would be impractical to assess empirically. We defined LRS as the total number of times, during her lifetime, a cow calved within the first 42 d of the calving season. Sire estimated breeding values for LRS and other traits were calculated using simulated daughter records. Daughter pregnancy rate in the first lactation (PD_1) was the strongest single predictor of a sire's genetic merit for LRS (R2 = 0.81). A simple predictive model containing PD_1, calving date for the second season and calving rate in the first season provided a good estimate of sire LRS (R2 = 0.97). Daughters from sires with extremely high (n = 99,995 daughters, sire LRS = +0.70) or low (n = 99,635 daughters, sire LRS = -0.73) LRS estimated breeding values were compared over a single generation. Of the 14 underlying component traits of fertility, 12 were divergent between the 2 lines. This suggests that genetic variation in female fertility has a complex and multifactorial genetic basis. When simulated phenotypes were compared, daughters of the high LRS sires (HiFERT) reached puberty 44.5 d younger and calved ∼14 d younger at each parity than daughters from low LRS sires (LoFERT). Despite having a much lower genetic potential for milk production (-400 L/lactation) than LoFERT cows, HiFERT cows produced 33% more milk over their lifetime due to additional lactations before culling. In summary, this simulation model suggests that LRS contributes substantially to cow productivity, and novel selection criteria would facilitate a more accurate prediction at a younger age.

Short communication: Estimates of genetic parameters for dairy fertility in New Zealand.

Reproductive performance of dairy cows in a seasonal calving system is especially important as cows are required to achieve a 365-d calving interval. Prior research with a small data set has identified that the genetic evaluation model for fertility could be enhanced by replacing the binary calving rate trait (CR42), which gives the probability of a cow calving within the first 42d since the planned start of calving at second, third, and fourth calving, with a continuous version, calving season day (CSD), including a heifer calving season day trait expressed at first calving, removing milk yield, retaining a probability of mating trait (PM21) which gives the probability of a cow being mated within the first 21d from the planned start of mating, and first lactation body condition score (BCS), and including gestation length (GL). The aim of this study was to estimate genetic parameters for the proposed new model using a larger data set and compare these with parameters used in the current system. Heritability estimates for CSD and PM21 ranged from 0.013 to 0.019 and from 0.031 to 0.058, respectively. For the 2 traits that correspond with the ones used in the current genetic evaluation system (mating trait, PM21 and BCS) genetic correlations were lower in this study compared with previous estimates. Genetic correlations between CSD and PM21 across different parities were also lower than the correlations between CR42 and PM21 reported previously. The genetic correlation between heifer CSD and CSD in first parity was 0.66. Estimates of genetic correlations of BCS with CSD were higher than those with PM21. For GL, direct heritability was estimated to be 0.67, maternal heritability was 0.11, and maternal repeatability was 0.22. Direct GL had moderate to high and favorable genetic correlations with evaluated fertility traits, whereas corresponding residual correlations remain low, which makes GL a useful candidate predictor trait for fertility in a multiple trait evaluation. The superiority of direct GL genetic component over the maternal GL component for predicting fertility was demonstrated. Future work planned in this area includes the implementation and testing of this new model on national fertility data.

Phenotypic associations between gestation length and production, fertility, survival, and calf traits.

Gestation length may be a useful selection criterion in the genetic evaluation of fertility for New Zealand's predominantly seasonally calving dairy herd. However, it is unknown if calves born following shorter gestation lengths have lower survival or are compromised in their subsequent performance as a milking cow. In this study, data from a large number (~38,000) of cows were first analyzed to determine if those animals born following a short (shortest 5%) or a long (longest 5%) gestation length differed in their subsequent fertility, milk production, and survival compared with intermediate-gestation-length animals. To determine the effect of gestation length on calving difficulty and perinatal mortality, the gestation records of the calves born to these cows (from their heifer and subsequent 6 parities) were also analyzed. Animals born following short gestation lengths had improved fertility (specifically, their probability of being presented for mating in the first 21 d of the mating season was increased by 4 to 5 percentage points and the day of the calving season at which they calved was 2 to 5d earlier), whereas those born following long gestation lengths had decreased fertility (3 to 4% less likely to be presented for mating in the first 21 d of the calving season and calved 3 to 5d later) compared with animals with average gestation lengths. Both short- and long-gestation-length animals produced significantly less milk and solids (e.g., 1.3 to 1.4 kg of protein over a standardized 270-d lactation) relative to intermediate-gestation-length cows, after adjusting for the day of the year they were born. However, for short-gestation-length cows, this effect disappeared when the earlier birth advantage was retained. Short-gestation-length cows did not exhibit a significant reduction in survival compared with intermediate-gestation-length cows. Short gestation length did not affect calving difficulty but long gestation length was negatively associated with this trait (i.e., about 2% higher incidence). Calves gestated for shorter or longer periods were more likely to die in the perinatal period than other calves (3 and 7% higher incidence of mortality, respectively). Overall, the net effects of shortened gestation lengths are likely to be economically positive.

