Dose-response effect of acute phencyclidine on functional connectivity and dopamine levels, and their association with schizophrenia-like symptom classes in rat

Paasonen, Jaakko; Salo, Raimo A.; Ihalainen, Jouni; Leikas, Juuso V.; Savolainen, Katja; Lehtonen, Marko; Forsberg, Markus; Gröhn, Olli

doi:10.1016/j.neuropharm.2017.03.024

Cited by 14 publications

(14 citation statements)

References 69 publications

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“…In this study, we found that the effect of PCP in mice is modulated by P2X7R in terms of positive and cognitive symptoms. Genetically deficient animals for the receptor displayed a lower susceptibility to the psychotomimetic effects of the dissociative anesthetic, while the overexpression of the purinergic receptor produced a typically positive symptom response within a sub-optimal PCP dose for psychosis-like activity (Paasonen et al, 2017) and exacerbated stereotypy with an acute psychotomimetic 10 mg/kg PCP dose. Most importantly, after a subchronic PCP treatment, P2rx7 −/− mice did not display a reduction in working memory, typical of the model's cognitive symptomatology.…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned above, PCP-induced neuropathological mechanisms unleash desynchronization and ungoverned activation in most SCZ-related CNS regions (Kargieman et al, 2007), resulting in lower inter-area functional connectivity (Paasonen et al, 2017).…”

Section: Introductionmentioning

confidence: 96%

“…More recently, we showed that P2X7R genetic deletion or pharmacological blockade alleviates the acute psychotomimetic effects of phencyclidine (PCP, 2, and 5 mg/kg; Koványi et al, 2016), which is a validated model for SCZ symptomatology (Paasonen et al, 2017). These changes were accompanied by alterations in SCZ-related genes in the PFC (Koványi et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…We have also extended our previous observations to a P2rx7 −/− subchronic PCP model, which better reflects the disease phenomenon in humans. Moreover, we tested the heterozygous animals overexpressing P2X7-EGFP (Kaczmarek-Hajek et al, 2018) using the acute treatment model of either a regular or a low dosage of PCP, which better depicts an array of negative symptoms (Paasonen et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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P2X7 Receptor-Dependent Layer-Specific Changes in Neuron-Microglia Reactivity in the Prefrontal Cortex of a Phencyclidine Induced Mouse Model of Schizophrenia

Calovi

Mut-Arbona

Tod

et al. 2020

Front. Mol. Neurosci.

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Background : It has been consistently reported that the deficiency of the adenosine triphosphate (ATP) sensitive purinergic receptor P2X7 (P2X7R) ameliorates symptoms in animal models of brain diseases. Objective : This study aimed to investigate the role of P2X7R in rodent models of acute and subchronic schizophrenia based on phencyclidine (PCP) delivery in animals lacking or overexpressing P2X7R, and to identify the underlying mechanisms involved. Methods : The psychotomimetic effects of acute i.p. PCP administration in C57Bl/6J wild-type, P2X7R knockout (P2rx7 −/− ) and overexpressing (P2X7-EGFP) young adult mice were quantified. The medial prefrontal cortex (mPFC) of P2rx7 −/− and heterozygous P2X7-EGFP acutely treated animals was characterized through immunohistochemical staining. The prefrontal cortices of young adult P2rx7 −/− and P2rx7 tg/+ mice were examined with tritiated dopamine release experiments and the functional properties of the mPFC pyramidal neurons in layer V from P2rx7 −/− mice were assessed by patch-clamp recordings. P2rx7 −/− animals were subjected to a 7 days subchronic systemic PCP treatment. The animals working memory performance and PFC cytokine levels were assessed. Results : Our data strengthen the hypothesis that P2X7R modulates schizophrenia-like positive and cognitive symptoms in NMDA receptor antagonist models in a receptor expression level-dependent manner. P2X7R expression leads to higher medial PFC susceptibility to PCP-induced circuit hyperactivity. The mPFC of P2X7R knockout animals displayed distinct alterations in the neuronal activation pattern, microglial organization, specifically around hyperactive neurons, and were associated with lower intrinsic excitability of mPFC neurons. Conclusions : P2X7R expression exacerbated PCP-related effects in C57Bl/6J mice. Our findings suggest a pleiotropic role of P2X7R in the mPFC, consistent with the observed behavioral phenotype, regulating basal dopamine concentration, layer-specific neuronal activation, intrinsic excitability of neurons in the mPFC, and the interaction of microglia with hyperactive neurons. Direct measurements of P2X7R activity concerning microglial ramifications and dynamics could help to further elucidate the molecular mechanisms involved.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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P2X7 Receptor-Dependent Layer-Specific Changes in Neuron-Microglia Reactivity in the Prefrontal Cortex of a Phencyclidine Induced Mouse Model of Schizophrenia

Calovi

Mut-Arbona

Tod

et al. 2020

Front. Mol. Neurosci.

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“…This difference may be due to time-and dose-dependent effects or actions on other neurotransmitter systems by NMDA ligands themselves at high dose (Kapur and Seeman, 2002). For example, FC among the prefrontal cortex, hippocampus and other cortical areas is increased at very low dose but decreased at higher doses of phencyclidine (PCP), a NMDA antagonist, together with impaired social interaction similar to that observed in schizophrenia (Paasonen et al, 2017). A potential confound in these studies is the interaction with anesthesia because several anesthetics, such as halothane and isoflurane, also act on NMDA receptors (Gozzi et al, 2008;Hodkinson et al, 2012).…”

Section: Glutamatergicmentioning

confidence: 99%

Functional networks and network perturbations in rodents

Chuang

Nasrallah

2017

NeuroImage

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Synchronous low-frequency oscillation in the resting human brain has been found to form networks of functionally associated areas and hence has been widely used to map the functional connectivity of the brain using techniques such as resting-state functional MRI (rsfMRI). Interestingly, similar resting-state networks can also be detected in the anesthetized rodent brain, including the default mode-like network. This opens up opportunities for understanding the neurophysiological basis of the rsfMRI signal, the behavioral relevance of the network characteristics, connectomic deficits in diseases and treatment effects on brain connectivity using rodents, particularly transgenic mouse models. In this review, we will provide an overview on the resting-state networks in the rat and mouse brains, the effects of pharmacological agents, brain stimulation, structural connectivity, genetics on these networks, neuroplasticity after behavioral training and applications in models of neurological disease and psychiatric disorders. The influence of anesthesia, strain difference, and physiological variation on the rsfMRI-based connectivity measure will be discussed.

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The Role of fMRI in Drug Development: An Update

Carmichael

2023

Advances in Neurobiology

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Dose-response effect of acute phencyclidine on functional connectivity and dopamine levels, and their association with schizophrenia-like symptom classes in rat

Cited by 14 publications

References 69 publications

P2X7 Receptor-Dependent Layer-Specific Changes in Neuron-Microglia Reactivity in the Prefrontal Cortex of a Phencyclidine Induced Mouse Model of Schizophrenia

P2X7 Receptor-Dependent Layer-Specific Changes in Neuron-Microglia Reactivity in the Prefrontal Cortex of a Phencyclidine Induced Mouse Model of Schizophrenia

Functional networks and network perturbations in rodents

The Role of fMRI in Drug Development: An Update

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