Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens, Adam L. Halberstadt & Mark A. Geyer, 2011

Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens

Adam L. Halberstadt & Mark A. Geyer

Neuropharmacology, 2011, 61, (3), 364–381.




Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT2 receptor agonists, whereas the indoleamines are relatively nonselective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5- HT2A receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT2 and non-5-HT2 receptors.

Keywords : hallucinogen; LSD; psilocybin; serotonin; drug discrimination; locomotor activity; head twitch; 5-HT1A receptor


1. Introduction

Hallucinogens are a class of pharmacological agents that increase the intensity and lability of affective responses and produce profound distortions of perceptual processes encompassing the visual, auditory and tactile modalities. These compounds, in the form of botanical preparations, have been used by humans for thousands of years to induce states of mysticism and inebriation (Schultes and Hofmann, 1980). Notable examples include the peyote cactus (Lophophora williamsii), which contains mescaline; teonanácatl mushrooms containing psilocin and psilocybin; and ayahuasca, a decoction prepared from the bark of β- carboline-containing Banisteriopsis species in combination with plants containing N,Ndimethyltryptamine (DMT). Hallucinogen use has remained relatively stable over the past decades, but these drugs are becoming more widely available with increased access to psychoactive natural products and the extant knowledge base on the use and preparation of these compounds introduced through the internet. For example, the sacramental use of ayahuasca originated in South America, but in recent years the use of this hallucinogen has spread to Europe and North America. Research into the profound effects of hallucinogens on perception has shaped our neurobiological understanding of consciousness and informed our understanding of neuropsychiatric disorders. For example, the notion that psychotic states seen in schizophrenia may involve serotonin (5-HT) dysfunction arose in part from the observed psychedelic effects of (+)-lysergic acid diethylamide (LSD) and other classical serotonergic hallucinogens (Geyer and Vollenweider, 2008; Quednow et al., 2010).

2. Chemical Structure of Hallucinogens

As shown in Figure 1, classical hallucinogens belong to two classes of chemicals: (1) indoleamines, including the ergoline LSD and indolealkylamines such as DMT, 5-methoxy- DMT (5-MeO-DMT), psilocin, and 4-phosphoryloxy-DMT (psilocybin); (2) phenylalkylamines, such as the phenethylamines mescaline and 2,5-dimethoxy-4- bromophenethylamine (2C-B), and the phenylisopropylamines 2,5-dimethoxy-4- iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), and 2,5-
dimethoxy-4-bromoamphetamine (DOB). Recently, highly potent rigid analogs of hallucinogenic phenylalkylamines have been synthesized in which the alkoxy ring substituents are incorporated into furanyl and/or pyranyl rings (e.g., 1-(8-bromobenzo[1,2-b; 4,5-b]difuran-4-yl)-2-aminopropane (“Bromo-Dragonfly”; Parker et al., 1998), or the ethylamine side chain is conformationally constrained by incorporation into a cycloalkane ring (e.g., TCB-2; McLean et al., 2006). Radioligand binding studies have shown that phenylalkylamine hallucinogens are highly selective for 5-HT2 sites (5-HT2A, 5-HT2B, and 5-HT2C receptors), and some of these compounds display over 1000-fold selectivity for agonist-labeled 5-HT2 receptors versus 5-HT1 sites (Titeler et al., 1988;Herrick-Davis and Titeler, 1988;Pierce and Peroutka, 1989). By contrast, indolealkylamines are relatively nonselective for 5-HT receptors, displaying moderate to high affinity for 5-HT1 and 5-HT2 subtypes (Pierce and Peroutka, 1989;McKenna et al., 1990;Deliganis et al., 1991;Blair et al., 2000). Tables I and II show the binding profiles of psilocin and DMT, respectively, for 5- HT receptors. It has been reported that DMT is a σ1 receptor agonist with moderate affinity (KD = 14.75 μM; Fontanilla et al., 2009); however, it is not clear whether this interaction contributes to the effects of DMT because the affinity of the drug for 5-HT1A and 5-HT2A receptors is ~2-orders of magnitude greater than for σ1 binding sites (see Table II). Further, other σ1 receptor agonists (e.g., cocaine) are not hallucinogenic, making it unlikely that σ1 activation by DMT plays a primary role in mediating its hallucinogenic effects. Certain indolealkylamines, including DMT, N,N-dipropyltryptamine (DPT), 5-MeO-DMT, and 5- methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) block 5-HT uptake at micromolar concentrations (Nagai et al., 2007;Sogawa et al., 2007;Cozzi et al., 2009) and serve as substrates for the 5-HT transporter (Cozzi et al., 2009). As shown in Table III, LSD binds to a number of 5-HT receptors with high (nanomolar) affinity (Peroutka, 1994), and also
interacts with dopaminergic and adrenergic receptors.

3. Unitary Effects of Serotonergic Hallucinogens in Humans