Analyses of genetic diversity in five Canadian dairy breeds using pedigree data.

The issue of loss of animal genetic diversity, worldwide in general and in Canada in particular, has become noteworthy. The objective of this study was to analyze the trend in within-breed genetic diversity and identify the major causes of loss of genetic diversity in five Canadian dairy breeds. Pedigrees were analyzed using the software EVA (evolutionary algorithm) and CFC (contribution, inbreeding, coancestry), and a FORTRAN package for pedigree analysis suited for large populations (PEDIG). The average rate of inbreeding in the last generation analyzed (2003 to 2007) was 0.93, 1.07, 1.26, 1.09 and 0.80% for Ayrshire, Brown Swiss, Canadienne, Guernsey and Milking Shorthorn, respectively, and the corresponding estimated effective population sizes were 54, 47, 40, 46 and 66, respectively. Based on coancestry coefficients, the estimated effective population sizes in the last generation were 62, 76, 43, 61 and 76, respectively. The estimated percentage of genetic diversity lost within each breed over the last four decades was 6, 7, 11, 8 and 5%, respectively. The relative proportion of genetic diversity lost due to random genetic drift in the five breeds ranged between 59.3% and 89.7%. The results indicate that each breed has lost genetic diversity over time and that the loss is gaining momentum due to increasing rates of inbreeding and reduced effective population sizes. Therefore, strategies to decrease rate of inbreeding and increase the effective population size are advised.

The reversal of cognitive, but not negative or positive symptoms of schizophrenia, by the mGlu2/3 receptor agonist, LY379268, is 5-HT1A dependent.

mGlu(2/3) receptor agonists were shown to possess an antipsychotic-like potential in animal studies. Recent clinical investigations revealed that their antipsychotic potential might also manifest in humans. LY379268, the group II mGlu receptor orthosteric agonist, was previously shown to exhibit antipsychotic-like action in animal models of schizophrenia. However, the mechanism of its action is not fully recognized. Here, we decided to investigate the involvement of 5-HT1A receptors in the LY379268-induced antipsychotic effects. We used models of positive, negative and cognitive symptoms of schizophrenia, such as MK-801- and amphetamine-induced hyperactivity tests, DOI-induced head twitches, social interaction and novel object recognition. LY379268 was active in a wide range of doses (0.5-5 mg/kg), depending on the paradigm. The effects of the drug were not antagonized by 5-HT(1A) antagonist, WAY100635 (0.1 mg/kg) in the models of positive and negative symptoms. Conversely, in the novel object recognition test, which exerts cognitive disturbances, the action of LY379268 was antagonized by WAY100635. Concomitantly, the action of a sub-effective dose of the drug was enhanced by the administration of a sub-effective dose of 5-HT(1A) agonist, (R)-(+)-8-Hydroxy-DPAT. Altogether, we propose that the antipsychotic-like action of group II mGlu receptors' agonist is 5-HT(1A) independent in context of positive and negative symptoms, while the action toward cognitive disturbances seems to be 5-HT(1A) dependent.

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'.

Rates of inbreeding and genetic diversity in Canadian Holstein and Jersey cattle.

