Transgenic mice overexpressing glycogen synthase kinase 3beta: a putative model of hyperactivity and mania.

Lithium is used as treatment for bipolar disorder with particular efficacy in the treatment of mania. Lithium inhibits glycogen synthase kinase 3beta (GSK-3beta) directly or indirectly via stimulation of the kinase Akt-1. We therefore investigated the possibility that transgenic mice overexpressing GSK-3beta could be of relevance to model bipolar disorder. Transgenic mice showed hypophagia, an increased general locomotor activity, and decreased habituation as assessed in an open field, an increased acoustic startle response, and again decreased habituation. The forced swim test revealed a reduced immobility in transgenic mice, but this is probably related to the hyperactivity of the animals. There were no differences in baseline and stress-induced increases of plasma adrenocorticotrophic hormone and corticosterone levels. Molecular analysis suggests compensatory mechanisms in the striatum of these transgenic mice for the overload of active GSK-3beta by dimming the endogenous GSK-3beta signaling pathway via upregulation of Akt-1 expression. Brain-derived neurotrophic factor protein levels were increased in the hippocampus of the transgenic mice. This suggests some kind of compensatory mechanism to the observed reduction in brain weight, which has been related previously to a reduced size of the somatodendritic compartment. Together, in mice overexpressing GSK-3beta, specific intracellular signaling pathways are affected, which is accompanied by altered plasticity processes and increased activity and reactivity, whereas habituation processes seem to be decreased. The behavioral observations led to the suggestion that the model at hand recapitulates hyperactivity as observed in the manic phase of bipolar disorder.

Lack of lithium-like behavioral and molecular effects in IMPA2 knockout mice.

Lithium is a potent mood-stabilizing medication in bipolar disorder. Despite 50 years of clinical use, the mechanism of action is unknown. Multiple effects have been attributed to lithium including the uncompetitive inhibition of inositol monophosphatase (IMPase). IMPA2, one of the genes that encode IMPase, is located in a region with linkage to bipolar disorder. Owing to the role of IMPase in cell signaling and the possibility that this enzyme is a target for mood-stabilizing drugs, we generated IMPA2(-/-) mice. Possible involvement of IMPase in complex behaviors related to affective disorders was assessed by monitoring the behavior of the IMPA2(-/-) mice in the forced swim test, the tail suspension test (TST), the elevated zero-maze and open field test. It has been described that chronically lithium-treated mice exhibit reduced immobility time in the forced swim test and decreased exploratory behavior. We found increased rearing of IMPA2(-/-) mice in the open field, suggesting an increased exploratory behavior. Although immobility time of IMPA2(-/-) female but not male mice in the forced swim test was reduced, no difference was found between male and female IMPA2(-/-) and IMPA2(+/+) mice in the TST and overall there was no clear effect of the deletion of IMPA2 on depression-like behavior. Frontal cortex IMPase activity and inositol levels in the IMPA2(-/-) mice did not differ from IMPA2(+/+) mice, but kidney inositol levels were reduced. In conclusion, phenotypic characterization of the IMPA2(-/-) mouse indicates that deleting IMPA2 does not mimic the effects of lithium treatment.

Effects of mGlu1 receptor blockade on anxiety-related behaviour in the rat lick suppression test.

RATIONALE: Group I metabotropic glutamate receptor antagonists, which block both the mGlu1 and mGlu5 receptors, have been shown to have anxiolytic effects in the lick suppression test in rats. OBJECTIVE: The anxiolytic potential of the selective mGlu1 antagonist 3,4-dihydro-2H-pyrano[2,3]beta-quinolin-7-yl)(cis-4-methoxycyclohexyl)methanone (JNJ16259685) was investigated and compared with the mGlu5 antagonist MPEP. METHODS: Anxiety-related behaviour was assessed in lick suppression and in the elevated zero maze in rats. Non-specific effects on pain threshold, water intake and locomotor activity were also measured. RESULTS: Acute administration of JNJ16259685 or MPEP increased the number of licks (lowest active dose 2.5 mg/kg IP for each compound). JNJ16259685 did not increase water intake or reduce acute pain threshold, suggesting that the anxiolytic-like properties are specific. However, acute administration decreased locomotor activity. The effects of chronic administration of JNJ16259685 over 14 days (5 mg/kg bid) on lick suppression were comparable to those seen after acute administration, arguing against development of behavioural tolerance or sensitisation. Yet, there was a tendency for an increase in locomotor activity after cessation of chronic treatment. Acute co-administration of both JNJ16259685 and MPEP had additive effects on the number of licks. No anxiolytic-like properties of JNJ16259685 were observed in the elevated zero maze. CONCLUSION: Our data suggest that the anxiolytic-like effects induced by group I metabotropic glutamate receptor antagonists are mediated through both mGlu1 and mGlu5 receptors. Rather than producing a general anxiolytic-like effect, the effects seen following mGlu1 antagonism seem task-dependent, as prominent effects were seen in a conflict procedure, but not in a task based on spontaneous exploration.

