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Recent Advances in the Neuropsychopharmacology of Serotonergic G Model BBR 9035 1–22 ARTICLE IN PRESS Behavioural Brain Research xxx (2014) xxx–xxx Contents lists available at ScienceDirect Behavioural Brain Research jou rnal homepage: www.elsevier.com/locate/bbr 1 Research report 2 Recent advances in the neuropsychopharmacology of serotonergic 3 hallucinogens ∗ 4 Q1 Adam L. Halberstadt 5 Department of Psychiatry, University of California San Diego, La Jolla, CA, United States 6 7 h i g h l i g h t s 8 • 9 Serotonergic hallucinogens are classified as phenylalkylamines and indoleamines. • 10 The two classes of hallucinogens produce similar subjective effects in humans and show cross-tolerance. • 11 Hallucinogen effects are primarily mediated by the serotonin 5-HT2A receptor. • 12 Many effects of hallucinogens are mediated in the prefrontal cortex. 13 2814 a r t i c l e i n f o a b s t r a c t 15 16 Article history: Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are some- 17 Received 18 April 2014 what enigmatic substances. Although these drugs are derived from multiple chemical families, they all 18 Received in revised form 7 July 2014 produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article 19 Accepted 8 July 2014 reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of hallucinogen 20 Available online xxx action. The 5-HT2A receptor is responsible for mediating the effects of hallucinogens in human subjects, 21 as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse 22 Keywords: inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded 23 Psychedelic important new findings regarding the psychopharmacology of these substances. Furthermore, the use 24 5-HT2A receptor of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens 25 Head twitch 26 Prefrontal cortex work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy. 27 Visual effects © 2014 Published by Elsevier B.V. 29 1. Introduction similar discriminative stimulus effects [3] and act as agonists of the 43 serotonin-2A (5-HT2A) receptor [4]. Therefore, it has been proposed 44 30 Hallucinogenic drugs have been used by humans for thousands [5] that in addition to having the characteristics listed above, hal- 45 31 of years, but western scientists only became interested in these lucinogens should also bind to the 5-HT2A receptor and produce 46 32 substances beginning in the late 1800s. These agents produce pro- full substitution in animals trained to discriminate the prototyp- 47 33 found changes in consciousness. Because other drug classes can ical hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM). 48 34 sometimes produce effects that overlap with those of the hallu- For this reason, hallucinogens are often categorized as classical hal- 49 35 cinogens, it has been important to develop a formal definition for lucinogens or serotonergic hallucinogens. This article will review 50 36 these compounds. This has turned out to be a difficult and con- the pharmacology of hallucinogens, including their mechanism-of- 51 37 tentious task. Hallucinogens have been defined as agents that alter action, their effects in animals and humans, and recent findings 52 38 thought, perception, and mood without producing memory impair- regarding how they interact with specific brain regions. 53 39 ment, delirium, or addiction [1,2]. However, this definition is overly 40 broad because it fails to exclude a wide-range of agents that are 41 generally not classified as hallucinogens, such as cannabinoids and 2. Pharmacology of hallucinogens 54 42 NMDA antagonists. It is now recognized that hallucinogens produce 2.1. Receptor interactions 55 ∗ Classical hallucinogens can be divided into two main struc- 56 Correspondence to: Department of Psychiatry, University of California San Diego, tural classes: indoleamines and phenylalkylamines [6]. Indoleamines 57 9500 Gilman Drive, La Jolla, CA 92093-0804, United States. Tel.: +1 619 471 0525. E-mail addresses: [email protected], [email protected] include the tetracyclic ergoline (+)-lysergic acid diethylamide (LSD) 58 http://dx.doi.org/10.1016/j.bbr.2014.07.016 0166-4328/© 2014 Published by Elsevier B.V. Please cite this article in press as: Halberstadt AL. Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.07.016 G Model BBR 9035 1–22 ARTICLE IN PRESS 2 A.L. Halberstadt / Behavioural Brain Research xxx (2014) xxx–xxx Fig. 1. Chemical structures of indolealkylamine, phenylalkylamine, and ergoline hallucinogens. 59 and the chemically simpler indolealkylamines, which includes (25I-NBOMe) and N-(2-methoxybenzyl)-2,5-dimethoxy-4- 84 60 N,N-dimethyltryptamine (DMT), N,N-dipropyltryptamine (DPT), bromophenethylamine (25B-NBOMe). The chemical structures 85 61 5-methoxy-DMT (5-MeO-DMT), and psilocybin (4-phosphoryloxy- of many of these hallucinogens are illustrated in Fig. 1. 