Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G(i/o) proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.

Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor osteoblast-specific disruption of β-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a β-Catenin–independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner this study broadens our understanding of bone remodeling and suggests novel therapies to increase bone mass.

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 ...

Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.

Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions. We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly, while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates them fully. This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms.

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Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.

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