Multiple Receptors Contribute to the Behavioral Effects of Indoleamine Hallucinogens

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Neuropharmacology 61 (2011) 364e381

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Neuropharmacology

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Invited review

Multiple receptors contribute to the behavioral effects of indoleaminehallucinogens

Adam L. Halberstadt*, Mark A. GeyerDepartment of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States

a r t i c l e i n f o

Article history:Received 29 August 2010Received in revised form3 December 2010Accepted 10 January 2011

Keywords:HallucinogenLSDPsilocybinSerotoninDrug discriminationLocomotor activityHead twitch5-HT1A receptor

* Corresponding author. Tel.: þ1 619 471 9358; faxE-mail address: [email protected] (A.L. Halbersta

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a b s t r a c t

Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugsinclude phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), andindoleamines such as (þ)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences inchemical structure, the two classes of hallucinogens produce remarkably similar subjective effects inhumans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT2 receptoragonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There isextensive evidence, from both animal and human studies, that the characteristic effects of hallucinogensare mediated by interactions with the 5-HT2A receptor. Nevertheless, there is also evidence that inter-actions with other receptor sites contribute to the psychopharmacological and behavioral effects of theindoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indole-amine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT2 and non-5-HT2 receptors.

This article is part of a Special Issue entitled ‘Serotonin: The New Wave’.� 2011 Elsevier Ltd. All rights reserved.

1. Introduction

Hallucinogens are a class of pharmacological agents thatincrease the intensity and lability of affective responses andproduce profound distortions of perceptual processes encompass-ing the visual, auditory and tactile modalities. These compounds, inthe form of botanical preparations, have been used by humans forthousands of years to induce states of mysticism and inebriation(Schultes and Hofmann, 1980). Notable examples include thepeyote cactus (Lophophora williamsii), which contains mescaline;teonanácatl mushrooms containing psilocin and psilocybin; andayahuasca, a decoction prepared from the bark of b-carboline-containing Banisteriopsis species in combination with plants con-taining N,N-dimethyltryptamine (DMT). Hallucinogen use hasremained relatively stable over the past decades, but these drugsare becoming more widely available with increased access topsychoactive natural products and the extant knowledge base onthe use and preparation of these compounds introduced throughthe internet. For example, the sacramental use of ayahuasca origi-nated in South America, but in recent years the use of this hallu-cinogen has spread to Europe and North America. Research into theprofound effects of hallucinogens on perception has shaped our

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neurobiological understanding of consciousness and informed ourunderstanding of neuropsychiatric disorders. For example, thenotion that psychotic states seen in schizophrenia may involveserotonin (5-HT) dysfunction arose in part from the observedpsychedelic effects of (þ)-lysergic acid diethylamide (LSD) andother classical serotonergic hallucinogens (Geyer and Vollenweider,2008; Quednow et al., 2010).

2. Chemical structure of hallucinogens

As shown in Fig.1, classical hallucinogens belong to two classes ofchemicals: (1) indoleamines, including the ergoline LSD and indo-lealkylamines such as DMT, 5-methoxy-DMT (5-MeO-DMT), psilo-cin, and4-phosphoryloxy-DMT(psilocybin); (2) phenylalkylamines,such as the phenethylamines mescaline and 2,5-dimethoxy-4-bromophenethylamine (2C-B), and the phenylisopropylamines2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), and 2,5-dimethoxy-4-bromoamphet-amine (DOB). Recently, highly potent rigid analogs ofhallucinogenic phenylalkylamines have been synthesized in whichthe alkoxy ring substituents are incorporated into furanyl and/orpyranyl rings (e.g., 1-(8-bromobenzo[1,2-b;4,5-b]difuran-4-yl)-2-aminopropane) (“Bromo-Dragonfly”; Parker et al., 1998), or theethylamine side chain is conformationally constrained by incorpo-ration into a cycloalkane ring (e.g., TCB-2; McLean et al., 2006).

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A.L. Halberstadt, M.A. Geyer / Neuropharmacology 61 (2011) 364e381 365

Radioligand binding studies have shown that phenylalkylaminehallucinogens are highly selective for 5-HT2 sites (5-HT2A, 5-HT2B,and 5-HT2C receptors), and some of these compounds display over1000-fold selectivity for agonist-labeled 5-HT2 receptors versus5-HT1 sites (Titeler et al., 1988; Herrick-Davis and Titeler, 1988;Pierce and Peroutka, 1989). By contrast, indolealkylamines arerelatively non-selective for 5-HT receptors, displaying moderate tohigh affinity for 5-HT1 and 5-HT2 subtypes (Pierce and Peroutka,1989; McKenna et al., 1990; Deliganis et al., 1991; Blair et al.,2000). Tables 1 and 2 show the binding profiles of psilocin andDMT, respectively, for 5-HT receptors. It has been reported that DMTis a s1 receptor agonist with moderate affinity (KD¼ 14.75 mM;Fontanilla et al., 2009); however, it is not clear whether this inter-action contributes to the effects of DMT because the affinity of thedrug for 5-HT1A and 5-HT2A receptors is w2-orders of magnitudegreater than for s1 binding sites (see Table 2). Furthermore, other s1receptor agonists (e.g., cocaine) are not hallucinogenic, making itunlikely that s1 activation byDMT plays a primary role inmediatingits hallucinogenic effects. Certain indolealkylamines, includingDMT,N,N-dipropyltryptamine (DPT), 5-MeO-DMT, and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) block 5-HT uptake at micro-molar concentrations (Nagai et al., 2007; Sogawa et al., 2007; Cozziet al., 2009) and serve as substrates for the 5-HT transporter (Cozzi

Fig. 1. Chemical structures of indoleamine

et al., 2009). As shown in Table 3, LSD binds to a number of 5-HTreceptors with high (nanomolar) affinity (Peroutka, 1994), and alsointeracts with dopaminergic and adrenergic receptors.

