Effects of subchronic phencyclidine on behaviour of female rats on the elevated plus maze and open field.

Female hooded-Lister rats received either subchronic phencyclidine (PCP) (2 mg/kg, n = 20) or vehicle (1 ml/kg, n = 20) intraperitoneally twice daily for 7 days, followed by a 7-day washout period. Rats were challenged with acute PCP or vehicle and tested for locomotor activity to ensure hyperactivity was observed in the subchronic PCP-treated rats. Rats were then tested on the elevated plus maze and in an open field for 10 min. Subchronic PCP did not significantly affect behaviour on the elevated plus maze or in the open field. In conclusion, subchronic PCP does not induce anxiety-like behaviour.

Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat.

RATIONALE: Positive allosteric modulators of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor do not stimulate AMPA receptors directly but delay deactivation of the receptor and/or slow its desensitisation. This results in increased synaptic responses and enhanced long-term potentiation. Thus, it has been suggested that such compounds may have utility for the treatment of cognitive impairment. OBJECTIVES: The objective of the study was to investigate the effect of an AMPA positive modulator, CX691, (1) in three rodent models of learning and memory, (2) on neurochemistry in the dorsal hippocampus and medial prefrontal cortex following acute administration, and (3) on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the rat hippocampus following acute and sub-chronic administration. RESULTS: CX691 attenuated a scopolamine-induced impairment of cued fear conditioning following acute administration (0.1 mg/kg p.o.) and a temporally induced deficit in novel object recognition following both acute (0.1 and 1.0 mg/kg p.o.) and sub-chronic (bi-daily for 7 days) administration (0.01, 0.03, 0.1 mg/kg p.o.). It also improved attentional set-shifting following sub-chronic administration (0.3 mg/kg p.o.). Acute CX691 (0.1, 0.3 and 1.0 mg/kg, p.o.) increased extracellular levels of acetylcholine in the dorsal hippocampus and medial prefrontal cortex and dopamine in the medial prefrontal cortex. Sub-chronic administration of CX691 (0.1 mg/kg, p.o.) elevated BDNF mRNA expression in both the whole and CA(1) sub-region of the hippocampus (P < 0.05). CONCLUSIONS: Collectively, these data support the pro-cognitive activity reported for AMPA receptor positive modulators and suggest that these compounds may be of benefit in treating disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.

The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.

RATIONALE: Group II metabotropic glutamate receptors (mGluRs) comprise the mGluR2 and mGluR3 subtypes, the activation and modulation of which has been suggested to be beneficial for treating schizophrenia. Genetic association studies suggest limited association between mGluR2 and schizophrenia but some association between mGluR3 and schizophrenia. Conversely, pre-clinical studies suggest that mGluR2 may be responsible for mediating the antipsychotic activity of mGluR2/3 agonists, although to date, the role of mGluR3 has not been specifically assessed. OBJECTIVES: The aim of this study is to use recently generated mGluR3 and mGluR2 knockout mice to investigate which of the group II mGluRs mediates the actions of the mGluR2/3 agonist, LY379268, in two mouse models predictive of antipsychotic activity. MATERIALS AND METHODS: LY379268 (0.3-10 mg/kg SC), phencyclidine (PCP; 1-5 mg/kg IP), and amphetamine 1-10 mg/kg IP) were assessed on locomotor activity and behaviour in C57Bl/6J and transgenic mice. LY379268 was then assessed on PCP (5 mg/kg IP)- and amphetamine (2.5 mg/kg IP)-induced hyperactivity and behaviour in C57Bl/6J and transgenic mice. RESULTS: PCP (5 mg/kg)-evoked hyperactivity and behavioural alterations, i.e. circling, falling, stereotypy and ataxia, as well as amphetamine (2.5 mg/kg)-evoked hyperactivity, were dose-dependently attenuated by LY379268 (0.3-3 mg/kg) in C57Bl/6J mice. One milligram per kilogram of LY379268 reversed PCP-evoked hyperactivity and behavioural alterations in wild-type (WT) and mGluR3 knockout mice but not in mice lacking mGluR2. Similarly, 3 mg/kg LY379268 reversed amphetamine-evoked hyperactivity in WT and mGluR3 knockout mice but not in mice lacking mGluR2. CONCLUSION: The mGlu2 but not the mGlu3 receptor subtype mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.

Investigating the effect of bilateral amygdala lesions on fear conditioning and social interaction in the male Mongolian gerbil.

