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 6 A. L. Halberstadt / Behavioural Brain Research xxx (2014) xxx-xxx Fig. 6. Chemical structure of lisuride. uniform discriminative stimulus cue that is mediated by the 5-HT 2A receptor. Although it is clear that the 5-HT 2Areceptor is primarily responsible for generating hallucinogen-induced stimulus control, interactions with other receptors may contribute to or mod-ify the stimulus effects of hallucinogens. This appears to be especially true for indoleamines, which are much less selec-tive than phenylalkylamines for 5-HT 2Asites. For example, there appears to be a time-dependent dopaminergic component to the LSD discriminative stimulus in rats [118,119]. There is evidence that the 5-HT 1Areceptor also contributes to the discriminative stimulus effects of LSD. 5-HT 1Aagonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and ipaspirone produce partial substitution in rats and mice trained with LSD [98,120-122]. The 5-HT 1Aantagonist WAY-100635 does not alter LSD discrimina-tion in rats [114,122,123], but the 5-HT 1Areceptor may make an more prominent contribution to the LSD cue in mice because dis-crimination can be partially blocked by administration of either WAY-100635 or M100907 [98]. However, the ability of R-(-)-DOB to substitute for LSD in mice is completely blocked by M100907 but not by WAY-100635, demonstrating the stimulus element gener-ated by 5-HT 1Ais a non-essential component of the LSD cue and not a shared aspect of hallucinogen pharmacology. Although cer-tain indolealkylamines produce compound stimulus cues involving both 5-HT 1A- and 5-HT 2A-mediated components [100,124,125], 5-HT1Areceptors do not play a role in the interoceptive effects of psilocybin [99] or 5-methoxy-N,N-diisopropyltryptamine [126]. A potential confound associated with drug discrimination stud-ies is the possibility of “false positive” results. False-positives occur where an animal trained to discriminate a hallucinogen general-izes to a drug that is known to be non-hallucinogenic in humans. Lisuride is one example of drug that can produce false-positive results. Lisuride is an isolysergic acid derivative that is struc-turally similar to LSD (see Fig. 6), and acts as an agonist at a variety of serotonergic, dopaminergic, and adrenergic receptors [12,14,127-130]. Despite the fact that lisuride has high afﬁnity for the 5-HT 2Areceptor and acts as an agonist [32,128,131], it is not hallucinogenic in humans [132-135] and has been used clini-cally to treat migraine and Parkinson's disease. Some studies have found that lisuride produces full substitution in rats trained with either LSD, DOI, or DOM [136-139], but in other studies it pro-duced only partial substitution [129,140]. Although clearly some degree of similarity exists between the stimulus cues evoked by lisuride and classical hallucinogens, there are also subtle differ-ences because rats can be trained to discriminate between lisuride and LSD using three-choice (drug-drug-vehicle) discrimination procedures [141]. Discrimination studies where animals are trained to discriminate between LSD and another drug such as pentobar-bital or cocaine also appear to be less sensitive to lisuride-induced false-positive responses [139]. González-Maeso et al. [28] have proposed that the behavioral differences between LSD and lisuride are due to 5-HT 2Afunctional selectivity. They found LSD and lisuride both activate Gq/11signal-ing via the 5-HT 2Areceptor, but only LSD increases the cortical expression of the immediate early genes egr-1 and egr-2 by acti-vating Gi/oand Src [28]. Therefore, they hypothesized that LSD is hallucinogenic because it is capable of activating speciﬁc signaling mechanisms that are not recruited by lisuride. Alternatively, the reason why lisuride fails to recruit Gi/omay have nothing to do with functional selectivity, and could be a consequence of its low intrin-sic efﬁcacy at 5-HT 2A[31,32,131]. Although animals trained with DOM will generalize to lisuride [137,138], the response to DOM is attenuated when it is co-administered with lisuride [142]. The fact that lisuride induces a response when administered alone but act as an antagonist in the presence of a full agonist (DOM) is consistent with the behavior of a partial agonist. 4. 2. 2. Head twitch response Many mammalian species display a paroxysmal rotational shaking of the head in response to mechanical or chemical irri-tation of the pinna. Mice show a similar behavior, known as the head twitch response (HTR), after administration of hallucinogens ([143] ;[144,145] ). Hallucinogens also induce head twitches in rats, but in that species the behavior often involves both the head and the trunk [146,147]. The responses made by rats are sometimes called wet-dog shakes because they resemble the behavior of a dog drying itself after emerging from the water. It is important to rec-ognize that the HTR can occur in response to administration of 5-HT precursors (e. g., l-tryptophan and l-5-hydroxytryptophan) and drugs that increase 5-HT release (e. g., fenﬂuramine and p-chloroamphetamine), and therefore the behavior is not speciﬁc to hallucinogens [148-151]. Nonetheless, the HTR has gained promi-nence as a behavioral proxy in rodents for human hallucinogen effects because the HTR is one of only a few behaviors that can reliably distinguish hallucinogenic and non-hallucinogenic 5-HT 2A agonists [28]. Indeed, even high doses of lisuride fail to induce the HTR in mice [28,152]. It is well-established that phenylisopropylamine and indoleamine hallucinogens induce the HTR (reviewed by: [20]), but the literature is less clear with regard to phenethylamine hallucinogens. Many studies have demonstrated that mescaline produces head twitch behavior in rats and mice [144,146,153]. It has also been reported that the hallucinogen 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) induces the HTR in mice [154]. Studies in rats, however, have shown 2C-I, 2C-B, and 2,5-dimethoxy-4-methylphenethylamine (2C-D) do not induce the HTR [155]. In contrast to those ﬁndings, we recently reported 2C-I and the N-benzyl derivatives 25I-NBOMe and N-(2,3-methylenedioxybenzyl)-2,5-dimethoxy-4-iodophenethylamine(25I-NBMD) produce dose-dependent increases in HTR behavior in C57BL/6J mice [156]. 25B-NBOMe also induces the HTR in mice [157]. The discrepant ﬁndings with regard to 2C-I and other phenethylamines may reﬂect the fact that mice are more sensitive than rats to the HTR induced by 5-HT 2Apartial agonists. 2C-I has relatively low intrinsic activity at the 5-HT 2Areceptor [155,158], and it may not have sufﬁcient efﬁcacy to provoke head twitches in rats. Nevertheless, we are not aware of any serotonergic hallucinogens that do not produce the HTR in mice. The kinematics of the HTR induced by DOI have been charac-terized in C57BL/6J mice and Sprague-Dawley rats [152]. When mice make a head twitch, the head rapidly twists from side-to-side. Each HTR consists of 5-11 head movements, with the head movements occurring at 78-98 Hz (i. e., each head movement lasts approximately 11 msec). The behavior is similar in rats but in that species the frequency of head movement is lower. One drawback to traditional HTR studies is that they require direct behavioral355 356357358359360361362363364365366367368369370371372373374375376377378379380381382383384385386387388389390391392393394395396397398399400401402403404405 406407408409410411412413414415416417418419420 421 422423424425426427428429430431432433434435436437438439440441442443444445446447448449450451452453454455456457458459460461462463464465466467468469