Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

YesRationale: 5-HT receptor mechanisms have been suggested to mediate improvements in cognition in schizophrenia. Aim: To investigate the involvement of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in female rats, a task of relevance to schizophrenia. Methods: Adult female hooded-Lister rats were trained to perform an operant reversal learning task and then received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for seven days, followed by 7-days washout. Rats then received an acute dose of the 5-HT7 receptor antagonist SB-269970A (1.0, 3.0, 10.0 mg/kg; i.p.) or vehicle. In experiment 2, PCP-treated rats received the selective 5-HT2C receptor antagonist, SB-243213A acutely (1.0, 3.0, 10.0 mg/kg; i.p.) or vehicle. In experiment 3, PCP-treated rats received the 5-HT1A receptor partial agonist, buspirone (0.15625, 0.3125, 0.625 mg/kg, i.p.) in combination with the selective 5-HT1A receptor antagonist WAY-100635 (0.3, 1.0 mg/kg). Results: In all experiments sub-chronic PCP significantly impaired reversal phase performance (P<0.01-0.001), with no effect in the initial phase. SB-269970A at 3.0 and 10.0 mg/kg significantly improved the PCP-induced deficit (P<0.05). SB-243213A also significantly attenuated the deficit at 10 mg/kg (P<0.05). In experiment 3, buspirone attenuated the deficit with significant effects at 0.3125 mg/kg and 0.625 mg/kg (P<0.05). WAY-100635 at 0.3 and 1.0 mg/kg produced a partial attenuation of buspirone’s effect as buspirone (0.3125 mg/kg) in the presence of WAY-100635 did not significantly reverse the PCP-induced deficit. Conclusions: These studies implicate the role of 5-HT7, 5-HT2C and 5-HT1A receptors in the improvement of cognitive dysfunction of relevance to schizophrenia

Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: Implications for therapy of cognitive dysfunction in schizophrenia

YesRationale: Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Aim: To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987. Methods: Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for seven days, followed by 7-days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20 mg/kg; s.c.) or vehicle and were tested in the reversal learning task. In cohort 2, PCP-treated rats received PNU-282987 (10 mg/kg; s.c.) or saline for 15 days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance. Results: Sub-chronic PCP produced significant deficits in both cognitive tasks (P<0.01-0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10 mg/kg (P<0.01) and 20 mg/kg (P<0.001), and in novel object recognition at 10 mg/kg on day 1 (P<0.01) and on day 15 (P<0.001). Conclusions: These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15 day daily dosing of PNU-282987 (10 mg/kg s.c.) does not cause tolerance in rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.SL McLean was supported by a joint University of Bradford–GSK postgraduate studentship

Dopamine dysregulation in the prefrontal cortex relates to cognitive deficits in the sub-chronic PCP-model for schizophrenia: a preliminary investigation

yesRationale: Dopamine dysregulation in the prefrontal cortex (PFC) plays an important role in cognitive dysfunction in schizophrenia. Sub-chronic phencyclidine (scPCP) treatment produces cognitive impairments in rodents and is a thoroughly validated animal model for cognitive deficits in schizophrenia. The aim of our study was to investigate the role of PFC dopamine in scPCP-induced deficits in a cognitive task of relevance to the disorder, novel object recognition (NOR). Methods: Twelve adult female Lister Hooded rats received scPCP (2 mg/kg) or vehicle via the intraperitoneal route twice daily for seven days, followed by seven days washout. In vivo microdialysis was carried out prior to, during and following the NOR task. Results: Vehicle rats successfully discriminated between novel and familiar objects and this was accompanied by a significant increase in dopamine in the PFC during the retention trial (P<0.01). scPCP produced a significant deficit in NOR (P<0.05 vs. control) and no PFC dopamine increase was observed. Conclusions: These data demonstrate an increase in dopamine during the retention trial in vehicle rats that was not observed in scPCP-treated rats accompanied by cognitive disruption in the scPCP group. This novel finding suggests a mechanism by which cognitive deficits are produced in this animal model and support its use for investigating disorders in which PFC dopamine is central to the pathophysiology

Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy

Subchronic administration of phencyclidine produces hypermethylation in the parvalbumin gene promoter in rat brain

Aim: A deficit in parvalbumin neurons is found in schizophrenia and several animal models of the disease. In this preliminary study, we determined whether one such model, phencyclidine (PCP) administration, results in changes in DNA methylation in the rat Pvalb promoter. Materials & methods: DNA from hippocampus and prefrontal cortex from rats, which 6 weeks previously received either 2 mg/kg PCP or vehicle for 7 days, underwent bisulphite pyrosequencing to determine methylation. Results: PCP administration induced significantly greater methylation at one of two Pvalb CpG sites in both prefrontal cortex and hippocampus, while no significant difference was found in long interspersed nucleotide element-1, a global measure of DNA methylation. Conclusion: Subchronic PCP administration results in a specific hypermethylation in the Pvalb promoter which may contribute to parvalbumin deficits in this animal model of psychosis

Oscillatory deficits in the sub-chronic PCP rat model for schizophrenia are reversed by mGlu5 receptor-positive allosteric modulators VU0409551 and VU0360172