3. Unitary effects of serotonergic hallucinogens in humans

Despite differences in their chemical structure, the classicalhallucinogens LSD, psilocybin, mescaline, and DOM produceextremely similar experiences in humans (Isbell, 1959; Wolbachet al., 1962a,b; Rosenberg et al., 1964; Snyder et al., 1967; Hollisteret al., 1969; Shulgin and Shulgin, 1991, 1997). By contrast, thesubjective effects of hallucinogens are readily distinguished fromthe effects of drugs in other pharmacological classes, includinganticholinergics, stimulants, entactogens, and NMDA antagonists(Gershon and Olariu, 1960; Rosenberg et al., 1963; Gouzoulis-Mayfrank et al., 1999, 2005). Tolerance rapidly develops to theeffects of hallucinogens, and indoleamine and phenylalkylaminehallucinogens produce cross-tolerance (Balestrieri and Fontanari,1959; Abramson et al., 1960; Isbell et al., 1961; Wolbach et al.,1962a). The similarity of their psychopharmacological effects andtheir ability to produce cross-tolerance indicate that indoleamineand phenylalkylamine hallucinogens act through a commonreceptor mechanism. It is generally accepted, based on evidence

and phenylalkylamine hallucinogens.

Table 1Binding of psilocin to 5-HT and other monoaminereceptors.

Binding site Ki (nM)a

SERT 38015-HT1A 567.45-HT1B 219.65-HT1D 36.45-HT2A 107.25-HT2B 4.65-HT2C 97.35-HT3 >10,0005-HT5 83.75-HT6 57.05-HT7 3.5a1A >10,000a1B >10,000a2A 1379a2B 1894a2C >10,000b1 >10,000D1 >10,000D2 >10,000D3 2645D4 >10,000D5 >10,000H1 304.6

a Data from the NIMH Psychoactive Drug ScreeningProgram (http://pdsp.med.unc.edu).

Table 3Binding of (þ)-LSD to 5-HT and other monoaminereceptors.


5-HT1A 1.15-HT1B 3.95-HT1e 93.05-HT2A 3.55-HT2B 30.05-HT2C 5.55-HT5a 9.05-HT6 6.95-HT7 6.6a2 37b

b1 140b2 740D1 180D2 120D3 27D4 56D5 340H1 1540

a Data from: Nichols et al., 2002.b Data from: Marona-Lewicka and Nichols, 1995.

A.L. Halberstadt, M.A. Geyer / Neuropharmacology 61 (2011) 364e381366

reviewed below, that the unitary mechanism responsible for theeffects of serotonergic hallucinogens is activation of the 5-HT2Areceptor (Halberstadt and Nichols, 2010; Nichols, 2004). Given thehigh affinity and selectivity of DOB and other phenylisopropylaminehallucinogens for 5-HT2 subtypes (Mos et al., 1992; Pierce andPeroutka, 1989; Herrick-Davis and Titeler, 1988; Leysen, 1989;Titeler et al., 1988), it follows that a member of the 5-HT2 receptorfamily is likely to be responsible for mediating the effects of thesecompounds. Nevertheless, although the unitary pharmacologicaleffects of hallucinogens are mediated by the 5-HT2A receptor, thisdoes not preclude the possibility that the interaction of indole-amines with non-5-HT2 receptors does have psychopharmacolog-ical and behavioral consequences. This article will review theevidence showing that both 5-HT2 and non-5-HT2 receptorscontribute to the behavioral effects of indoleamine hallucinogens.

4. Recent clinical studies of hallucinogens

Although neglected for several decades, clinical testing ofhallucinogens has resumed in recent years (Vollenweider andKometer, 2010). The majority of this clinical work has focused onpsilocybin (Vollenweider et al., 1997; Gouzoulis-Mayfrank et al.,1999; Moreno et al., 2006; Griffiths et al., 2006; Grob et al., 2011),

Table 2Binding of DMT to 5-HT receptors.


5-HT1A 1835-HT1B 1295-HT1D 395-HT1e 5175-HT2A 1275-HT2B 1845-HT2C 3605-HT5a 21355-HT6 4645-HT7a 206

a Data from: Keiser et al., 2009.

althoughmescaline (Hermle et al., 1992, 1998) and DMT (Strassmanand Qualls, 1994; Strassman et al., 1994; Gouzoulis-Mayfrank et al.,2005; Heekeren et al., 2007) have also been studied.

Most of the studies listed above were designed to characterizethe subjective and physiological effects of hallucinogens. Studieshave also examined whether psilocybin is effective at reducingsymptoms in patients with obsessive-compulsive disorder (OCD)(Moreno et al., 2006), and anxiety in terminal cancer patients (Grobet al., 2011). Other groups have revisited the hypothesis thathallucinogens can be used to model the symptoms of psychosis innormal subjects. Gouzoulis-Mayfrank and colleagues (Gouzoulis-Mayfrank et al., 2005) conducted a double-blind crossover studycomparing the subjective effects of DMT with those of thenoncompetitive NMDA antagonist S-ketamine. This study isnotable because it demonstrated that DMT produced effects thatprimarily resembled the positive symptoms of schizophrenia,whereas the effect of S-ketamine resembled the negative andcognitive symptoms of schizophrenia. In addition to confirmingthat serotonergic and glutamatergic hallucinogens evoke dis-tinguisible psychological effects, these findings clearly demonstratethat both drug classes can be used to model different aspects ofschizophrenia.

