Serotonin model of schizophrenia: emerging role of glutamate mechanisms

Aghajanian, G

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

Cited by 529Schizophrenia research and treatmentPsychedelics and Drug StudiesNeurotransmitter Receptor Influence on Behavior

Serotonin model of schizophrenia: emerging role of glutamate mechanisms

Aghajanian, G·2000·Brain Research Reviews

DOI 10.1016/s0165-0173(99)00046-6

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Abstract

The serotonin (5-HT) hypothesis of schizophrenia arose from early studies on interactions between the hallucinogenic drug LSD (D-lysergic acid diethylamide) and 5-HT in peripheral systems. More recent studies have shown that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and phenethylamines (e.g. , mescaline), produce their central effects through a common action upon 5-HT(2) receptors. This review focuses on two brain regions, the locus coeruleus and the cerebral cortex, where the actions of indoleamine and the phenethylamine hallucinogens have been shown to be mediated by 5-HT(2A) receptors; in each case, the hallucinogens (via 5-HT(2A) receptors) have been found to enhance glutamatergic transmission. In the prefrontal cortex, 5-HT(2A)-receptors stimulation increases the release of glutamate, as indicated by a marked increase in the frequency of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) in the apical dendritic region of layer V pyramidal cells; this effect is blocked by inhibitory group II/III metabotropic glutamate agonists acting presynaptically and by an AMPA/kainate glutamate antagonist, acting postsynaptically at non-NMDA glutamate receptors. A major alternative drug model of schizophrenia, previously believed to be entirely distinct from that of the psychedelic hallucinogens, is based on the psychotomimetic properties of antagonists of the NMDA subtype of glutamate receptor (e.g., phencylidine and ketamine). However, recently it has been found that many of the effects of the NMDA antagonists may also (1) involve 5-HT(2A) receptors and (2) be mediated through excess activity at non-NMDA (i.e., AMPA/kainate) glutamate receptors. Moreover, pharmacological manipulations of glutamate transmission (e. g., by inhibitory metabotropic glutamate agonists) provide unexpected parallels between the actions of these two classes of drugs. Given an emerging recognition of the importance of alterations in glutamatergic transmission in the actions of both psychedelic hallucinogens an NMDA antagonists, this review concludes with of implications for the pathophysiology and therapy of schizophrenia.

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LSD alters glutamatergic function but does not impair NMDA signaling and may actually enhance it.
“Intriguingly, contrary to ketamine, LSD alters glutamatergic function but it does not impair NMDA signaling 23 and may actually enhance it.152”
From Are hallucinations due to an imbalance between excitatory and inhibitory influences on the brain? (2016) · cites this paper as [23]

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Authors: Aghajanian, G.
Affiliations: Yale University (US)
Corresponding author: Aghajanian, G
Venue: Brain Research Reviews
Publisher: Elsevier BV
Published: 2000-03
Volume: 31
Issue: 2-3
Pages: 302-312
ISSN: 0165-0173 (ISSN-L)
DOI: 10.1016/s0165-0173(99)00046-6
OpenAlex: W2009823135
Cited by: 529
References: 87
Citations by year: 2026: 2 · 2025: 4 · 2024: 7 · 2023: 15 · 2022: 9 · 2021: 9 · 2020: 18 · 2019: 5 · 2018: 11 · 2017: 15 · 2016: 17 · 2015: 18 · 2014: 15 · 2013: 16 · 2012: 14
FWCI: 26.59
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Brain Research Reviews (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: 5-HT2A receptor, glutamatergic neurotransmission, LSD, mescaline, NMDA receptor antagonists, ketamine, phencyclidine, metabotropic glutamate receptors, prefrontal cortex, locus coeruleus, non-NMDA receptors, excitatory postsynaptic potentials, schizophrenia pathophysiology
MeSH terms: Animals, Brain, Humans, Receptors, Serotonin, Schizophrenia, Serotonin, Receptors, Glutamate, Glutamic Acid

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Serotonin model of schizophrenia: emerging role of glutamate mechanisms

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