Identification of the selective neurokinin NK(1) receptor antagonist, 2-(R)-(1-(R)-3,5-Bis(trifluromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5yl)methylmor-phine (MK-869), as a novel therapeutic approach for anxiety/depression has led to increased use of the Mongolian gerbil in behavioural studies since the gerbil NK(1) receptor pharmacology is similar to human, but not rat or mouse. Within this species, foot tapping and immobility elicited by aversive conditioning, as well as social interaction have been shown to be sensitive to clinically used anxiolytic and antidepressant agents and also NK(1) receptor antagonists. The high levels of NK(1) receptor binding in the amygdala as well as preclinical studies demonstrating increased release of substance P and corresponding internalisation of NK(1) receptors in the basolateral amygdala in response to stressful stimuli suggest that the BLA may represent a potential site of action for NK(1) receptor antagonists in anxiety and/or depression. Therefore, in the current study, we assessed the effect of bilateral BLA lesions in male Mongolian gerbils on footshock-induced foot tapping and immobility, social interaction, and NK(1)-agonist-induced foot tapping. Lesioned gerbils exhibited reduced immobility time during fear conditioning, a non-significant reduction in immobility time when re-exposed to the conditioned stimulus (CS) 24 h later, and increased social interaction in the gerbil social interaction task. In contrast, BLA lesions had no effect on NK(1)-agonist-induced foot tapping. These data provide further support that the gerbil BLA is a potential site for NK(1) receptor antagonists to attenuate anxiety-related behaviours.

Age-related impairments in operant DMTP performance in the PS2APP mouse, a transgenic mouse model of Alzheimer's disease.

One of the earliest signs of Alzheimer's disease (AD) is loss of memory for recent events. This deficit in short term memory has been characterised in mild/moderate AD patients as a delay-dependent deficit in a delayed matching to sample (DMTS) task. PS2APP mice co-expressing hPS2mut and hAPPswe exhibit a spatial-temporal elevation in brain amyloid deposition and inflammation associated with temporal cognitive decline. The aim of the current study was to train PS2APP mice (C57BL/6JxDBA/2 mixed background) and appropriate control mice (B6D2F1 background) in a rodent delayed response task, the delayed matching to position (DMTP) task, prior to the onset of plaque formation and subsequently at 2-4 monthly intervals to investigate the effect of aging and increasing plaque load on DMTP performance. At 5 months of age (baseline) DMTP performance was equivalent with both PS2APP and control mice demonstrating a working memory curve across increasing delay intervals of 1-24s. A comparison of PS2APP and control mice across ages revealed a selective age-related, delay-dependent, impairment on choice accuracy in PS2APP mice, consistent with the cognitive decline and temporal amyloidosis previously described for this mouse model. These data are also relevant for other conditional transgenic mouse models which allow time-sensitive induction or inhibition of gene expression such that mice can be trained to perform the task prior to activation or inactivation of the gene and tested thereafter.

The relationship between maternal self-efficacy and parenting practices: implications for parent training.

The present study examined the relationship between maternal self-efficacy, dysfunctional discipline practices and child conduct problems. Specifically, three levels of self-efficacy, global, domain and task-specific self-efficacy, were assessed in mothers of 2- to 8-year-old children with conduct problems (clinic group, n=45) and non-clinic mothers from the community (non-clinic group, n=79). Measures of global, domain and task-specific self-efficacy were completed by mothers. Clinic mothers reported significantly lower self-efficacy than non-clinic mothers for all but one of the parenting tasks assessed. Both groups of mothers reported lowest self-efficacy for similar parenting tasks. In the sample as a whole self-efficacy measures were significant predictors of maternal discipline style after controlling for other parent, child and risk factors. Of the self-efficacy variables behavioural self-efficacy was the best predictor of mothers discipline style. The findings support the importance of developing parenting strategies that enable parents to generalize their parenting skills to a diverse range of diverse parenting contexts both in the home and in the community.

5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism.

