Journal of Neuroscience
October 1, 2003
Javier González-Maeso, Tony Yuen, Barbara J. Ebersole et al.
295 citations
Different drugs that activate the same serotonin receptor (5-HT2AR) can produce distinct patterns of gene expression in the brain, which correspond to different behavioral effects. The hallucinogens DOI and LSD triggered a head-twitch response in mice and produced similar changes in the somatosensory cortex transcriptome, while the nonhallucinogenic drug lisuride did not cause this behavior and generated a different transcriptome fingerprint. These effects were absent in mice lacking the 5-HT2AR, confirming the receptor's role. The findings suggest that drugs acting at the same receptor can induce unique cellular response patterns in the living brain, detectable through transcriptome analysis.
Current Medicinal Chemistry
March 1, 2009
Javier González-Maeso, Stuart C. Sealfon
74 citations
G protein-coupled receptors (GPCRs) are the most common target for therapeutic drugs. The traditional ternary complex model, where receptors shift between active and inactive states, has been revised because different agonists can activate distinct signaling pathways from the same receptor. This agonist-trafficking model proposes that agonists stabilize unique receptor conformations that preferentially trigger specific pathways. Hallucinogenic drugs like LSD, psilocybin, and mescaline, which act on serotonin 5-HT2A receptors, offer a useful system to study this phenomenon. Non-hallucinogenic chemicals like lisuride show similar in vitro activity at the same receptor but do not induce hallucinogenic effects, highlighting unresolved questions about how agonist-trafficking determines behavioral outcomes.
Molecular Pharmacology
January 1, 2003
Barbara J. Ebersole, Irache Visiers, Harel Weinstein et al.
72 citations
Indole agonists at the human serotonin 5-HT2A receptor achieve differing efficacies through specific hydrogen-bond interactions with serine residues in helices 3 and 5. Serotonin forms hydrogen bonds with Ser3.36 and Ser5.46; methyl-substitution of the cationic primary amine or the backbone N1-amine disrupts these bonds and reduces efficacy. Mutating Ser3.36 to alanine largely eliminates efficacy differences caused by cationic amine substitution, while mutating Ser5.46 to alanine reduces the efficacy loss from N1-amine substitution. Computational modeling shows these interactions shift the agonist's position in the binding pocket, and the indole ring's position correlates with agonist activity. The findings support a mechanism where agonist position, influenced by specific helix interactions, determines receptor activation, likely shared by other class A G-protein coupled receptors.
Neuroscience Letters
January 16, 2013
José L. Moreno, Terrell Holloway, Vinayak Rayannavar et al.
44 citations
Hallucinogenic drugs like LSD, mescaline, and psilocybin all bind strongly to the serotonin 5-HT(2A) receptor. Drugs that affect metabotropic glutamate 2/3 (mGlu2/3) receptors can alter the cellular and behavioral effects of hallucinogens. In mice, chronic treatment (21 days) with the mGlu2/3 receptor antagonist LY341495 (1.5 mg/kg) reduced the hallucinogenic-like effects of LSD (0.24 mg/kg). This treatment decreased binding of a radiolabeled tracer to 5-HT(2A) receptors in the somatosensory cortex of normal mice, but not in mice lacking the mGlu2 receptor. It also reduced head-twitch behavior and the expression of certain genes (c-fos, egr-1, egr-2) that are normally triggered by hallucinogenic drugs. These results suggest that repeatedly blocking mGlu2 receptors dampens the 5-HT(2A) receptor-mediated effects of LSD.
Trends in Neurosciences
April 1, 2009
Javier González-Maeso, Stuart C. Sealfon
Research on psychedelics like LSD and dissociative drugs such as PCP has converged with studies of schizophrenia, as their effects mimic core symptoms of the disorder. Some atypical antipsychotics were identified by their high affinity for serotonin 5-HT(2A) receptors, the same target as LSD-like drugs. Effects of PCP-like drugs are strongly influenced by modulation of both 5-HT(2A) and metabotropic glutamate 2/3 receptors. A serotonin-glutamate receptor complex in cortical pyramidal neurons may be the target of both psychedelics and certain antipsychotics. Recent findings on receptor, signaling, and circuit mechanisms could unify the serotonin and glutamate neurochemical hypotheses of schizophrenia.