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 7 Fig. 7. Effect of pretreatment with the selective 5-HT 2Aantagonist M100907 on the head twitch response induced by 0. 3 mg/kg 25I-NBOMe in C57BL/6J mice. Data are presented as group means ± SEM for 20-min test sessions. **p < 0. 01, signiﬁcant difference from. 25I-NBOMe alone. Data from Ref. [156]. observation that can be extremely time-consuming. However, as we have recently demonstrated, it is possible to detect the behavior with a head-mounted magnet and a magnetometer coil, provid-ing a highly sensitive, semi-automated assessment of the behavior [152,156]. The HTR induced by hallucinogens and other 5-HT agonists is closely linked to 5-HT 2Aactivation. It was proposed in 1982 that the mescaline-induced HTR is mediated by the 5-HT 2Areceptor, based on the fact that the relative potency of 5-HT antagonists to block the behavior is correlated (r = 0. 875) with their 5-HT 2Aafﬁn-ity [159]. Similar ﬁndings were later reported for the HTR induced by DOI [160,161]. Numerous studies have shown M100907 blocks the HTR induced by hallucinogens (Table 2). For example, we found M100907 blocks the HTR induced by the hallucinogen 25I-NBOMe with an ID50= 6. 2 /H9262g/kg (Fig. 7; [156] ). Based on ex vivo binding data it is unlikely M100907 produces any appreciable occupation of 5-HT 2Creceptors at that dose level [162]. Studies have also demon-strated that the highly selective 5-HT 2Aantagonist MDL 11,939 blocks the HTR induced by DOI and TCB-2 in mice [163,164]. Mice lacking the 5-HT 2Areceptor gene do not produce head twitches in response to mescaline, DOI, DOM, LSD, DMT, 5-Me O-DMT, psilocin, or 1-methylpsilocin [28,165,166], although the response can be res-cued by selectively restoring the 5-HT 2Areceptor gene to cortical regions [28]. By contrast, 1 mg/kg DOI produces a signiﬁcant (albeit somewhat blunted) HTR in 5-HT 2Cknockout mice [167]. The fact that DOI can provoke head twitches in 5-HT 2Cknockout mice but not in 5-HT 2Aknockout mice strongly indicates the 5-HT 2Arecep-tor is the member of the 5-HT 2family responsible for mediating the HTR. Similarly, there is a consensus in the literature that the ability of DOI to induce the HTR is not blocked by selective 5-HT 2C antagonists or mixed 5-HT 2C/2B antagonists [160,168-171]. Although it has been conclusively established that the 5-HT2Creceptor is not required for generation of the HTR, there is some evidence that 5-HT 2Csites may play a modulatory role. 5-HT 2agonists that are selective for 5-HT 2Csites, such as (S)-6-chloro-5-ﬂuoro-/H9251-methyl-1 H-indole-1-ethanamine (Ro 60-0175), 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), and m CPP, do not induce the HTR in rats unless administered in combination with the 5-HT 2Cantagonist SB 242,084 [170]. There is also evidence thatthe ability of DOI to induce the HTR is signiﬁcantly attenuated by pretreatment with selective 5-HT 2Cagonists, including Ro 60-0175, CP-809,101, and m CPP [160,171-173]. These ﬁndings indicate 5-HT2Cactivation suppresses expression of the HTR. Likewise, DOI produces a biphasic dose-response curve in NIH Swiss and Swiss-Webster mice, and SB 242084 reportedly shifts the descending arm of the DOI response to the right [171]. Here again there is evi-dence that the 5-HT 2Creceptor can inhibit the HTR. On the other hand, as was noted above, Canal and colleagues have reported that 5-HT 2Cknockout mice show a blunted HTR to 1 mg/kg DOI [167]. Furthermore, in contrast to many other reports, the same investigators found pretreatment with SB 242,084 or SB 206,553 diminished the magnitude of the HTR induced by 1 mg/kg DOI in C57BL/6J and DBA/2J mice [167,173]. It is not clear why the 5-HT 2C receptor attenuates the HTR in certain studies and augments the response in others, but Fantegrossi et al. [171] have argued these differences may be strain dependent. For example, there are strain differences in the editing of 5-HT 2Cm RNA [174,175]. Since 5-HT 2C editing can inﬂuence the downstream coupling of the receptor [176], the nature of the interactions between 5-HT 2Aand 5-HT 2C could potentially vary by mouse strain. 4. 2. 3. Prepulse inhibition of startle Prepulse inhibition (PPI) refers to the phenomenon where a weak prestimulus presented prior to a startling stimulus will atten-uate the startle response; PPI is often used as an operational measure of sensorimotor gating, and reﬂects central mechanisms that ﬁlter out irrelevant or distracting sensory stimuli [177]. Rats treated with DOI [178,179], DOB [180], LSD [181,182], mescaline [183], and 2C-B [184] show reductions in PPI. These effects can be blocked by M100907 and MDL 11,939 [179,181,182,185]. By con-trast, neither SB 242,084 nor the 5-HT 2C/2B antagonist SER-082 are effective. Although one study found haloperidol can block the PPI disruption produced by hallucinogens [178], this was not replicated by subsequent investigations [181,186]. Lisuride also disrupts PPI in rats, but this effect is blocked by the D2/3antagonist raclopride and not by MDL 11,939 [182]. 4. 2. 4. Interval timing Temporal perception can be markedly altered by hallucinogens. Subjects under the inﬂuence of mescaline and LSD often report that their sense of time appears to speed up or slow down, or they may experience a sensation of timelessness [187-191]. Psilocybin also alters performance on laboratory measures of timing [192]. Temporal perception can be assessed in rodents using interval timing paradigms. For example, in the free-operant psychophys-ical task, animals are trained to respond on two levers, and they must respond on one lever during the ﬁrst half of the trial and on the other lever during the second half [193]. In the discrete-trials task, animals are trained to press one lever in response to short duration stimuli and another lever in response to long duration stimuli, and are then challenged with a variety of stimulus dura-tions [194]. DOI disrupts the performance of rats in both of these tasks [195-197]. Although DOI affects performance in the discrete trials task, it does not affect performance in a similar task where rats have to discriminate different light intensities, indicating that DOI is speciﬁcally inﬂuencing temporal perception and not disrupting stimulus control or attentional processes [198]. The effect of DOI in the discrete-trials task and that free-operant task are blocked by ketanserin and M100907 [196,197], demonstrating the involve-ment of 5-HT 2A. 4. 2. 5. Exploratory and investigatory behavior Measures of locomotor activity are often used to character-ize the effects of psychoactive drugs on exploratory behavior. Locomotion alone, however, is not necessarily a reliable measure470 471472473474475476477478479480481482483484485486487488489490491492493494495496497498499500501502503504505506507508509 510511512513514515516517518519520521522523524525526527528529 530 531532533534535536537538539540541542543544 545 546547548549550551552553554555556557558559560561562563564565566567 568 569570571