Article

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: 15.98). 03/2007; 53(3):439-52. DOI: 10.1016/j.neuron.2007.01.008
Source: PubMed

ABSTRACT 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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    • "A possible explanation for these effects is that mGlu2 receptors colocalize with 5-HT 2A receptors to form heteroreceptor complexes (Delille et al. 2012; Gonzalez- Maeso et al. 2008; Gonzalez-Maeso et al. 2007). It has been suggested that the heteroreceptors induce a hallucinogenspecific second messenger cascade (Gonzalez-Maeso et al. 2008; Gonzalez-Maeso et al. 2007), although this has not been definitely established (Delille et al. 2012). "
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    • "Although DOI acts on 5-HT 2A and 5-HT 2C receptors, DOI-induced head-twitch response (Dursun and Handley, 1996; Willins and Meltzer, 1997; Fantegrossi et al., 2010), c-Fos (Scruggs et al., 2000) and Egr-2 (Gonzalez-Maeso et al., 2007) expression have been proven to be mediated via activation of 5-HT 2A receptors, but not 5-HT 2C receptors. We found that MA-exposed mice have greater responsiveness to DOI and higher levels of 5-HT 2A receptors compared with controls. "
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    • "Political pressure in the late 1960s led to the illegalization of psychedelics and this had a significant negative impact on legitimate scientific research (Grinspoon and Bakalar, 1979; Lee and Shlain, 1985)—a problem that continues today (Nutt et al., 2013). Despite this however, there has been a resurgence of scientific interest in psychedelics in recent years (Vollenweider et al., 1998; Nichols, 2004; Griffiths et al., 2006, 2008; Moreno et al., 2006; Gonzalez-Maeso et al., 2007; Grob et al., 2011; Carhart-Harris et al., 2012a). The dominant theoretical and therapeutic approach during the early era of psychedelic research was psychoanalytic. "
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