86 62 DMT) and its active O-dephosphorylated metabolite psilocin Nichols and colleagues have also developed conformationally 87 63 (4-hydroxy-DMT). DMT is found in several hallucinogenic snuffs restricted derivatives of phenylalkylamine hallucinogens: bromo- 88 64 used in the Caribbean and in South America. It is also a com- DragonFLY (1-(8-bromobenzo[1,2-b;4,5-b]difuran-4-yl)-2-amino- 89 65 ponent of ayahuasca, an infusion or decoction prepared from propane; [9]); TCB-2 (4-bromo-3,6-dimethoxybenzocyclobuten- 90 66 DMT-containing plants in combination with species of Banisteriop- 1-yl)methylamine; [10]; and 2S,6S-DMBMPP ((2S,6S)-2-(2,5- 91 67 sis containing ␤-carboline alkaloids that act as monoamine oxidase dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine; 92 68 inhibitors [7]. Psilocybin and its metabolite psilocin are the active [11]). Likewise, lysergic acid 2,4-dimethylazetidide was developed 93 69 components of hallucinogenic teonanácatl mushrooms belonging as a rigid analog of LSD that shows similar in vivo potency [12]. 94 70 to the genus Psilocybe. Fig. 2 shows examples of rigid hallucinogen analogs. 95 71 The phenylalkylamines can be subdivided into phenethy- Phenylalkylamine hallucinogens are selective for 5-HT2 recep- 96 72 lamines, such as mescaline from the peyote cactus (Lophophora tors, including 5-HT2A, 5-HT2B, and 5-HT2C sites [13–15]. The 97 73 williamsii), 2,5-dimethoxy-4-bromophenethylamine (2C- indolealkylamines, by contrast, bind non-selectively to 5-HT recep- 98 74 B), and 2,5-dimethoxy-4-iodophenethylamine (2C-I); and tors. Certain indolealkylamines, most notably DMT and some 99 75 phenylisopropylamines (“amphetamines”), including DOM, of its derivatives, bind to ␴1 receptors [16] and the trace 100 76 2,5-dimethoxy-4-iodoamphetamine (DOI), and 2,5-dimethoxy- amine receptor [17], and are substrates for the 5-HT trans- 101 77 4-bromoamphetamine (DOB). Although N-alkyl substituted porter (SERT) [18,19]. However, compared with ␴1 and SERT, 102 78 phenylalkylamines are usually inactive as hallucinogens, the tryptamines are more potent at 5-HT1A and 5-HT2A receptors 103 79 addition of a N-benzyl group to phenethylamines can dramat- by several orders of magnitude, so the former sites probably 104 80 ically increase their activity, and N-benzylphenethylamines do not contribute to the hallucinogenic response. LSD and other 105 81 are a new class of potent hallucinogenic compounds [8]. ergoline hallucinogens display high affinity for 5-HT receptors, 106 82 Examples of N-benzylphenethylamine hallucinogens include as well as dopaminergic and adrenergic receptors (reviewed by: 107 83 N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine [6,20]). 108 Please cite this article in press as: Halberstadt AL. Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.07.016 G Model BBR 9035 1–22 ARTICLE IN PRESS A.L. Halberstadt / Behavioural Brain Research xxx (2014) xxx–xxx 3 (formerly known as the 5-HT2F receptor), and 5-HT2C (formerly 140 known as the 5-HT1C receptor) [26]. 141 The 5-HT2A receptor couples to Gq and activates phospholi- 142 pase C␤ (PLC␤) signaling, resulting in the hydrolysis of membrane 143 phospholipids to inositol triphosphate (IP3) and diacylglycerol, 144 2+ and mobilization of intracellular Ca (see Fig. 4). There is evi- 145 dence that 5-HT2A is coupled to several non-canonical signaling 146 ␤ pathways, including -arrestin-2, Src (potentially involving Gi/o- 147 associated G␤␥ subunits), extracellular-regulated kinase (ERK), 148 p38 mitogen-activated protein (MAP) kinase, phospholipase A2 149 (downstream from ERK 1,2 and p38 MAP kinase), Akt, and phos- 150 pholipase D (dependent on the small G protein ADP-ribosylation 151 factor-1 (ARF1)) [27–30]. However, the signaling pathways respon- 152 sible for mediating the characteristic effects of hallucinogens have 153 not been conclusively identified. Activation of the canonical Gq- 154 ␤ PLC signaling pathway is apparently not sufficient to produce 155 hallucinogen-like behavioral effects in animal models [28,31,32]. 156 Multiple signaling pathways may be involved because the behav- 157 ioral response to DOI is partially blunted in Gq knockout mice 158 Fig. 2. Chemical structures of conformationally restricted hallucinogens. [33]. Schmid and colleagues have reported that ␤-arrestin-2 is not 159 required for the behavioral effects of DOI and 5-MeO-DMT [29,34]. 160 There also does not appear to be a direct relationship between 161 109 2.2. Pharmacology of the 5-HT2A receptor phospholipase A2 activation and generation of hallucinogen effects 162 [32]. 163 110 The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT, 111 see Fig. 3) has potent contractile effects upon smooth muscle, espe- 112 cially rat uterus and guinea pig ileum. The first indication that there 3. Evidence that serotonergic hallucinogens belong to a 164 113 are multiple 5-HT receptor subtypes came from studies conducted unitary class 165 114 by Gaddum and Picarelli [21].
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