Vollenweider and colleagues have conducted a series of studiesexamining the contribution of 5-HT and dopamine (DA) receptorsto the subjective and behavioral effects of psilocybin in humanvolunteers. These studies have demonstrated that most of thesubjective effects of psilocybin are blocked by the 5-HT2 antagonistketanserin (20e50 mg, p.o.; Vollenweider et al., 1998; Carter et al.,2005, 2007). Similar findings were reported for the mixed D2/5-HT2A antagonist risperidone (0.5e1.0 mg, p.o.), whereas the DAD2 antagonist haloperidol (0.021 mg, i.v.) produced very littleblockade of psilocybin effects (Vollenweider et al., 1998). Takentogether, these findings confirm that the hallucinogenic effects ofpsilocybin are primarily mediated by the 5-HT2A receptor. Thisconclusion is supported by the results of a recent PET study withthe 5-HT2A ligand [18F]altanserin, which demonstrated that theintensity of psilocybin-induced subjective effects is directly corre-lated with 5-HT2A occupation in the anterior cingulate and medialprefrontal cortices (Quednow et al., 2010). Importantly, however,ketanserin does not block some of the effects of psilocybin,including slowing of binocular rivalry, impairment of multipleobject tracking, and reduction of measures of arousal and vigilance

http://pdsp.med.unc.edu


(Carter et al., 2005, 2007). Although the 5-HT2A receptor isresponsible for most of the effects of psilocybin, it is clear thatinteractions with non-5-HT2A receptors also contribute to theeffects of the drug.

The mechanism for the subjective effects of DMT has also beeninvestigated clinically. Blockade studies with low doses of the non-selective 5-HT2 antagonist cyproheptadine produced inconclusiveresults (Tueting et al., 1992), and the sedative effects of cyprohep-tadine precluded testing higher doses (Strassman, 2001). Bycontrast, Strassman has reported that the mixed 5-HT1A/1B/b-adrenergic antagonist pindolol markedly potentiates thesubjective effects of DMT (Strassman, 1996). Since DMT has onlylow affinity for b-adrenergic receptors, this finding indicates thatinteractions with 5-HT1A receptors serve to attenuate the action ofDMT at the 5-HT2A receptor. It is likely that the effects of otherindoleamines at the 5-HT2A receptor are also modulated by their5-HT1A agonist activity.

5. Presynaptic versus postsynaptic effects of hallucinogens

It was recognized as early as 1954 that the profound intoxicatingeffects of LSD are likely to result from interactions with serotonin(5-hydroxytryptamine, 5-HT) in the brain (Woolley and Shaw,1954). Although it was soon widely accepted that the hallucino-genic effects of LSD result from effects on central serotonergicsystems, it took several more years for researchers to find evidencethat directly supported this contention. In 1968, Aghajanian andcolleagues found that intravenous LSD (10e20 mg/kg) completelyinhibits the firing of serotonergic neurons in the dorsal (DRN) andmedian (MRN) raphe nuclei in rats (Aghajanian et al., 1970, 1968). Itwas subsequently demonstrated that psilocin, DMT, and 5-MeO-DMT-induced similar raphe-depressant effects in rats and cats(Aghajanian et al., 1970; Aghajanian and Haigler, 1975; Mosko andJacobs, 1977; Trulson et al., 1981). The microiontophoretic appli-cation of these agents directly to raphe cells allowed workers todetermine that the depressant effects of indoleamines upon raphefiring are mediated by somatodendritic 5-HT autoreceptors(Aghajanian and Haigler, 1975; de Montigny and Aghajanian, 1977).

There is extensive evidence that LSD and other indoleaminehallucinogens inhibit the firing of serotonergic DRN neurons byactivating 5-HT1A receptors. Like the indoleamine hallucinogens,5-HT1A receptor-selective agonists (e.g., 8-hydroxy-2-(di-n-propy-lamino)tetralin (8-OH-DPAT), ipsapirone, gepirone, and buspirone)inhibit DRN firing (Fornal et al., 1994; Blier and de Montigny, 1990;VanderMaelen et al., 1986; Sprouse and Aghajanian, 1985; deMontigny et al., 1984). It has also been shown that 5-HT1A antag-onists block the inhibition of DRN neuronal activity induced by LSD(Romero et al., 1996; Quérée et al., 2009). As noted earlier, hallu-cinogenic indoleamines, including LSD, psilocin, DMT, 5-MeO-DMT,N,N-diethyltryptamine (DET), and N,N-dipropyltryptamine (DPT),bind to the 5-HT1A receptor with moderate to high affinity (Pierceand Peroutka, 1989; McKenna et al., 1990), and are potentagonists at 5-HT1A receptors negatively coupled to adenylatecyclase (DeVivo and Maayani, 1986; Dumuis et al., 1988; Deliganiset al., 1991; Blair et al., 2000; Thiagaraj et al., 2005). LSD is esti-mated to suppress DRN firing in rats with an EC50 of 4.6 nM(Bennett and Aghajanian, 1976), consistent with the reportedaffinity of LSD for the rat 5-HT1A receptor, with Ki values rangingfrom 3.9 to 5.1 nM (Monte et al., 1995; Huang et al., 1994; Peroutka,1986). Anatomical studies have confirmed that 5-HT1A receptorsare primarily expressed in the DRN and MRN as somatodendriticautoreceptors (Mengod et al., 1996; Pompeiano et al., 1992; Pazosand Palacios, 1985). Indeed, following the destruction of 5-HT-containing nerve cells by intracerebral injection of the selectiveserotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), the

density of [3H]8-OH-DPAT-labeled 5-HT1A binding sites in the DRNis greatly reduced (Pranzatelli et al., 1994; Hensler et al., 1991;Verge et al., 1985).

