Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex

González-Maeso, Javier; Yuen, Tony; Ebersole, Barbara J.; Wurmbach, Elisa; Lira, Alena; Zhou, Ming‐Ming; Weisstaub, Noelia V.; Hen, René; Gingrich, Jay A.; Sealfon, Stuart C.

doi:10.1523/jneurosci.23-26-08836.2003

Cited by 264 publications

(335 citation statements)

References 55 publications

(71 reference statements)

Supporting

Mentioning

318

Contrasting

Order By: Relevance

“…The pattern of G protein regulation in cortical pyramidal neurons has been shown to predict specific behavioural responses to 2AR agonists. Hallucinogenic drugs and non-hallucinogenic drugs activate the same population of 2ARs in cortical pyramidal neurons, but differ in the 2AR-dependent pattern of G protein regulation and gene induction they elicit 8,9 . In brain cortical neurons, the signalling elicited by hallucinogenic and non-hallucinogenic 2AR agonists causes induction of c-fos and requires G q/11 -dependent phospholipase C activation.…”

mentioning

confidence: 99%

“…Drugs that interact with metabotropic glutamate receptors (mGluR) also show potential for the treatment of schizophrenia [5][6][7] . The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide (LSD), require the 2AR [8][9][10] and resemble some of the core symptoms of schizophrenia [10][11][12] . Here we show that the mGluR2 interacts via specific transmembrane helix domains with the 2AR, a member of an unrelated G protein-coupled receptor (GPCR) family, to form functional complexes in brain cortex.…”

mentioning

confidence: 99%

“…However, the signalling of hallucinogens such as DOI and LSD acting at the 2AR also induces egr-2, which is G i/o -dependent. Thus c-fos expression results from any 2AR-signalling, and egr-2 induction is a specific marker for hallucinogen signalling via the 2AR 8,9 . The finding that mGluR2 modulates the G i protein coupling of the 2AR (Fig.…”

mentioning

confidence: 99%

“…S8, S9 and S10 for FISH results with LSD treatment, and real-time PCR gene assay results with DOI, DOM, DOB, LSD, lisuride and ergotamine). We also studied the effects of LY379 on the headtwitch response (HTR) behavior, which is hallucinogen-specific 8,9 . Similar to its effects on G protein activation and gene induction, the glutamate agonist LY379 suppressed the induction of the HTR by either DOI or LSD (Supplementary Fig.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Identification of a serotonin/glutamate receptor complex implicated in psychosis

González-Maeso

Ang²,

Yuen³

et al. 2008

Nature

Self Cite

723

766

View full text Add to dashboard Cite

The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception 1,2 . Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT 2A receptors (2AR) 3,4 . Drugs that interact with metabotropic glutamate receptors (mGluR) also show potential for the treatment of schizophrenia [5][6][7] . The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide (LSD), require the 2AR [8][9][10] and resemble some of the core symptoms of schizophrenia [10][11][12] . Here we show that the mGluR2 interacts via specific transmembrane helix domains with the 2AR, a member of an unrelated G protein-coupled receptor (GPCR) family, to form functional complexes in brain cortex. The 2AR/mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen specific signalling and behavioural responses. In postmortem human brain from untreated schizophrenic subjects, the 2AR is up-regulated and the mGluR2 is down-regulated, a pattern that could predispose to psychosis. These regulatory changes suggest that the 2AR/mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and represents a promising new target for the treatment of psychosis.Correspondence and requests for materials should be addressed to: J.G.M (e-mail: Javier.Maeso@mssm.edu) S.C.S. (e-mail: Stuart.Sealfon@mssm.edu). The 2AR and mGluR2/3 show an overlapping distribution in brain cortex in autoradiography studies 13 . The mGluR2 and mGluR3 are not distinguished by autoradiographic ligands. We used fluorescent in situ hybridization (FISH) to determine whether either of these receptor subtypes are co-expressed by the same neurons. In layer V mouse somatosensory cortex (SCx), 2AR mRNA positive cells were mostly mGluR2 mRNA positive. The level of expression in SCx was much lower for mGluR3 mRNA, which rarely co-localized with 2AR mRNA (Fig. 1a). Control studies validated assay sensitivity and specificity, and similar 2AR/mGluR2 mRNA co-localization was found in cortical primary cultures (Figs. 1a,b,c, and Supplementary Fig. S1). Translation of 2AR protein in cortical pyramidal neurons was found to be necessary for normal mGluR2 expression. Mice with globally disrupted 2AR expression (htr2A−/− mice) showed reduced cortical mGluR2 binding and expression, while mice in which 2AR expression was selectively restored in cortical pyramidal neurons 8,14 showed control expression levels (Supplementary Table S1, and Supplementary Fig. S2). The effects of mGluR2/3 activation on 2AR responses have been generally attributed to synaptic mechanisms 5,6,13,15 . However, the co-localization of 2AR and mGluR2 and the reduction of mGluR2 expression levels in htr2A−/− mice motivated us to examine whether a direct mechanism contributed to cortical crosstalk between these two receptor systems. NIH Public AccessRecent studies have demonstrated that some GPCRs belonging to the same sequence classes can form ...

