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 5 Fig. 5. Subjective effects of psilocybin as measured by the 5-Dimension Altered States of Consciousness instrument (5D-ASC). The values reported by Grob et al. [56] were re-analyzed using the 11 new homogenous APZ subscales developed by Studerus et al. [65]. Values are the mean (SEM) percentages of the total possible score. The placebo was niacin. similar experiences and induce cross-tolerance indicates that these compounds share a common mechanism of action. 4. Involvement of the 5-HT 2Areceptor in hallucinogen effects 4. 1. Evidence from human studies Multiple, converging lines of evidence point to 5-HT 2Arecep-tor activation as the unitary mechanism responsible for mediating hallucinogenesis. Indoleamine and phenylalkylamine hallucino-gens bind to 5-HT 2sites with moderate to high afﬁnity [80-83]. Although indoleamine hallucinogens show relatively promiscu-ous binding proﬁles, phenylisopropylamine hallucinogens such as DOM and DOB are highly selective for 5-HT 2receptors [13,15] and therefore it is likely that their effects are mediated by a member of the 5-HT 2family. Additionally, there is a very strong correla-tion (r = 0. 90-0. 97) between 5-HT 2Areceptor afﬁnity and human hallucinogenic potency [13,82,84]. Another compelling ﬁnding is that 5-HT 2Areceptor blockade ameliorates most of the effects of psilocybin in human subjects. A series of studies conducted by Franz Vollenweider and colleagues at the University Hospital of Psychiatry in Zürich have shown that the effects of psilocybin (215-260 /H9262g/kg, p. o. ) on the OB, AED, and VR dimensions of the APZ-OAV and 5D-ASC are completely blocked by pretreatment with either the 5-HT 2A/2C antagonist ketanserin or the mixed 5-HT 2A/D2 antagonist risperidone [85-90]. By contrast, pretreatment with the dopamine D2antagonist haloperidol had no effect on psilocybin-induced VR scores and actually intensiﬁed the effect of psilocybin on scores in the AED dimension [85]. Ketanserin also blocks the effects of psilocybin on a variety of neurophysiological measures in humans, including tests of spatial working memory [85], prepulse inhibition of acoustic startle [90], N170 visual-evoked potentials [89], semantic interference in the Stroop test [90], and recogni-tion of emotional facial cues in a go/nogo task [88]. Furthermore, a positron emission tomography (PET) study with the 5-HT 2Aradio-tracer [18F]altanserin has shown that the intensity of the responseto psilocybin is directly correlated with the level of 5-HT 2Aoccupa-tion [91]. 4. 2. Evidence from animal behavioral models Because of regulatory constraints on human studies, animal behavioral models are the primary methodology used to study hallucinogens in vivo. Although it has been difﬁcult to develop appropriate models of hallucinogenic activity because of the vari-ability and complexity of their effects, several animal models have made important contributions to our understanding of hal-lucinogen pharmacology. Importantly, although there are some exceptions, almost all the behavioral effects of hallucinogens stud-ies in laboratory animals are mediated by the 5-HT 2Areceptor. 4. 2. 1. Drug discrimination Laboratory animals can be trained to discriminate hallucino-gens from saline using operant conditioning techniques. Rats are the species most commonly employed, although mice and mon-keys have also been used. Many classical hallucinogens have been used as training drugs, including LSD, mescaline, DOM, DOB, DOI, psilocybin, 5-Me O-DMT, DMT, and DPT [3,92-102]. All of these hallucinogens produce cross-generalization, suggesting that they evoke similar interoceptive stimulus cues. By contrast, drugs from other pharmacological classes do not produce hallucinogen-like stimulus effects [3,101,103]. There is a great deal of evidence that the discriminative stimulus effects of hallucinogens are mediated by the 5-HT 2Areceptor. For example, Glennon and colleagues con-ducted substitution tests with 22 hallucinogens in rats trained to discriminate 1 mg/kg DOM from saline and found that the ED50 values for stimulus generalization are highly correlated (r = 0. 938) with 5-HT 2Abinding afﬁnity [84]. Another study with 18 hallu-cinogens found a strong correlation (r = 0. 90) between ED50values for stimulus generalization to 1 mg/kg DOM and afﬁnity at 5-HT2Areceptors labeled with [3H]DOB [13]. The stimulus effects of hallucinogens can be blocked by the selective 5-HT 2antag-onists ketanserin and pirenperone [4,96,104-106]. Blockade by ketanserin and pirenperone, however, does not eliminate the pos-sibility of 5-HT 2Creceptor involvement because those antagonists are relatively nonselective for 5-HT 2Aversus 5-HT 2Csites. Impor-tantly, M100907, a 5-HT 2Aantagonist with high selectivity versus the 5-HT 2Creceptor, blocks stimulus control in animals trained with DOI [97,107-109], DOM [101,110], R-(-)-DOM [111], LSD [98,112-114], and psilocybin [99]. Conversely, neither the selective 5-HT 2Cantagonist SB 242,084 nor the mixed 5-HT 2C/2B antagonists SB 200,646A and SB 206,553 block stimulus control induced by DOI, LSD, or psilocybin [99,107-109,114]. Furthermore, Fiorella et al. [115] tested eleven 5-HT 2antagonists and found the rank order of potencies for blocking R-(-)-DOM substitution in LSD-trained rats parallels their afﬁnities for 5-HT 2A(r = 0. 95) but not for 5-HT 2C (r = -0. 29). Although most phenalkylamines are relatively nonselective for 5-HT 2Aversus 5-HT 2C, 2S,6S-DMBMPP displays 124-fold selectiv-ity for 5-HT 2Areceptors [11]. Although racemic trans-DMBMPP is less selective, it still shows 98-fold higher afﬁnity for 5-HT2Aover 5-HT 2Creceptors. Importantly, trans-DMBMPP fully substitutes in rats trained to discriminate 0. 08 mg/kg LSD. By contrast, several studies have demonstrated that 5-HT 2Cago-nists fail to mimic the hallucinogen discriminative stimulus. Neither 1-(3-triﬂuoromethylphenyl)piperazine (TFMPP) nor m-chlorophenylpiperazine (m CPP) substitute for DOM, DOI, or LSD [103,116,117]. These ﬁndings demonstrate that 5-HT 2Aactivation is sufﬁcient to produce hallucinogen-like stimulus effects. Further-more, 5-HT 2Cactivation does not play a role in mediating the hallucinogen discriminative stimulus cue. The available data pro-vide strong support for the conclusion that hallucinogens evoke a258 259 260 261 262 263 264265266267268269270271272273274275276277278279280281282283284285286287288289290291292 293 294 295 296297298299300301302303 304 305306307308309310311312313314315316317318319320321322323324325326327328329330331332333334335336337338339340341342343344345346347348349350351352353354