Metabotropic glutamate receptor 1 blockade impairs acquisition and retention in a spatial Water maze task.

Metabotropic glutamate receptors, including the mGlu1 receptor, have received considerable attention as potential targets for anxiolytic, antidepressant, antipsychotic and antinociceptive drugs. mGlu1 receptors have also been suggested to play a role in the modulation of cognitive processes, but knowledge is still very limited. In the present study the effects of the selective mGlu1 receptor antagonist 3,4-dihydro-2H-pyrano[2,3]beta-quinolin-7-yl)(cis-4-methoxycyclohexyl)methanone (JNJ16259685, 0.63-10 mg/kg s.c.) on more or less spatially demanding learning and spatial memory (retention and re-acquisition) were investigated in mice performing in a water maze. Selective mGlu1 receptor blockade with JNJ16259685 impaired spatial acquisition processes, irrespective of spatial load, as well as spatial re-acquisition, already at the lowest dose tested (0.63 mg/kg). In contrast, effects on spatial retention performance were relatively mild in mice that had learned to locate the position of the escape platform prior to treatment. Thigmotaxic behaviour and locomotor activity appeared to be unaffected by JNJ16259685. These data suggest that blockade of the mGlu1 receptor primarily affects learning of new information, but leaves retention of spatial information relatively unaffected. Blockade of the mGlu5 receptor with MPEP also impaired spatial learning, although only at the highest dose tested (10 mg/kg). An ex vivo receptor occupancy study in rats revealed that MPEP occupied central mGlu5 receptors with an ED(50) of 2.0 mg/kg one hour after subcutaneous administration. This is 50-150 times higher than the ED(50) reported for JNJ16259685 at central mGlu1 receptors and suggests that one reason why the two compounds cause cognitive effects at different doses might be due to differences in central mGlu receptor occupancy, rather than fundamentally different roles of mGlu1 and mGlu5 receptors in the modulation of cognitive function.

A hierarchical Binomial-Poisson model for the analysis of a crossover design for correlated binary data when the number of trials is dose-dependent.

The differential reinforcement of a low-rate 72-seconds schedule (DRL-72) is a standard behavioral test procedure for screening a potential antidepressant compound. The data analyzed in the article are binary outcomes from a crossover design for such an experiment. Recently, Shkedy et al. (2004) proposed to estimate the treatments effect using either generalized linear mixed models (GLMM) or generalized estimating equations (GEE) for clustered binary data. The models proposed by Shkedy et al. (2004) assumed the number of responses at each binomial observation is fixed. This might be an unrealistic assumption for a behavioral experiment such as the DRL-72 because the number of responses (the number of trials in each binomial observation) is expected to be influenced by the administered dose level. In this article, we extend the model proposed by Shkedy et al. (2004) and propose a hierarchical Bayesian binomial-Poisson model, which assumes the number of responses to be a Poisson random variable. The results obtained from the GLMM and the binomial-Poisson models are comparable. However, the latter model allows estimating the correlation between the number of successes and number of trials.

Behavioral testing of antidepressant compounds: an analysis of crossover design for correlated binary data.

The differential reinforcement of low-rate 72 seconds schedule (DRL-72) is a standard behavioral test procedure for screening potential antidepressant compounds. The protocol for the DRL-72 experiment, proposed by Evenden et al. (1993), consists of using a crossover design for the experiment and one-way ANOVA for the statistical analysis. In this paper we discuss the choice of several crossover designs for the DRL-72 experiment and propose to estimate the treatment effects using either generalized linear mixed models (GLMM) or generalized estimating equation (GEE) models for clustered binary data.