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 8 A. L. Halberstadt / Behavioural Brain Research xxx (2014) xxx-xxx Table 2 The selective 5-HT 2Aantagonist M100907 blocks the head twitch response induced by hallucinogens in rats and mice. Hallucinogen M100907 Species Reference Drug Dose Routea Potencyb Effective dosec Routea 5-Me O-DMT 30 mg/kg IP ID50= 0. 03 IP Mouse [448] 5-Me O-DMT 10 mg/kg IP 0. 05 mg/kg IP Mouse [29] DPT 3 mg/kg IP 0. 01 mg/kg IP Mouse [100] DOI 2. 5 mg/kg IP ID50= 0. 005 0. 04 mg/kg SC Rat [160] DOI 3 mg/kg IP 1 mg/kg IP Rat [169] R-(-)-DOI 3 mg/kg IP ID50= 0. 01 0. 1 mg/kg SC Mouse [449] DOI 2. 5 mg/kg IP 0. 25 mg/kg IP Mouse [33] DOI 2 mg/kg IP 0. 3 mg/kg IP Mouse [450] DOI 1 mg/kg IP 0. 05 mg/kg IP Mouse [34] DOI 1 mg/kg IP 0. 25 mg/kg SC Mouse [167] DOI 1 mg/kg IP 0. 025 mg/kg SC Mouse [173] 2C-I 3 mg/kg SC ID50= 0. 0045 0. 1 mg/kg SC Mouse [156] 25I-NBOMe 0. 3 mg/kg SC ID50= 0. 0062 0. 1 mg/kg SC Mouse [156] 25I-NBMD 3 mg/kg SC ID50= 0. 0015 0. 1 mg/kg SC Mouse [156] a IP, intraperitoneal; SC, subcutaneous b ID50= inhibitory dose 50in mg/kg. c Dose of M100907 that produced 90-100% blockade of the head twitch response. of exploration because it includes does not distinguish speciﬁc exploratory responses to environmental stimuli from other types of motor activity [199]. Given the complexity of hallucinogen effects, it is not surprising that hallucinogens cannot be distinguished from other drug classes using traditional open ﬁeld locomotor mea-sures [144]. However, multivariate assessment methods have been more successful. One example is the Behavioral Pattern Monitor (BPM), which combines features from activity chambers and hole-boards and provides quantitative as well as qualitative measures of the spatial and temporal structure of activity [200,201]. BPM studies have shown hallucinogens produce a very characteristic proﬁle of behavioral effects. When rats are tested in unfamiliar BPM chambers after administration of hallucinogens (including mesca-line, DOM, DOI, LSD, DMT, 5-Me O-DMT, and psilocin), the animals display reduced amounts of locomotor activity, rearings, and hole-pokes at the beginning of the test session, and avoidance of the center of the BPM chamber is increased [202-205]. Most of these effects are markedly diminished in animals habituated to the BPM chambers, indicating that hallucinogens act by enhancing neopho-bia. The ability of hallucinogens to increase the avoidance of novel (and potentially threatening) test chambers by rats may be anal-ogous to the enhanced sensitivity and reactivity to environmental stimuli that occurs in humans [206]. Extensive testing has conﬁrmed this pattern of effects in the BPM is highly speciﬁc to hallucinogens [200,207-210]. For example, although 8-OH-DPAT and other selective 5-HT 1Aagonists reduce locomotor activity, rearings, and holepokes in rats, these effects are not inﬂuenced by environmental familiarity and hence are likely to reﬂect sedation [208]. When Adams and Geyer [211] compared lisuride and LSD in the BPM, they found the two com-pounds produce markedly different patterns of effects. Lisuride produces effects that are similar to those of apomorphine and other dopamine agonists, with sedative effects occurring at low doses and perseverative patterns of hyperactivity occurring at higher doses. The 5-HT 2Areceptor is responsible for mediating most of the effects of hallucinogens in the rat BPM. It was ﬁrst shown that ritanserin and ketanserin block the effects of mescaline, DOM, and DOI in the BPM, indicating 5-HT 2involvement [204]. Later studies demonstrated that the effects of DOI are blocked by M100907 but not by SER-082 [212], conﬁrming mediation by 5-HT 2A. The action of indoleamine hallucinogens in the BPM is more complex mech-anistically, with 5-HT 1Aand 5-HT 2Areceptors contributing to the effects of LSD and 5-Me O-DMT [205,213-215]. Hallucinogens have also been tested in a version of the BPM designed for mice [216]. In contrast to rats, phenylalkylamineand indolealkylamine hallucinogens produce disparate effects on exploratory and investigatory behavior in C57BL/6J mice. Phenylalkylamines, including DOI, mescaline, and TCB-2, inhibit investigatory behavior and alter locomotor activity in a dose-dependent manner, increasing activity at low to moderate doses and reducing activity at high doses [217,218]. Other groups have reported similar ﬁndings with DOM and DOI in mice [146,219-221]. The increase in locomotor activity induced by 1 mg/kg DOI, 25 mg/kg mescaline, or 3 mg/kg TCB-2 is blocked by low doses of M100907 and is absent in 5-HT 2Aknockout mice. By contrast, the reduction of locomotor activity induced by 10 mg/kg DOI is attenu-ated by SER-082. Taken together, it appears that 5-HT 2Aand 5-HT 2C receptors have countervailing effects on locomotor activity, with 5-HT2Aactivation increasing activity and 5-HT 2Cactivation reducing activity. Administration of psilocin and 5-Me O-DMT to C57BL/6J mice reduces locomotor activity and investigatory behavior [166]. These effects are blocked by WAY-100635 but are unaffected by SB 242,084 or by 5-HT 2Agene deletion. Similarly, 5-Me O-DMT has no effect on activity in 5-HT 1Aknockout mice [222]. Hence, whereas the phenylalkylamines act through 5-HT 2sites to alter behavior in the mouse BPM, indoleamine hallucinogens appear to act via the 5-HT 1Areceptor. 4. 3. Tolerance studies As noted in Section 3. 2, serotonergic hallucinogens produce a profound degree of tolerance and cross-tolerance in animals and humans. Although very little is known about the mechanisms lead-ing to the development of tolerance to hallucinogens in humans, there is evidence in animals that tolerance is linked to 5-HT 2A downregulation. Rats treated repeatedly with DOM, LSD, or psilocin show a signiﬁcantly lowered density of 5-HT 2Areceptors in sev-eral brain regions [223-225]. Binding to 5-HT 1A, 5-HT 1B, /H92512, /H92521, or D2receptors is unaffected. Another study demonstrated that treat-ment with 1 mg/kg DOI for 8 days produced a signiﬁcant reduction in the density of 5-HT 2Areceptors in the cortex, but there was no change in 5-HT 2Creceptor expression [109]. An identical treatment regimen caused tolerance to develop in rats trained to discriminate DOI. Likewise, there is a signiﬁcant reduction of 5-HT 2A-stimulated [35S]GTP /H9253S binding in the medial prefrontal cortex (m PFC) and anterior cingulate cortex in rats treated with LSD (0. 13 mg/kg/day) for 5 days [226] ; this indicates tolerance to LSD is associated with a reduction of 5-HT 2Asignaling. Although most hallucinogens produce tolerance in humans, DMT seems to be the exception. 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