In addition to their depressant effects upon raphe activity, LSD,psilocin, DMT, and 5-MeO-DMT inhibit cells downstream from theraphe nuclei by stimulating postsynaptic 5-HT1A receptors. Theseagents are approximately 4e5 times more potent at presynapticthan postsynaptic sites (de Montigny and Aghajanian, 1977;Aghajanian and Haigler, 1975; Haigler and Aghajanian, 1974), andthus they tend to preferentially inhibit DRN cells while leavingdownstream neurons relatively unaffected. The preferential actionof indoleamine hallucinogens on somatodendritic 5-HT1A autor-eceptors contrasts with the effect of 5-HT, which inhibits cells in theDRN and in DRN target regionswith similar potencies (deMontignyand Aghajanian, 1977; Haigler and Aghajanian, 1974). The ability ofindoleamine hallucinogens to selectively inhibit DRN cells probablyresults from themarked (>50%) 5-HT1A receptor reserve present onthe cell bodies of serotonergic raphe cells (Cox et al., 1993) but noton postsynaptic membranes (Yocca et al., 1992). It has been shownthat 5-HT1A receptors in the DRN and hippocampus couple pref-erentially to Gi3 and Go, respectively (Mannoury La Cour et al.,2006), and this difference in G-protein coupling may alsocontribute to the different efficacies of indoleamine hallucinogensat presynaptic versus postsynaptic sites. The evidence outlinedabove led to the hypothesis that by selectively depressing theactivity of neurons in the DRN and thereby decreasing 5-HT release,hallucinogens remove the tonic inhibition of downstream neuronsmediated by 5-HT. It was theorized that LSD and related agentsinduce hallucinogenic effects indirectly by disinhibiting brainregions targeted by DRN efferents. The observation by Haigler andAghajanian (1974) that LSD, at an intravenous dose of 20 mg/kg,accelerates the firing of cells targeted by inhibitory DRN projectionsprovided additional support for the “presynaptic hypothesis” ofhallucinogen action.

Further research identified several problems with thishypothesis:

1. Trulson and coworkers observed dissociations between thebehavioral and raphe inhibitory effects of hallucinogens. Thedepression of DRN neuronal firing induced by LSD in cats istransient and does not correspond to the time course of LSD-induced behavioral effects (Trulson et al., 1981; Trulson andJacobs, 1979b). Furthermore, low doses of LSD and psilocinproduce significant behavioral alterations but have negligibleeffects on DRN unit activity (Trulson et al., 1981).

2. Although humans and laboratory animals develop tolerance tothe effects of LSD and other hallucinogens after chronicadministration, DRN neurons fail to develop a tolerance to theinhibitory effects of those drugs (Trulson et al., 1981; Lee andGeyer, 1980; Trulson et al., 1977). By contrast, 5-HT2A recep-tors are downregulated by treatment with LSD, psilocybin, DOI,DOB, and DOM (Owens et al., 1991; Buckholtz et al., 1990;Leysen et al., 1989; McKenna et al., 1989; Buckholtz et al.,1985; Trulson and Jacobs, 1979a).

3. Antagonists at postsynaptic 5-HT receptors, including main-serin, ketanserin, and metergoline, attenuate many of thebehavioral effects of LSD but fail to block the effect of that drugupon DRN activity (Trulson, 1986; Jacobs, 1985; Heym et al.,1984).

4. Phenylalkylamine hallucinogens such as mescaline, DOI, andDOM have inconsistent effects upon raphe firing (Penington,1996; Penington and Reiffenstein, 1986; Trulson et al., 1981;Haigler and Aghajanian, 1973; Aghajanian et al., 1969), andbind to 5-HT1A sites with negligible affinity (Leysen, 1989;Pierce and Peroutka, 1989; Titeler et al., 1988). Furthermore,

Fig. 2. Relationship between binding affinity at [3H]DOB-labeled 5-HT2A receptors in ratfrontal cortex and ED50 values for stimulus generalization in rats trained with 1.0 mg/kgDOM(r¼ 0.90). Data taken from: Titeleret al.,1988.DMA, dimethoxyamphetamine;DOB,2,5-dimethoxy-4-bromoamphetamine; DOBU, 2,5-dimethoxy-4-butylamphetamine;DOET, 2,5-dimethoxy-4-ethylamphetamine; DOI, 2,5-dimethoxy-4-iodoamphetamine;DOM, 2,5-dimethoxy-4-methylamphetamine; DOPR, 2,5-dimethoxy-4-propylamphet-amine; LSD, lysergic acid diethylamide; MDA, 3,4-methylenedioxyamphetamine; MEM,2,5-dimethoxy-4-ethoxyamphetamine; TMA, trimethoxyamphetamine.


DOM is completely inactive as a 5-HT1A receptor agonist(Pauwels et al., 1993).