The accumulation of inbreeding and the loss of genetic diversity is a potential problem in the modern dairy cattle breeds. Therefore, the purpose of this study was to analyze the pedigrees of Canadian Holstein and Jersey cattle to estimate the past and current rates of inbreeding and genetic diversity, and to identify the main causes of diversity loss. Completeness and depth of the pedigrees were good for both breeds. For Holsteins, the average rates of inbreeding per generation showed a decreasing trend in recent years when compared with the 1990s. The estimated current effective population size was about 115 for Holsteins and is not expected to significantly change in the near future if generation intervals stay at current value, as rates of increase in inbreeding and coancestry showed decreasing trends. For Jerseys, the estimated effective population size was about 55 and it is expected to decrease in the near future due to the observed increasing rates of coancestry and inbreeding. Ancestors with the highest marginal genetic contributions to the gene pool in current years and with the highest contributions to inbreeding were identified. The 2 most heavily used and represented ancestors in the Holstein pedigree (i.e., Round Oak Rag Apple Elevation and his son Hanoverhill Starbuck), accounted for 30% of inbreeding. Analyses revealed that the most important cause of genetic diversity loss in both breeds was genetic drift accumulated over nonfounder generations, which occurred due to small effective population size. Therefore, a need exists in both breeds, particularly in Jerseys, for managing selection and mating decisions to control future coancestry and inbreeding, which would lead to better handling of the effective population size.

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.

Anxiolytic-like action of MTEP expressed in the conflict drinking Vogel test in rats is serotonin dependent.

The purpose of the present study was to investigate whether the anxiolytic-like action of a selective and brain penetrable group I metabotropic glutamate (mGlu5) receptor antagonist 3-[(2-methyl-1,3-tiazol-4-yl)ethynyl]-pyridine (MTEP) is dependent upon the serotonergic system. Experiments were performed on male Wistar rats. The Vogel conflict drinking test was used to detect anxiolytic-like activity. MTEP administered intraperitoneally at doses of 1, 3 and 6 mg/kg induced anxiolytic-like effect. The potential anxiolytic effect of MTEP (1 mg/kg) was inhibited by a nonselective 5-HT receptor antagonist metergoline (2 mg/kg i.p.) and 5-HT2A/2C receptor antagonist ritanserin (0.5 mg/kg i.p.), but not by a 5-HT1A receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY 100635) (0.1 mg/kg i.p). The anxiolytic effect of MTEP (6 mg/kg) was attenuated by ritanserin (1 mg/kg i.p.). Moreover, MTEP-induced a dose-dependent release of serotonin in the frontal cortex. The obtained results suggest that the potential anxiolytic effect of the mGlu5 receptor antagonist MTEP is due to the increased serotonin release with subsequent activation of 5-HT2A/2C receptors, most probably located postsynaptically, but not by the 5-HT1A receptors.

Anxiolytic-like effect of group III mGlu receptor antagonist is serotonin-dependent.

Literature data have provided evidence that antagonists of group I metabotropic glutamate receptors (mGluRs) and agonists of group II/III mGluRs show anxiolytic-like properties in preclinical studies. However data reporting anxiolytic-like action of group III mGlu receptor antagonists were also published. In the present paper we investigated the anxiolytic-like activity of the group III mGlu receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). To examine its anxiolytic-like effects, the basolateral amygdala was chosen as an injection site, as this brain region is involved in the regulation of anxiety-related behavior. To detect anxiolytic-like activity, the Vogel conflict-drinking test in rats was used. Intra-amygdalar injections of CPPG exhibited dose-dependent, potent anxiolytic-like action at a dose of 75 nmol, which was blocked by a concomitant administration of the group III mGlu receptor agonist CI (S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) at a dose of 7.5 nmol. The benzodiazepine receptor antagonist flumazenil (given intraperitoneally, 10 mg/kg) did not change the anxiolytic-like effect of CPPG, but that effect was abolished by the non-selective antagonist of 5-HT receptors metergoline and the antagonist of 5-HT2A/C receptors ritanserin (both given intraperitoneally at doses of 2 and 0.5 mg/kg, respectively). These findings suggest that the blockade of group III mGlu receptors in the amygdala is responsible for anxiolysis and that serotonergic, but not the benzodiazepine recognition site of the GABA-ergic system are involved in the anxiolytic-like response induced by group III mGlu antagonist.

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.