Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior

Department of Biological Sciences, Columbia University, New York, New York, United States
Neuron (Impact Factor: 15.05). 03/2007; 53(3):439-52. DOI: 10.1016/j.neuron.2007.01.008
Source: PubMed


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.

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    • "HTR is considered to be a rodent behavioural proxy for human hallucinogenic effects because it can distinguish between hallucinogenic and non-hallucinogenic 5-HT 2A agonists. [43] [44] [45] [46] Although HTR has traditionally been assessed using direct observation, new methods have been developed to detect HTR in a semi-automated fashion using a head-mounted magnet and a magnetometer coil. [46] [47] The present report details the analytical characterization of 1P-LSD using various chromatographic, mass spectrometric, and spectroscopic methods relevant to clinical and forensic investigations . "
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    ABSTRACT: 1-Propionyl-d-lysergic acid diethylamide hemitartrate (1P-LSD) has become available as a ‘research chemical’ in the form of blotters and powdered material. This non-controlled derivative of d-lysergic acid diethylamide (LSD) has previously not been described in the published literature despite being closely related to 1-acetyl-LSD (ALD-52), which was developed in the 1950s. This study describes the characterization of 1P-LSD in comparison with LSD using various chromatographic and mass spectrometric methods, infrared and nuclear magnetic resonance spectroscopy. An important feature common to LSD and other serotonergic hallucinogens is that they produce 5-HT2A-receptor activation and induce the head-twitch response (HTR) in rats and mice. In order to assess whether 1P-LSD displays LSD-like properties and activates the 5-HT2A receptor, male C57BL/6 J mice were injected with vehicle (saline) or 1P-LSD (0.025–0.8 mg/kg, IP) and HTR assessed for 30 min using magnetometer coil recordings. It was found that 1P-LSD produced a dose-dependent increase in HTR counts, and that it had ~38% (ED50 = 349.6 nmol/kg) of the potency of LSD (ED50 = 132.8 nmol/kg). Furthermore, HTR was abolished when 1P-LSD administration followed pretreatment with the selective 5-HT2A receptor antagonist M100907 (0.1 mg/kg, SC), which was consistent with the concept that the behavioural response was mediated by activation of the 5-HT2A receptor. These results indicate that 1P-LSD produces LSD-like effects in mice, consistent with its classification as a serotonergic hallucinogen. Nevertheless, the extent to which 1P-LSD might show psychoactive effects in humans similar to LSD remains to be investigated.
    Drug Testing and Analysis 10/2015; DOI:10.1002/dta.1884 · 2.51 Impact Factor
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    • "[6] [7] 5-HT 2A receptor agonist activity appears to be a necessary requirement for a compound to display psychedelic effects although this might not always be sufficient. [8] It is this particular feature, however, that has led to the recreational and commercial exploration, including manufacturing and sale via various outlets, such as online retailers or 'head shops'. The translation of laboratory-based research into a wider commodified open market has attracted concern worldwide . "
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    ABSTRACT: RationaleSubstances based on the N-(2-methoxybenzyl)phenethylamine template ('NBOMe' derivatives) play an important role in medicinal research but some of these derivatives have also appeared as 'research chemicals' for recreational use which has attracted attention worldwide. A major challenge associated with newly emerging substances includes the lack of analytical data and the ability to correctly identify positional isomers.Methods Six N-benzylphenethylamines based on the 2,5-dimethoxy-4-iodophenethylamine structure ('25I') and twelve substituted N-benzyl-5-methoxytryptamines ('5MT') have been prepared and extensively characterized. Techniques used for characterization were gas chromatography/ion trap mass spectrometry in electron and chemical ionization mode, liquid chromatography/diode array detection (DAD), infrared spectroscopy, electrospray high mass accuracy quadrupole time-of-flight tandem mass spectrometry, and triple quadrupole tandem mass spectrometry.ResultsThe characterization of 18 'NBOMe' compounds provided a comprehensive collection of chromatographic and spectral data. Four groups of three positional isomers, i.e. 25I-NB2OMe, 25I-NB3OMe, 25I-NB4OMe, 25I-NB2B, 25I-NB3B, 25I-NB4B and their 5-methoxytryptamine counterparts, were included and assessed for ability to obtain differentiation. Six meta-substituted N-benzyl derivatives of 5-methoxytryptamine (CF3, F, CH3, Cl, I, SCH3) were also studied.Conclusions The implementation of mass spectral techniques was helpful for the differentiation between isomers, for example, when considering the difference in a number of ion ratios. This was considered beneficial in cases where chromatographic separation was only partially achieved under liquid chromatography (LC) conditions. The use of LC/DAD analysis was also found to be valuable for this particular purpose, which confirmed the integrative value of complementary techniques used in areas related to forensic toxicology.
    Rapid Communications in Mass Spectrometry 04/2015; 29(7). DOI:10.1002/rcm.7134 · 2.25 Impact Factor
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    • "We then compared the cortical brain layer in the two groups, and we also tested the participants for neuropsychological performance. The rationale behind this study was data from pharmacological studies that showed that psychedelic 5-HT 2A agonists, such as DMT, stimulate neurotrophic factors (Gewirtz et al. 2002), and transcription factors (Frankel and Cunningham 2002; González-Maeso et al. 2007), associated with synaptic plasticity. By comparing the structural images, we expected we would detect areas of the brain where structural changes such as increased dendritic arborization, enhanced vascularization, and glial cell proliferation might have occurred. "
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    ABSTRACT: New World indigenous peoples are noted for their sophisticated use of psychedelic plants in shamanic and ethnomedical practices. The use of psychedelic plant preparations among New World tribes is far more prevalent than in the Old World. Yet, although these preparations are botanically diverse, almost all are chemically similar in that their active principles are tryptamine derivatives, either DMT or related constituents. Part 1 of this paper provides an ethnopharmacological overview of the major tryptamine-containing New WorldNew World hallucinogensHallucinogens .
    Current Topics in Behavioral Neurosciences 02/2015; DOI:10.1007/7854_2015_368
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