5. Despite the fact that the LSD congener lisuride has high affinityfor the 5-HT1A receptor (Millan et al., 2002; Marona-Lewickaet al., 2002) and inhibits the firing of DRN neurons whenadministered to rats at intravenous doses of 1e5 mg/kg (Pieriet al., 1983; Rogawski and Aghajanian, 1979; Laurent andPieri, 1978), it is not a hallucinogenic drug in humans(Herrmann et al., 1977).

6. Even though theycompletely suppress thefiring of serotonergicneurons in the raphe nuclei, selective 5-HT1A receptor agonistsare not hallucinogenic when administered to humans. Indeed,buspirone and ipsapirone are used clinically as anxiolyticagents. As was found with the indoleamine hallucinogens,8-OH-DPAT and gepirone act preferentially on presynaptic5-HT1A sites (Blier et al., 1993). Hence, the ability of hallucino-genic indoleamines to selectively activate presynaptic 5-HT1Areceptors per se is not responsible for their psychoactive effects.

7. If the effects of hallucinogens are mediated by inhibition ofraphe neurons, then destruction of the raphe nuclei shouldevoke behavioral alterations identical to those produced byhallucinogens. Likewise, hallucinogens should have onlyminimal effects on behavior when administered to animalswith raphe lesions because the anatomical locus where theseagents act is not intact. However, lesioning the midbrain raphenuclei of laboratory animals does not produce hallucinogen-like behavioral effects (Appel et al., 1970) nor does it diminishthe effectiveness of mescaline or other hallucinogens (Geyeret al., 1979; Browne, 1978).

All of the aforementioned evidence contradicts the hypothesisthat inhibition of the raphe nuclei plays a primarily mechanisticrole in the effects of hallucinogenic agents. The ability to evokea cessation of serotonergic cell firing is clearly an epiphenomenonunrelated to the production of hallucinogenic activity. Importantly,some of the evidence against the presynaptic hypothesis indicatedthat postsynaptic 5-HT receptor mechanisms are likely involved inmediating the effects of this class of agents. Hence, the presynaptichypothesis of hallucinogen action is untenable and has correctlybeen abandoned in favor of a postsynaptic mechanism.

6. Behavioral effects of hallucinogens

6.1. Drug discrimination

The phenomenon of drug-induced stimulus control has beenapplied successfully to the study of hallucinogens, and thesemethodologies have proven especially useful when applied to themechanistic analysis of these compounds. Hirschhorn and Winterfirst demonstrated in 1971 that rats can be trained to discriminatemescaline and LSD from saline using standard two-lever operantprocedures (Hirschhorn andWinter, 1971), and it was subsequentlyshown that many classical hallucinogenic drugs (e.g., LSD, mesca-line, DOM, DOB, DOI, psilocybin, 5-MeO-DMT, and DPT) are capableof serving as discriminative stimuli in the drug discriminationparadigm (Glennon et al., 1979, 1982, 1983a; Young et al., 1981;Glennon, 1988; Winter et al., 2007; Fantegrossi et al., 2008). Theinteroceptive stimulus cues evoked by a variety of hallucinogenicagents in laboratory animals appear to be uniform in nature, ascross-generalization occurs between all of these drugs. Most drugdiscrimination studies with hallucinogens have employed rats,although pigeons (Jarbe, 1980), mice (Smith et al., 2003;Benneyworth et al., 2005; Winter et al., 2005), and rhesusmonkeys (Li et al., 2008, 2009) have also been used. The drugdiscrimination assay displays pronounced pharmacological

specificity, and members of other drug classes, including opiates,sedatives, stimulants, NMDA antagonists (e.g., phencyclidine andketamine), salvinorin A, cannabinoids, and anticholinergics,consistently fail to evoke hallucinogen-like stimulus effects(Glennon et al., 1982; Appel and Cunningham, 1986; Killinger et al.,2010). There is also evidence demonstrating that hallucinogens and5-HT1A receptor-selective agonists produce distinct interoceptivecues (Koek and Colpaert, 1989).

6.1.1. Involvement of 5-HT2A receptors in the stimulus effects ofhallucinogens

The hallucinogen discriminative stimulus is blocked to varyingdegrees by a variety of non-selective 5-HT antagonists, includingmethysergide, metergoline, mianserin, methiothepin, and cypro-heptadine (Fiorella et al.,1995b; Schreiber et al.,1994;Glennon et al.,1986; Colpaert et al., 1982; Kuhn et al., 1978). The high affinity,selective 5-HT2 receptorantagonists pirenperoneandketanserin arealso potent and highly efficacious antagonists of the discriminativestimulus properties of DOM and LSD (Colpaert and Janssen, 1983;Colpaert et al., 1982), and of DOM-stimulus generalization to LSD,mescaline, and 5-MeO-DMT (Glennon et al., 1983b). Based on thesefindings, Glennon and colleagues (Glennon et al., 1983b) proposedthat the stimulus effects of hallucinogenic drugs aremediated by the5-HT2A receptor. It was soon demonstrated that a significantcorrelation (r¼ 0.938) exists between the 5-HT2A affinities ofvarious phenylalkylamine hallucinogens and their ED50 valuesobtained fromstimulus generalization studies using 1.0 mg/kgDOMas the training drug (see Fig. 2); also observed was a significantcorrelation (r¼ 0.90e0.97) between the 5-HT2A receptor affinitiesand the potencies of these drugs in humans (Sadzot et al., 1989;Titeler et al., 1988; Glennon et al., 1984). Taken together, thesefindings strongly indicate that the stimulus effects of hallucinogensare mediated by the 5-HT2A receptor.