5-HT(6) receptors are expressed in brain regions associated with learning and memory, and blockade of their function increases central cholinergic and glutamatergic neurotransmission and enhances cognitive processes. This study examined the effects of acute systemic administration of two selective 5-HT(6) receptor antagonists Ro 04-6790 and SB-271046 (10 mg kg(-1) i.p.) on acquisition, consolidation, and retrieval in the novel object discrimination (NOD) task, a two-trial test of recognition memory in which rats exposed to two identical objects during a familiarisation trial can discriminate a novel from a familiar object during the subsequent choice trial, following inter-trial delays of up to 3 h. 5-HT(6) receptor antagonist administration 20 min prior to or immediately after the familiarisation trial, but not 20 min prior to the choice trial reversed the deficit in object discrimination produced by a 4 h inter-trial interval. The nootropic effects of the 5-HT(6) receptor antagonists in this task thus appear to involve enhanced consolidation. Pre-treatment with the non-competitive NMDA receptor antagonist MK-801 (0.05 mg kg(-1) i.p.) prevented the effect of Ro 04-6790 on delay-induced deficits in object discrimination. This suggests that the 5-HT(6) receptor antagonist-induced enhancement of consolidation involves increased central glutamatergic neurotransmission.

A role for 5-ht6 receptors in retention of spatial learning in the Morris water maze.

This study investigates the effect of intracerebroventricular administration of a 5-ht6 antisense oligonucleotide (AO) complementary to bases 1-18 of the rat 5-ht6 cDNA initiation sequence (Mol. Pharmacol. 43 (1993) 320) (1.5 microg twice daily for six days) and i.p. injection of a selective 5-ht6 receptor antagonist Ro 04-6790 (10 or 30 mg/kg once daily for three days) on acquisition and retention in the Morris water maze. Neither the 5-ht6 AO (which reduced cortical [3H]-LSD binding sites by 10-16%) nor Ro 04-6790 affected acquisition, but both enhanced retention of the learned platform position such that rats spent significantly longer searching the trained platform position than any other area during the probe tests. Furthermore, neither AO nor Ro 04-6790 had any effect on the time taken to reach a raised visible platform, indicating that visual acuity was unimpaired. In addition, AO reduced both food consumption and body weight and the later effect was also seen following Ro 04-6790, suggesting a role for the 5-ht6 receptor in the regulation of feeding. Hence, while the underlying mechanism remains unclear, enhanced retention of spatial learning following both AO and 5-ht6 antagonist administration strongly indicate a role for this receptor in memory processes.

Activity of 2,3-benzodiazepines at native rat and recombinant human glutamate receptors in vitro: stereospecificity and selectivity profiles.

The activity and selectivity of the glutamate receptor antagonists belonging to the 2,3-benzodiazepine class of compounds have been examined at recombinant human non-NMDA glutamate receptors expressed in HEK293 cells and on native rat NMDA and non-NMDA receptors in vitro. The racemic 2,3-benzodiazepines GYKI52466, LY293606 (GYKI53405) and LY300168 (GYKI53655) inhibited AMPA (10 microM)-mediated responses in recombinant human GluR1 receptors expressed in HEK293 cells with approximate IC50 values of 18 microM, 24 microM and 6 microM, respectively and AMPA (10 microM) responses in recombinant human GluR4 expressing HEK293 cells with approximate IC50 values of 22 microM, 28 microM and 5 microM, respectively. GYKI 52466, LY293606 and LY300168 were non-competitive antagonists of AMPA receptor-mediated responses in acutely isolated rat cerebellar Purkinje neurons with approximate IC50 values of 10 microM, 8 microM and 1.5 microM, respectively. The activity of racemic compounds LY293606 and LY300168 was established to reside in the (-) isomer of each compound. At a concentration of 100 microM, GYKI52466, LY293606 and LY300168 produced < 30% inhibition of kainate-activated currents evoked in HEK293 cells expressing either human homomeric GluR5 or GluR6 receptors or heteromeric GluR6+KA2 kainate receptors. The activity of the 2,3-benzodiazepines at 100 microM was weak at kainate receptors, but was stereoselective. Similar levels of inhibition were observed for kainate-induced currents in dorsal root ganglion neurons. Intact tissue preparations were also used to examine the stereoselective actions of the 2,3-benzodiazepines. In the cortical wedge preparation, the active isomer of LY300168, LY303070, produced a non-competitive antagonism of AMPA-evoked depolarizations with smaller changes in depolarizations induced by kainate and no effect on NMDA-dependent depolarizations. LY303070 was also effective in preventing 30 microM AMPA-induced depolarizations in isolated spinal cord dorsal roots with an approximate IC50 value of 1 microM. Synaptic transmission in the hemisected spinal cord preparation was stereoselectively antagonized by the active isomers of LY300168 and LY293606. In summary, these results indicate that 2,3-benzodiazepines are potent, selective and stereospecific antagonists of the AMPA subtype of the non-NMDA glutamate receptor.