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. 016ARTICLE IN PRESSG Model BBR 9035 1-22 A. L. Halberstadt / Behavioural Brain Research xxx (2014) xxx-xxx 3 Fig. 2. Chemical structures of conformationally restricted hallucinogens. 2. 2. Pharmacology of the 5-HT 2Areceptor The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT, see Fig. 3) has potent contractile effects upon smooth muscle, espe-cially rat uterus and guinea pig ileum. The ﬁrst indication that there are multiple 5-HT receptor subtypes came from studies conducted by Gaddum and Picarelli [21]. They reported that treatment with either dibenzyline or morphine alone could only partially block the effect of 5-HT on guinea pig ileum. However, in tissue exposed to dibenzyline for 30 min, morphine markedly antagonized 5-HT-induced contraction, and dibenzyline acted as a full 5-HT antagonist in tissue previously exposed to morphine. These ﬁndings demon-strated that 5-HT was acting through two different receptor classes (type D and type M) to induce contraction of guinea pig ileum. Soon after the development of radioreceptor techniques to demonstrate receptor binding, this methodology was applied to the investigation of 5-HT receptors. The ﬁrst radioligands utilized were [3H]LSD and [3H]5-HT [22,23]. Both of those radioligands bind to rat brain membranes with high-afﬁnity in a reversible, saturable, and stereoselective manner, suggesting they are inter-acting with speciﬁc recognition sites. After introduction of the dopamine antagonist radioligand [3H]spiperone, it was recog-nized that [3H]spiperone binds to 5-HT receptors distinct from the sites labeled by [3H]5-HT [24]. The sites labeled by [3H]5-HT and [3H]spiperone were designated as 5-HT 1and 5-HT 2receptors, respectively, and it was recognized that [3H]LSD labeled both sites. The D receptor was eventually shown to be equivalent to the 5-HT2receptor, whereas the M receptor is pharmacologically distinct from 5-HT 1sites and was later classiﬁed by Bradley and coworkers [25] as the 5-HT 3receptor. The 5-HT 2receptor class was later reor-ganized to include three subtypes: 5-HT 2A(equivalent to the site known historically as the 5-HT 2receptor or the D receptor), 5-HT 2B Fig. 3. Structure of serotonin. (formerly known as the 5-HT 2Freceptor), and 5-HT 2C(formerly known as the 5-HT 1Creceptor) [26]. The 5-HT 2Areceptor couples to Gq and activates phospholi-pase C/H9252 (PLC/H9252) signaling, resulting in the hydrolysis of membrane phospholipids to inositol triphosphate (IP3) and diacylglycerol, and mobilization of intracellular Ca2+(see Fig. 4). There is evi-dence that 5-HT 2Ais coupled to several non-canonical signaling pathways, including /H9252-arrestin-2, Src (potentially involving Gi/o-associated G/H9252/H9253 subunits), extracellular-regulated kinase (ERK), p38 mitogen-activated protein (MAP) kinase, phospholipase A2 (downstream from ERK 1,2 and p38 MAP kinase), Akt, and phos-pholipase D (dependent on the small G protein ADP-ribosylation factor-1 (ARF1)) [27-30]. However, the signaling pathways respon-sible for mediating the characteristic effects of hallucinogens have not been conclusively identiﬁed. Activation of the canonical Gq-PLC/H9252 signaling pathway is apparently not sufﬁcient to produce hallucinogen-like behavioral effects in animal models [28,31,32]. Multiple signaling pathways may be involved because the behav-ioral response to DOI is partially blunted in Gq knockout mice [33]. Schmid and colleagues have reported that /H9252-arrestin-2 is not required for the behavioral effects of DOI and 5-Me O-DMT [29,34]. There also does not appear to be a direct relationship between phospholipase A2activation and generation of hallucinogen effects [32]. 3. Evidence that serotonergic hallucinogens belong to a unitary class 3. 1. Subjective effects Despite having different chemical structures, phenylalkylamine, tryptamine, and ergoline hallucinogens produce remarkably simi-lar subjective effects [35-42]. It is very difﬁcult for hallucinogen-experienced subjects to distinguish between psilocybin and LSD if those substances are administered in a blinded fashion, with the only apparent difference being the duration of action [41]. Similar ﬁndings have been reported when mescaline, LSD, and psilocy-bin are compared in the same subjects [37-39]. By contrast, the effects of hallucinogens can be distinguished from those of other drug classes. The effects of classical hallucinogens and anticholin-ergic agents are qualitatively distinct [43,44]. Studies using the Addiction Research Center Inventory (ARCI) instrument [45] have conﬁrmed that the effects of LSD are dissimilar from those of (+)-amphetamine [46] and /Delta19-tetrahydrocannabinol [47]. The ARCI can also distinguish between the subjective responses to 20 mg (+)-amphetamine and an ayahuasca preparation containing the equivalent of a 1 mg/kg dose of DMT [48]. Although it does not appear that any studies have directly compared the experiences produced by classical hallucinogens and the /H9260-opioid receptor ago-nist salvinorin A from Salvia divinorum, there is evidence that the phenomenology of salvinorin A is unique [49], and the ARCI is rel-atively insensitive to the effects of salvinorin A [50]. Several recent studies have compared the effects of hallu-cinogens and other drug classes using psychometrically validated instruments. One instrument that has been widely used to assess the subjective response to hallucinogens is the Altered States of Consciousness Questionnaire (APZ), as well as well as APZ vari-ants such as the APZ-OAV and the 5D-ASC. These rating scales are designed to assess altered states of consciousness indepen-dent of their etiology [51,52]. The APZ and APZ-OAV include three core dimensions: Oceanic Boundlessness (OB), Anxious Ego Dissolu-tion (AED) and Visionary Restructuralization (VR). The OB dimension reﬂects a pleasant state of depersonalization and derealization, the AED dimension measures dysphoric effects such as ego disintegra-tion, delusions, loss of self-control, thought disorder, and anxiety,109 110 111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140 141142143144145146147148149150151152153154155156157158159160161162163 164 165 166 167 168169170171172173174175176177178179180181182183184185186187188189190191192193194195196197198199200201