The existence of the 5-HT2C receptor was first proposed by Pazosand associates in 1984, and these and other workers were able tolabel 5-HT2C sites in porcine and rat choroid plexus membraneswith radioligands such as [3H]5-HT, [3H]mesulergine, and [125I]2-iodo-LSD (Hoyer et al., 1986; Yagaloff and Hartig, 1985; Cortéset al., 1984; Pazos et al., 1984). Soon after the discovery of 5-HT2C


sites, it was recognized that LSD binds to 5-HT2C sites with nano-molar affinity (Egan et al., 1998; Peroutka, 1994; Titeler et al., 1988;Yagaloff and Hartig, 1985). Subsequent work demonstrated thatphenylalkylamine and indolealkylamine hallucinogens bind to5-HT2C receptors with moderately high affinity (Glennon et al.,1994, 1992a; Titeler et al., 1988). Binding studies using agonistradioligands have shown that hallucinogens are relatively non-selective for 5-HT2A and 5-HT2C receptors (Porter et al., 1999;Nelson et al., 1999).

The observation that hallucinogens interact with 5-HT2Creceptors confounded the hypothesis that activation of 5-HT2Areceptors is the primary mechanism for the effects of serotonergichallucinogens. This hypothesis was proposed prior to the discoveryof 5-HT2C sites, and was partially based on evidence demonstratingthat ketanserin and pirenperone block the behavioral effects ofhallucinogens in several animal paradigms. However, ketanserinand pirenperone exhibit less than a 100-fold difference in affinityfor 5-HT2A receptors versus 5-HT2C receptors, and therefore displayonly moderate selectivity for the 5-HT2A receptor (Newton et al.,1996; Hoyer, 1988a,b). It was also reported that there is a signifi-cant correlation (r¼ 0.78) between the affinities of various phe-nylalkylamine hallucinogens for 5-HT2C receptors and theirpsychoactive potency in humans (Titeler et al., 1988). However,5-HT2A and 5-HT2C receptors display parallel structureeaffinityrelationships for ligand binding (Nelson et al., 1999; Glennon et al.,1994; Glennon et al., 1992b), so it is not clear whether this corre-lation is due to the involvement of 5-HT2C receptors in the effects ofhallucinogens or whether it merely reflects the relationshipbetween 5-HT2A and 5-HT2C binding affinities. Because the potencyof hallucinogens strongly correlates with their 5-HT2A receptoraffinity, and given that the 5-HT2A and 5-HT2C affinities of halluci-nogens are correlated, it might be expected that a correlationbetween hallucinogen potency and 5-HT2C affinity would exist evenif the 5-HT2C receptor played absolutely no role in the effects ofthese compounds.

The potent action of hallucinogens at 5-HT2C receptors has led tospeculation that 5-HT2C receptor occupationmay play an importantmechanistic role in the action of hallucinogenic drugs (Sanders-Bush, 1994; Burris et al., 1991; Glennon, 1990; Sanders-Bush et al.,1988; Titeler et al., 1988). In order to determine whether the5-HT2C receptor is involved in mediating the discriminative stim-ulus effects of hallucinogens, attempts have been made to block theeffects of hallucinogens with 5-HT2 subtype-selective antagonists.Before 1993, the most selective agent known was the butyrophe-none neuroleptic spiperone, an antagonist at dopaminergic D2/D4and serotonergic 5-HT1A receptors that displays 500- to 1000-foldhigher affinity for 5-HT2A than for 5-HT2C binding sites (Metwallyet al., 1998; Hoyer, 1988b; Sanders-Bush and Conn, 1986). Unfor-tunately, most (but not all) of the antagonist blockade studies withspiperone produced inconclusive results because the compoundcan severely disrupt responding when administered in combina-tion with LSD or DOM (Fiorella et al., 1995b; Glennon, 1991; Appeland Cunningham, 1986; Colpaert et al., 1982). It has been reported,however, that the ether analog of spiperone (AMI-193), a 5-HT2Areceptor antagonist with 2150-fold selectivity versus 5-HT2C sites,blocks DOM-induced stimulus control in rats at very low doses(ED50¼ 0.003 mg/kg) without altering the response rate (Ismaielet al., 1993). More recently, it has been demonstrated that stim-ulus control in animals trained with DOI (Schreiber et al., 1994;Smith et al., 1999, 2003), DOM (Li et al., 2007, 2008), LSD (Winteret al., 2004; Gresch et al., 2007), and 2C-T-7 (Fantegrossi et al.,2005) is blocked by the highly selective 5-HT2A antagonistM100,907 (formerly MDL 100,907). The LSD cue is also blocked byMDL 11,939, a 5-HT2A antagonist with high selectivity versus the5-HT2C receptor (Marona-Lewicka and Nichols, 2007). The apparent

lack of 5-HT2C involvement in the stimulus effects of hallucinogensis supported by the fact that even high doses of themixed 5-HT2C/2Bantagonists SB 200,646A and SB 206,553 fail to alter DOI- and LSD-induced responding in rats (Smith et al., 1998, 1999; Schreiber et al.,1994; Gresch et al., 2007). It has also reported that the selective5-HT2C antagonist SB 242,084 does not block the psilocybindiscriminative stimulus (Winter et al., 2007). Furthermore, anantagonist correlation analysis study (Fiorella et al., 1995b) foundthat the rank order of potencies for blockade of LSD-like stimuluseffects by 5-HT2 antagonists parallels their binding affinities for the5-HT2A receptor (r¼ 0.95) but not for the 5-HT2C receptor(r¼�0.29). In sum, it appears that the hallucinogen discriminativestimulus is mediated by the 5-HT2A receptor and not by the 5-HT2Creceptor.