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Identification of a serotonin/glutamate receptor complex implicated in psychosis

González-Maeso

Ang²,

Yuen³

et al. 2008

Nature

Self Cite

723

766

View full text Add to dashboard Cite

show abstract

“…Microinjection of DOI into the prefrontal cortex of the rat elicits HTR (Willins and Meltzer, 1997). LSD-and DOI-induced HTR is abolished in 5-HT 2A receptor null-mutant mice (González-Maeso et al, 2003) and can be rescued in these mice by genetic restoration of 5-HT 2A receptor expression exclusively in the cortex (González-Maeso et al, 2007). Since the density of 5-HT 2A receptors in SERT KO mice is substantially decreased throughout the cerebral cortex (Rioux et al, 1999), such an adaptation might underlie the absence of LSD discrimination in these mice.…”

Section: Discussionmentioning

confidence: 97%

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

Krall

Richards

Rabin

et al. 2008

Pharmacology Biochemistry and Behavior

View full text Add to dashboard Cite

Rationale-Based upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT 2A receptors, with serotonergic receptors of the 5-HT 1A and 5-HT 2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT 2A receptor density is decreased and, at a functional level, the head twitch response following the administration of DOI, an index of activation of 5-HT 2A receptors, is reduced. Taken together, these studies led us to hypothesize that the efficacy of LSD in establishing stimulus control is diminished or abolished in mice lacking the serotonin transporter.Objective-Determine the efficacy of LSD for establishing stimulus control in SERT knockout (KO) mice.Methods-SERT KO mice and wildtype (WT) littermates were trained in a visual discrimination on a progressive fixed ratio (FR) water-reinforced task and subsequently trained on a FR10 schedule with LSD (0.17 or 0.30 mg/kg) or vehicle. To control for general deficiencies in drug discrimination, mice were trained with pentobarbital (15 or 30 mg/kg) or vehicle.Results-The visual stimulus exerted control in both genotypes. LSD induced stimulus control in 90% of WT mice but only 31% of SERT KO mice. In contrast, pentobarbital induced stimulus control in 80% of WT mice and 54% of knockout mice.Conclusions-Although SERT KO mice exhibited stimulus control by the non-serotonergic drug, pentobarbital, the efficacy of LSD in these animals was markedly decreased, suggesting that reduced density of 5-HT 1A and/or 5-HT 2A receptors underlies the absence of stimulus control by LSD.

show abstract

Oligomerization of G‐Protein‐Coupled Receptors

López-Giménez

González-Maeso

2012

Therapeutic Targets

View full text Add to dashboard Cite

Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex

Cited by 264 publications

References 55 publications

Identification of a serotonin/glutamate receptor complex implicated in psychosis

Identification of a serotonin/glutamate receptor complex implicated in psychosis

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

Oligomerization of G‐Protein‐Coupled Receptors

Contact Info

Product

Resources

About