Serotonin model of schizophrenia: emerging role of glutamate mechanisms

Aghajanian, G K

doi:10.1016/s0165-0173(99)00046-6

Cited by 500 publications

(272 citation statements)

References 75 publications

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“…The fact that local perfusion of PCP, ketamine, and MK-801 in the mPFC failed to elicit the increase in glutamate and/or 5-HT (Lorrain et al, 2003;Amargós-Bosch et al, 2006, this study) indicates that the NMDA receptors responsible for these effects are located outside the mPFC. Our results are consistent with other data showing that the increased locomotion and firing or EPSCs of putative pyramidal neurons of the mPFC following systemic administration of NMDA receptor antagonists (Suzuki et al, 2002;Jodo et al, 2003;Jackson et al, 2004) were not mimicked by intra-mPFC application of these compounds (Aghajanian and Marek, 2000;Suzuki et al, 2002;Jodo et al, 2005). What is the actual localization of these NMDA receptors and the source of the cortical hyperglutamatergic transmission induced by their blockade?…”

Section: Discussionsupporting

confidence: 92%

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

López-Gil

Babot

Amargós-Bosch

et al. 2007

Neuropsychopharmacol

170

162

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The administration of noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine and ketamine has been shown to increase the extracellular concentration of glutamate and serotonin (5-HT) in the medial prefrontal cortex (mPFC). In the present work, we used in vivo microdialysis to examine the effects of the more potent noncompetitive NMDA receptor antagonist, MK-801, on the efflux of glutamate and 5-HT in the mPFC, and whether the MK-801-induced changes in the cortical efflux of both transmitters could be blocked by clozapine and haloperidol given systemically or intra-mPFC. The systemic, but not the local administration of MK-801, induced an increased efflux of 5-HT and glutamate, which suggests that the NMDA receptors responsible for these effects are located outside the mPFC, possibly in GABAergic neurons that tonically inhibit glutamatergic inputs to the mPFC. The MK-801-induced increases of extracellular glutamate and 5-HT were dependent on nerve impulse and the activation of mPFC AMPA/ kainate receptors as they were blocked by tetrodotoxin and NBQX, respectively. Clozapine and haloperidol blocked the MK-801-induced increase in glutamate, whereas only clozapine was able to block the increased efflux of 5-HT. The local effects of clozapine and haloperidol paralleled those observed after systemic administration, which emphasizes the relevance of the mPFC as a site of action of these antipsychotic drugs in offsetting the neurochemical effects of MK-801. The ability of clozapine to block excessive cortical 5-HT efflux elicited by MK-801 might be related to the superior efficacy of this drug in treating negative/cognitive symptoms of schizophrenia.

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Section: Discussionsupporting

confidence: 92%

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

López-Gil

Babot

Amargós-Bosch

et al. 2007

Neuropsychopharmacol

170

162

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“…The fact that psilocybin, in contrast to DOI, displays moderate agonistic activity at 5-HT 1A (K i ¼ 190 nM) receptors in addition to having strong agonistic action at 5-HT 2A receptors (K i ¼ 6 nM) (Aghajanian et al, 1972;Haigler and Aghajanian, 1974;Marek and Aghajanian, 1996;McKenna et al, 1990), raises the possibility that the dual effects of psilocybin on PPI in humans depend on some combination of 5-HT 2A or 5-HT 1A receptor stimulation, although downstream effects upon the glutamate and dopamine systems may also be implicated (Vollenweider et al, 1999b;Aghajanian and Marek, 2000). Moreover, the mechanism by which psilocybin reduces PPI at short and increases PPI at longer ISIs cannot be derived from the present study, but the currently available data on the effects of hallucinogens in animals and humans allow several possible explanations.…”

Section: Discussionmentioning

confidence: 99%

The Effects of the Preferential 5-HT2A Agonist Psilocybin on Prepulse Inhibition of Startle in Healthy Human Volunteers Depend on Interstimulus Interval

Vollenweider

Csomor

Knappe

et al. 2007

Neuropsychopharmacol

156

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Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT 2A receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT 2A receptor agonist psilocybin increases PPI in healthy humans. Hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on PPI in healthy humans. Sixteen subjects each received placebo or 115, 215, and 315 mg/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. PPI at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (ISIs) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. The effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the Altered States of Consciousness Rating Scale (5D-ASC) and the Frankfurt Attention Inventory (FAIR). Psilocybin dosedependently reduced PPI at short (30 ms), had no effect at medium (60 ms), and increased PPI at long (120-2000 ms) ISIs, without affecting startle reactivity or habituation. Psilocybin dose-dependently impaired sustained attention and increased all 5D-ASC scores with exception of Auditory Alterations. Moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30 ms ISI and not with the concomitant increases in PPI observed at long ISIs. These results confirm the psilocybin-induced increase in PPI at long ISIs and reveal that psilocybin also produces a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia.

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“…13,[15][16][17][18] NRG1 is also involved in the glutamatergic pathway; the involvement of this system in schizophrenia development is one of the most prominent neurochemical hypothesis proposed to explain the biological component of this disease. 7,[19][20][21][22] In the Stefansson et al 9 study of NRG1, a number of overlapping haplotypes were shown to be significantly over-represented in patients compared to controls. These 'at-risk' haplotypes, all shared a common 'core' consisting of five SNPs and two microsatellite markers, the so-called Hap ICE , and extended a length of 290 kb from the 5 0 end of the GGF2 variant of the NRG1 and into the first exon of this splice form (see Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Extreme population differences across Neuregulin 1 gene, with implications for association studies

et al. 2005

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Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 Mb gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme F ST values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results.

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Serotonin model of schizophrenia: emerging role of glutamate mechanisms

Cited by 500 publications

References 75 publications

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

The Effects of the Preferential 5-HT2A Agonist Psilocybin on Prepulse Inhibition of Startle in Healthy Human Volunteers Depend on Interstimulus Interval

Extreme population differences across Neuregulin 1 gene, with implications for association studies

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