6.1.2. Complex stimulus effects of LSDNumerous studies, cited above, demonstrate that the intero-

ceptive state governing hallucinogen discrimination in animals isprimarily mediated by 5-HT2A receptor interactions. Although thephenylalkylamines and the indoleamines act via a common 5-HT2Amechanism, the former agents have high affinity only for 5-HT2receptors and therefore produce a discriminative stimulus which isless complex and more selective than that of the indoleamines(Fiorella et al., 1995b; Glennon, 1988). For example, Fiorella andcolleagues (Fiorella et al., 1995b) examined the correlation betweenthe 5-HT2A affinity of ten 5-HT antagonists and their medianeffective dose (ID50 values) for blocking the LSD stimulus and foundthat 5-HT2A receptor affinity alone could only account for 56% of thevariance in the LSD-antagonist potencies of the compounds;however, interactions with the 5-HT2C receptor did not account forthe remaining variability in antagonist potency. In contrast to theabove findings, variance in the potency for inhibiting R-(�)-DOMsubstitution in LSD-trained animals was almost completelyaccounted for by 5-HT2A affinity (Fiorella et al., 1995b). These datasupport the notion that LSD evokes a compound stimulus, whereasthe phenylalkylamine cue displays greater selectivity with respectto the 5-HT2A receptor. Moreover, there is considerable evidencethat higher doses of antagonists are consistently required to blockthe LSD discriminative stimulus than are required to block phe-nylalkylamine-induced stimulus control (Meert, 1996; Fiorellaet al., 1995a; Koek et al., 1992). Indeed, while cinanserin potentlyantagonizes DOM and mescaline, it is much less effective againstLSD- and 5-MeO-DMT-appropriate responding (Young et al., 1986;Glennon et al., 1983a; Kuhn et al., 1978). Such findings are indicativeof the complex nature of the LSD cue.

LSD evokes a compound stimulus; although the most salientcomponent of the LSD stimulus is transduced through the 5-HT2Areceptor, it appears that ancillary interactions with other mono-amine receptors are responsible for secondary non-essentialcomponents of the LSD stimulus complex (Marona-Lewicka andNichols, 1995; Meert et al., 1989; Winter and Rabin, 1988). Thesecondary elements of the LSD cue have been attributed to occu-pation of 5-HT1A receptors (Marona-Lewicka and Nichols, 1995;Winter and Rabin, 1988) and DA D2 receptors (Meert, 1996; Meertet al., 1989; Minnema and Rosecrans, 1984; Appel et al., 1982). Aswith any drug possessing complex stimulus properties, the natureof the LSD discriminative stimulus will vary depending upon thetraining and testing conditions.

There is considerable evidence that the 5-HT1A subtypecontributes to the discriminative effects of LSD. It has been reportedthat LSD, at a dose of 0.48 mmol/kg, elicits intermediate levels ofdrug-lever selection in rats trained with 1.2 mmol/kg 8-OH-DPAT(Arnt, 1989). Unfortunately, trials with larger doses of LSD wereprecluded because the partial generalization was accompanied bysevere disruption of behavior. When ipsapirone was tested in LSD-


discriminating rats it occasioned a maximum of 71% drug-leverresponding (i.e., partial substitution; Arnt, 1989). 8-OH-DPAT hasalso been shown to produce partial substitution in rats and micetrained to discriminate LSD (Winter and Rabin, 1988; Benneyworthet al., 2005; Reissig et al., 2005). Interestingly, data from drugdiscrimination studies with yohimbine reveal that this drug canfully substitute for LSD in rats (Colpaert, 1984; Marona-Lewicka andNichols, 1995; Appel et al., 1999), though this finding has beendisputed by Winter (Winter, 1978; Fiorella et al., 1995c). Althoughnormally classified as a a2-adrenoceptor antagonist, yohimbineactually displays comparable affinities for a2-adrenoceptors and5-HT1A sites (Winter and Rabin, 1992). Cross-substitution has beenobserved to occur between yohimbine, 8-OH-DPAT, and ipsapirone(Winter and Rabin, 1992; Sanger and Schoemaker, 1992; Winter,1988), indicating that the yohimbine discriminative stimulus isprimarily mediated by the 5-HT1A receptor (Winter and Rabin,1992). Given these facts, the observation by Marona-Lewicka andNichols (1995) that yohimbine but not the selective a2-adreno-ceptor antagonist RS 2026-197 substitutes for LSD indicates thatthere is a 5-HT1A-mediated stimulus component common to bothyohimbine and LSD.

