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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    ABSTRACT: Serotonin 5-HT2A and 5-HT2C receptors are thought to be the primary pharmacological mechanisms for serotonin-mediated hallucinogenic drugs, but recently there has been interest in metabotropic glutamate (mGluR2) receptors as contributors to the mechanism of hallucinogens.
    Psychopharmacology 07/2014; DOI:10.1007/s00213-014-3658-3 · 3.99 Impact Factor
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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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    ABSTRACT: The repeated administration of methamphetamine (MA) to animals in a single-day 'binge' dosing regimen produces damage to dopamine and serotonin terminals and psychosis-like behaviours similar to those observed in MA abusers. The present study aimed to examine the effects of MA binge exposure on 5-HT2A receptors, the subtype of serotonin receptors putatively involved in psychosis. ICR male mice were treated with MA (4 × 5 mg/kg) or saline at 2 h intervals. Recognition memory and social behaviours were sequentially evaluated by a novel location recognition test, a novel object recognition test, a social interaction and a nest-building test to confirm the persistent cognitive and behavioural impairments after this dosing regimen. Subsequently, a hallucinogenic 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch, molecular and electrophysiological responses were monitored. Finally, the levels of 5-HT2C, 5-HT1A, 5-HT2A and mGlu2 receptors in the medial prefrontal cortex were determined. MA binge exposure produced recognition memory impairment, reduced social behaviours, and increased DOI-induced head-twitch response, c-Fos and Egr-2 expression and field potentials in the medial prefrontal cortex. Furthermore, MA binge exposure increased 5-HT2A and decreased mGlu2 receptor expression in the medial frontal cortex, whereas 5-HT2C and 5-HT1A receptors were unaffected. These data reveal that the increased behavioural, molecular and electrophysiological responses to DOI might be associated with an up-regulation of 5-HT2A receptors in the medial prefrontal cortex after MA binge exposure. Identifying the biochemical alterations that parallel the behavioural changes in a mouse model of MA binge exposure may facilitate targeting therapies for treatment of MA-related psychiatric disorders.
    The International Journal of Neuropsychopharmacology 04/2014; 17(10):1-12. DOI:10.1017/S1461145714000455 · 5.26 Impact Factor
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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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    ABSTRACT: Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neurodynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of "primary states" is elevated entropy in certain aspects of brain function, such as the repertoire of functional connectivity motifs that form and fragment across time. Indeed, since there is a greater repertoire of connectivity motifs in the psychedelic state than in normal waking consciousness, this implies that primary states may exhibit "criticality," i.e., the property of being poised at a "critical" point in a transition zone between order and disorder where certain phenomena such as power-law scaling appear. Moreover, if primary states are critical, then this suggests that entropy is suppressed in normal waking consciousness, meaning that the brain operates just below criticality. It is argued that this entropy suppression furnishes normal waking consciousness with a constrained quality and associated metacognitive functions, including reality-testing and self-awareness. It is also proposed that entry into primary states depends on a collapse of the normally highly organized activity within the default-mode network (DMN) and a decoupling between the DMN and the medial temporal lobes (which are normally significantly coupled). These hypotheses can be tested by examining brain activity and associated cognition in other candidate primary states such as rapid eye movement (REM) sleep and early psychosis and comparing these with non-primary states such as normal waking consciousness and the anaesthetized state.
    Frontiers in Human Neuroscience 02/2014; 8:20. DOI:10.3389/fnhum.2014.00020 · 2.90 Impact Factor
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