The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

Meltzer, Herbert Y.; Horiguchi, Masaaki; Massey, Bill W.

doi:10.1007/s00213-010-2137-8

Cited by 112 publications

(86 citation statements)

References 168 publications

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“…As the neuromodulatory nuclei defined in this study included both the DR and the MR, sources of serotonergic innervation to the PFC, and the LC, a primary source of noradrenergic innervation to the PFC, the enhanced connectivity between these neural subsystems is consistent with the known ability of acute ketamine to profoundly enhance both serotonin (Lindefors et al, 1997;Amargos-Bosch et al, 2006) and noradrenaline levels in the PFC (Kubota et al, 1999). The altered connectivity of these neuromodulatory neurotransmitter systems may directly contribute to the disruption of PFCdependent processes by acute NMDA receptor blockade, a suggestion supported by the observation that the application of antagonist for the receptors of these neuromodulatory systems can attenuate the disruptive effects of NMDA receptor antagonists on PFC-dependent cognitive processes (Metzer et al, 2011;Mirjana et al, 2004), PFC physiology (Jentsch et al, 1998), and other translationally relevant behaviors (Bakshi and Geyer, 1997;Stuchlik et al, 2009). Overall, our data suggest that the connectivity of the neuromodulatory subsystem to the PFC is profoundly altered by acute ketamine treatment and is likely to contribute to ketamine's disruptive effects on PFC-dependent cognitive processes.…”

Section: Discussionsupporting

confidence: 66%

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

Dawson

McDonald

Higham

et al. 2014

Neuropsychopharmacol

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Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia.

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Section: Discussionsupporting

confidence: 66%

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

Dawson

McDonald

Higham

et al. 2014

Neuropsychopharmacol

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“…Hyperlocomotion induced by noncompetitive NMDA receptor antagonists is commonly used as an animal model of positive symptoms (16). We first exposed AAV-expressing mice to the open field and allowed them to habituate; no differences were observed in basal open field activity between AAV-GFP (6,832 ± 395 cm) and AAV-DN1 (7,099 ± 451 cm; P = 0.663) expressing mice (SI Appendix, Fig.…”

Section: Creation Of Dominant Negative Reagents To Disrupt the Synapticmentioning

confidence: 99%

Disrupting the clustering of GABA_Areceptor α2 subunits in the frontal cortex leads to reduced γ-power and cognitive deficits

Hines

Houston

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In schizophrenia, cognitive dysfunction is highly predictive of poor patient outcomes and is not responsive to current medications. Postmortem studies have suggested that cognitive deficits in schizophrenia are correlated with modifications in the number and size of inhibitory synapses. To test if these modifications lead to cognitive deficits, we have created a dominant-negative virus [adeno-associated (AAV)-DN1] that disrupts the clustering of γ-aminobutyric acid type A receptors (GABA A Rs) at postsynaptic inhibitory specializations. When injected into the frontal cortex of mice, AAV-DN1 impairs GABA A R α2 subunit and GABA transporter 1 (GAT-1) clustering, but increases GABA A R α1 subunit clustering on the perisomatic region, with no influence on axon-initial segment clustering. Mice expressing AAV-DN1 have prepulse inhibition deficits and impairments in working memory. Significantly, these behavioral deficits are paralleled by a reduction in electroencephalography γ-power. Collectively, our study provides functional evidence revealing that GABAergic synapses in the prefrontal cortex directly contribute to cognition and γ-power. In schizophrenia, the classical positive and negative symptoms are accompanied by striking cognitive deficits, and notably, the cognitive deficits are not ameliorated by conventional antipsychotic medications (1-3). Thus, understanding the molecular basis of these deficits is key to development of more efficacious treatments. In addition to modifications in the dopaminergic system, there is compelling evidence that modifications in signaling by γ-aminobutyric acid receptors (GABA A R) contributes to the cognitive deficits in schizophrenia. GABA A Rs are the principle mediators of fast synaptic inhibition in the brain and are pentameric heteroligomers that are principally assembled from α1-6, β1-3, γ1-3, and δ subunits (4). Within the cortex, GABA A Rs containing α2 subunits are enriched on the axoninitial segments (AIS) and perisomatic regions of neurons, where their activation has been shown to underlie oscillatory activity and cognition (5, 6).Postmortem analysis has revealed increased levels of α2 subunit immunoreactivity on the AIS of principal cortical neurons in schizophrenia and parallel deficits in the number of GABA transporter (GAT-1) positive presynaptic elements. However, whether these modifications in inhibitory synapse structure contribute to the cognitive deficits of schizophrenia remains unknown. To address this issue we have used virally encoded dominantnegative reagents to disrupt the function of inhibitory synapses containing α2 subunits in the cortex of mice. This resulted in prepulse inhibition deficits and impairments in working memory that were paralleled by a reduction in electroencephalography γ-power. Thus, α2 subunit-containing GABA A Rs are important determinants of cognition, and selectively potentiating their activity may be beneficial in improving the outcome of patients with schizophrenia. Results Creation of Dominant Negative Reagents to Disrupt the ...

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“…The 5-HT 1A agonists, eg, tandospirone, have a lower side effect burden than most atypical APDs, especially of the metabolic variety (Feighner and Boyer, 1989). It is noteworthy that lurasidone shares important structural similarities with tandospirone, and that lurasidone is also a 5-HT 1A partial agonist (Meltzer et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…The effects of NMDA receptor antagonists on cognitive function in rodents and monkeys have been intensively studied as an animal model of CIS (Gunduz-Bruce, 2009). Acute or subchronic administration of PCP, MK-801, or ketamine to rodents produces cognitive impairments that model CIS, eg, novel object recognition (NOR; Neill et al, 2010, Meltzer et al, 2011. Acute administration of atypical APDs (eg, clozapine), but not the typical APD, haloperidol, has been reported to reverse cognitive deficits induced by subchronic PCP treatment in rat NOR (Grayson et al, 2007;Snigdha et al, 2010;Horiguchi et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%

Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT1A Partial Agonist

Horiguchi

Hannaway

Adelekun

et al. 2012

Neuropsychopharmacol

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Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT) 2A /dopamine D 2 antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT 1A partial agonist properties, tandospirone, a selective 5-HT 1A partial agonist, haloperidol, a D 2 antagonist, and pimavanserin, a 5-HT 2A inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1 mg/kg), tandospirone (5 mg/kg), pimavanserin (3 mg/kg), or haloperidol (1 mg/kg) b.i.d. 30 min before PCP (2 mg/kg, b.i.d.) for 7 days (day1-7), followed by a 7-day washout (day8-14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT 1A antagonists, further evidence for the importance of 5-HT 1A receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.

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The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

Abstract: Multiple 5-HT receptors contribute to effective treatments to reverse adverse effects of NMDA-RA which model psychosis and cognitive impairment.

Cited by 112 publications

References 168 publications

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

Disrupting the clustering of GABA_Areceptor α2 subunits in the frontal cortex leads to reduced γ-power and cognitive deficits

Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT1A Partial Agonist

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The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

Abstract: Multiple 5-HT receptors contribute to effective treatments to reverse adverse effects of NMDA-RA which model psychosis and cognitive impairment.

Cited by 112 publications

References 168 publications

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

Disrupting the clustering of GABAAreceptor α2 subunits in the frontal cortex leads to reduced γ-power and cognitive deficits

Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT1A Partial Agonist

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Disrupting the clustering of GABA_Areceptor α2 subunits in the frontal cortex leads to reduced γ-power and cognitive deficits