LSD binds to DA D1, D2, D3, D4, and D5 receptors with highaffinity (Marona-Lewicka et al., 2009; Nichols et al., 2002; Wattset al., 1995; Table 3), and acts as a partial agonist at DA D1 and D2receptors (Seeman et al., 2009; Watts et al., 1995) and as a fullagonist at DA D4 receptors (Marona-Lewicka et al., 2009). There issome evidence that interactions with DA receptors contribute tothe LSD cue. For example, rats trained with 0.25 mg/kg of the DAD1/D2 agonist apomorphine respond to LSD with partial general-ization (Appel et al., 1982). However, although the apomorphinecue is antagonized by the D2 antagonist haloperidol but not the5-HT antagonist pizotifen, substitution of LSD for apomorphinecould be blocked by pizotifen but not haloperidol, implicatingserotonergic mechanisms rather than dopaminergic mechanismsin the substitution. The mixed 5-HT2A/D2 antagonist risperidoneblocks the LSD cue with much greater potency than the 5-HT2antagonist ritanserin. Specifically, risperidone blocks LSD discrim-ination with 414 times the potency of ritanserin (Meert, 1996;Meert and Awouters, 1991; Meert et al., 1990), a finding that issurprising because risperidone has only slightly higher affinity forthe 5-HT2A receptor than ritanserin (Leysen, 1990). Although0.63 mg/kg ritanserin produces full occupation of 5-HT2A sites, itfails to attenuate the LSD stimulus; ritanserinmust be administeredat 40 mg/kg to completely antagonize the LSD cue, and at that doseritanserin produces significant occupation of catecholaminereceptors (Koek et al., 1992; Meert et al., 1990). By contrast, ris-peridone and ritanserin display nearly identical potencies asantagonists of the DOM cue (Meert, 1996). These findings indicatethat both 5-HT2A and DA D2 receptor interactions contribute to theinteroceptive state governing LSD discrimination, whereas only the5-HT2A receptor is involved in DOM discrimination. Supporting thisconclusion is the fact that the potency of ritanserin as an antagonistof LSD stimulus control is markedly potentiatedwhen administeredin combinationwith low doses of haloperidol (Meert and Awouters,1991). Stimulus antagonism studies have shown that DA antago-nists alone have no effect on the discriminability of LSD (Kuhn et al.,1978; White and Appel, 1982). Therefore, it appears that the LSDcue is most effectively and potently antagonized by concurrentblockade of 5-HT2A and DA sites. In this regard, risperidone issimilar in potency to the combination of ritanserin and haloperidol.

Recent reports indicate that the dopaminergic component of theLSD discriminative stimulus is time-dependent (Marona-Lewickaet al., 2005). Drug discrimination studies using LSD as thetraining drug have typically used 15e30 min pretreatment times,and have shown consistently that 5-HT2A antagonists block LSD-

induced stimulus control. However, when rats are trained todiscriminate LSD with a longer 90 min pretreatment time, theresulting stimulus cue evoked by LSD is mediated by D2-likereceptors and not by 5-HT2A receptors (Marona-Lewicka andNichols, 2007; Marona-Lewicka et al., 2009). These findingsdemonstrate that the stimulus effects of LSD occur in two temporalphases, the first phase involving 5-HT2A receptors and the secondinvolving DA receptors. It is not clear whether the delayed dopa-minergic cue is a direct effect of LSD or is produced by an LSDmetabolite with selective DA agonist activity.

6.1.3. Complex stimulus effects of indolealkylamine hallucinogensSimilar to LSD, certain hallucinogenic indolealkylamines

produce stimulus effects that are both DOM- and 8-OH-DPAT-like.For instance, the hallucinogen 5-methoxy-N,N-dipropyltryptamine(5-MeO-DPT), which displays nearly identical affinities for 5-HT1Areceptors (Ki¼ 4.0 nM) and agonist-labeled 5-HT2A receptors(Ki¼ 7.1 nM), produces complete generalization in animals trainedwith DOM and in animals trained with 8-OH-DPAT (Glennon et al.,1988). The 5-MeO-DMT discriminative stimulus also involves5-HT1A- and 5-HT2A-mediated components. Generalization occursbetween DOM, LSD, and 5-MeO-DMT regardless of which is used asthe training drug. Winter and Rabin (1988) proposed that theability of 5-MeO-DMT to substitute for DOM involves 5-HT2Areceptors whereas the ability of 5-MeO-DMT to substitute for LSDinvolves both 5-HT1A and 5-HT2A receptors. Not only do thediscriminative stimulus properties of 5-MeO-DMT vary dependingupon conditions of training and testing, however, but may alsodepend upon the dose of 5-MeO-DMT. Nevertheless, there isevidence that 5-MeO-DMT-induced stimulus control primarilyinvolves 5-HT1A receptors, with 5-HT2A receptors playing onlya secondary role (Winter et al., 2000; Schreiber and DeVry, 1993;Spencer et al., 1987). This conclusion is consistent with the factthat the behavioral response to the drug in rats and mice ispredominantly 5-HT1A-mediated (Lucki et al., 1984; Tricklebanket al., 1985; Smith and Peroutka, 1986; Berendsen et al., 1989;Eison and Wright, 1992; Sanchez et al., 1996; Krebs-Thomsonet al., 2006; Halberstadt et al., 2010). The 5-MeO-DMT discrimi-native stimulus completely generalizes to 8-OH-DPAT and ipsapir-one (Winter et al., 2000; Schreiber and DeVry, 1993; Spencer et al.,1987), and the ability of these and other agents to substitute for 5-MeO-DMT is correlated with their 5-HT1A, but not 5-HT2A, affinities(Spencer et al., 1987). Both WAY-100,635 and pindolol antagonizethe 5-MeO-DMT cue and its generalization to 8-OH-DPAT andipsapirone (Winter et al., 2000; Spencer et al., 1987). By contrast,the 5-HT2 antagonists pirenperone, ketanserin, and ritanserin aremuch less effective antagonists. Several studies have shown that 5-MeO-DMT evokes intermediate levels of 8-OH-DPAT-likeresponding followed by considerable behavioral disruption athigher doses (Schreiber and DeVry, 1993; Arnt, 1989; