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

McLean, Samantha L.; Harte, Michael K.; Neill, Joanna C.; Young, Andrew M. J.

doi:10.1177/0269881117704988

Cited by 14 publications

(12 citation statements)

References 55 publications

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“…This provides an important explanation for the cognitive deficits in scPCP treated animals and a possible target for drug action. This is consistent with our recent in vivo microdialysis work (McLean et al, 2017) in which we observed that vehicle and scPCP-treated rats have the same PFC dopamine basal levels and the same PFC dopamine concentration throughout the 10 min habituation phase, the 10 min acquisition trial and during the 10 min ITI. During the 10 min retention trial, however, vehicle-treated rats show an increase in dopamine levels in the PFC, compared to the basal level, which was abolished by scPCP treatment.…”

Section: Accepted Manuscriptsupporting

confidence: 93%

NMDA receptor antagonist rodent models for cognition in schizophrenia and identification of novel drug treatments, an update

et al. 2018

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Negative and cognitive deficit symptoms in schizophrenia remain an unmet clinical need. Improved understanding of the neuro- and psychopathology of cognitive dysfunction in the illness is urgently required to enhance the development of new improved therapeutic strategies. Careful validation of animal models that mimic the behaviour and pathology of complex psychiatric disorders is an essential step towards this goal. Non-competitive NMDAR (N-Methyl-d-aspartate receptor) antagonists e.g. phencyclidine (PCP), ketamine and dizocilpine (MK-801) can effectively replicate certain aspects of negative and cognitive deficits associated with schizophrenia in animals. In 2010 we reviewed the effects of NMDAR antagonism in tests for domains of cognition affected in schizophrenia, social behaviour and neuropathology, and in 2014, in tests for negative symptoms. In this update, we evaluate the most recent pharmacological strategies for restoring cognition in schizophrenia using NMDAR antagonist models, published since our original review in 2010 (cited over 225 times, excluding self-citations). Tests reviewed are, novel object recognition for visual recognition memory, attentional set shifting for executive function, and operant tests incorporating recent touchscreen technology for a range of domains including working memory, problem solving and attention, all impaired in schizophrenia. Moreover, we include an update on parvalbumin (PV)-expressing GABAergic interneurons and review, for the first time, the effects of NMDAR antagonists on gamma oscillations, circuitry integral for effective cognition. Data summarized in this review strongly confirm the reliability and usefulness of NMDAR antagonist animal models for evaluating novel therapeutic candidates, and for improving our understanding of the pathophysiology of cognitive deficits in schizophrenia. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

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Section: Accepted Manuscriptsupporting

confidence: 93%

NMDA receptor antagonist rodent models for cognition in schizophrenia and identification of novel drug treatments, an update

et al. 2018

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“…accompanying cognitive deficiency seen after this treatment (McLean et al, 2017). In this context, the ability of IRL752 to enhance extracellular levels of DA and NA in the PFC but not in (the DA-dominated) striatal and nucleus accumbens areas is particularly noteworthy.…”

Section: Discussionmentioning

confidence: 93%

(3S)‐3‐(2,3‐difluorophenyl)‐3‐methoxypyrrolidine (IRL752) —a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent

Stephan

Waters

Tedroff

et al. 2020

J Pharmacol Exp Ther

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Here we describe for the first time the distinctive pharmacological profile for (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 mmol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypoactivity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)-and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognitionrelated immediate early genes (IEGs), however, increased by 1.5fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to ∼250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to ∼250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmissionpromoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptamine 7 receptor and a2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT This report describes the distinctive preclinical profile of (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.

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“…On the basis on the link between mGluR function and dopamine-dependent behaviours (see above), and the evidence to suggest that PCP pretreatment affects glutamate/dopamine interactions (Javitt, 2007;Jentsch et al, 1998a,b;Jentsch & Roth, 1999), the second key question addressed in this study was whether the effects of sub-chronic PCP are mediated through changes in mGluR regulation of dopamine release. Previous studies have shown that impairments in NOR performance following PCP pretreatment are reversed by dopamine D1 receptor (McLean et al, 2009) and D4 receptor (Sood et al, 2011) stimulation, while saline pretreated animals show a significant increase in dopamine utilization during the retention trial compared to PCP counterparts (McLean et al, 2017;Neill et al, 2010), albeit that this effect was seen in the prefrontal cortex rather than NAc.…”

Section: Discussionmentioning

confidence: 88%

Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices

Gupta

Young

2018

Brain Research

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The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release. We showed that the orthosteric mGluR2 agonist LY379268 (0.1 µM, 1 µM and 10 µM) and mGluR5 positive allosteric modulator CDPPB (1 µM and 10 µM) both attenuated potassium-evoked dopamine release, underscoring their role in modulating dopamine neurotransmission in the nucleus accumbens. Sub-chronic PCP treatment, which caused cognitive deficits measured by performance in the novel object recognition task, modelling aspects of behavioral deficits seen in schizophrenia, induced neurobiological changes that enhanced dopamine release in the nucleus accumbens, but had no effect on mGluR2 or mGluR5 mediated changes in dopamine release. Therefore it is unlikely that schizophrenia-related behavioural changes seen after sub-chronic phencyclidine pre-treatment are mediated through mGluR modulation of dopamine release.

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

Cited by 14 publications

References 55 publications

NMDA receptor antagonist rodent models for cognition in schizophrenia and identification of novel drug treatments, an update

NMDA receptor antagonist rodent models for cognition in schizophrenia and identification of novel drug treatments, an update

(3S)‐3‐(2,3‐difluorophenyl)‐3‐methoxypyrrolidine (IRL752) —a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent

Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices

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