The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent model for schizophrenia via distinct changes in PFC intracellular signalling molecules. Here, we have assessed ex vivo gamma oscillatory activity in PFC slices from scPCP rats and investigated the effects of VU0409551 and VU0360172 upon oscillatory power. mGlu5 receptor, protein kinase C (PKC), and phospholipase C (PLC) inhibition were also used to examine ‘modulation bias’ in PAM activity. The amplitude and area power of gamma oscillations were significantly diminished in the scPCP model. Slice incubation with either VU0409551 or VU0360172 rescued scPCP-induced oscillatory deficits in a concentration-dependent manner. MTEP blocked the PAM-induced restoration of oscillatory power, confirming the requirement of mGlu5 receptor modulation. Whilst PLC inhibition prevented the power increase mediated by both PAMs, PKC inhibition diminished the effects of VU0360172 but not VU0409551. This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits

Cost-effectiveness of psilocybin-assisted therapy for severe depression: exploratory findings from a decision analytic model

Background There is growing evidence to support the use of the psychedelic drug psilocybin for difficult-to-treat depression. This paper compares the cost-effectiveness of psilocybin assisted psychotherapy (PAP) with conventional medication, cognitive behavioural therapy (CBT), and the combination of conventional medication and CBT. Methods A decision model simulated patient events (response, remission, and relapse) following treatment. Data on probabilities, costs and quality-adjusted life years (QALYs) were derived from previous studies or from best estimates. Expected healthcare and societal costs and QALYs over a 6-month time period were calculated. Sensitivity analyses were used to address uncertainty in parameter estimates. Results The expected healthcare cost of PAP varied from £6132 to £7652 depending on the price of psilocybin. This compares to £3528 for conventional medication alone, £4250 for CBT alone, and £4197 for their combination. QALYs were highest for psilocybin (0.310), followed by CBT alone (0.283), conventional medication alone (0.278), and their combination (0.287). Psilocybin was shown to be cost-effective compared to the other therapies when the cost of therapist support was reduced by 50% and the psilocybin price was reduced from its initial value to £400 to £800 per person. From a societal perspective, psilocybin had improved cost-effectiveness compared to a healthcare perspective. Conclusions Psilocybin has the potential to be a cost-effective therapy for severe depression. This depends on the level of psychological support that is given to patients receiving psilocybin and the price of the drug itself. Further data on long-term outcomes are required to improve the evidence base

Maternal Immune Activation Induces Adolescent Cognitive Deficits Preceded by Developmental Perturbations in Cortical Reelin Signalling.

Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developing schizophrenia and other neurodevelopmental disorders. To understand the biological mechanisms underlying the link between MIA and increased risk, preclinical animal models have focussed on specific signalling pathways in the brain that mediate symptoms associated with neurodevelopmental disorders such as cognitive dysfunction. Reelin signalling in multiple brain regions is involved in neuronal migration, synaptic plasticity and long-term potentiation, and has been implicated in cognitive deficits. However, how regulation of Reelin expression is affected by MIA across cortical development and associated cognitive functions remains largely unclear. Using a MIA rat model, here we demonstrate cognitive deficits in adolescent object-location memory in MIA offspring and reductions in Reln expression prenatally and in the adult prefrontal cortex. Further, developmental disturbances in gene/protein expression and DNA methylation of downstream signalling components occurred subsequent to MIA-induced Reelin dysregulation and prior to cognitive deficits. We propose that MIA-induced dysregulation of Reelin signalling contributes to the emergence of prefrontal cortex-mediated cognitive deficits through altered NMDA receptor function, resulting in inefficient long-term potentiation. Our data suggest a developmental window during which attenuation of Reelin signalling may provide a possible therapeutic target

The comparative effects of mGlu5 receptor positive allosteric modulators VU0409551 and VU0360172 on cognitive deficits and signalling in the sub-chronic PCP rat model for schizophrenia

The metabotropic glutamate receptor mGlu5 has been implicated in the neuropathology of several debilitating disorders. In schizophrenia, mGlu5 receptor hypofunction has been linked with neuropathology and cognitive deficits, making it an attractive therapeutic target. The cognitive impairment associated with schizophrenia remains an unmet clinical need, with existing antipsychotics primarily targeting positive symptoms and failing to induce consistent, substantial improvements in cognition, thus providing incomplete treatment. Using the sub-chronic phencyclidine (scPCP) rat model, widely shown to mimic the cognitive impairment and neuropathology of schizophrenia, we have investigated two mGlu5 receptor positive allosteric modulators (PAMs), VU0409551 and VU0360172. We compared the efficacy of these compounds in restoring cognitive deficits and, since these two PAMs have reportedly distinct signalling mechanisms, changes in mGlu5 receptor signalling molecules AKT and MAPK in the prefrontal cortex. Although not effective at 0.05 and 1mg/kg, cognitive deficits were significantly alleviated by both PAMs at 10 and 20 mg/kg. The compounds appeared to have differential effects on the scPCP-induced increases in AKT and MAPK phosphorylation: VU0409551 induced a significant decrease in expression of p-AKT, whereas VU0360172 had this effect on p-MAPK levels. Thus, the beneficial effects of PAMs on scPCP-induced cognitive impairment are accompanied by at least partial reversal of scPCP-induced elevated levels of p-MAPK and p-AKT, dysfunction of which is strongly implicated in schizophrenia pathology. These promising data imply an important role for mGlu5 receptor signalling pathways in improving cognition in the scPCP model and provide support for mGlu5 receptor PAMs as a possible therapeutic intervention for schizophrenia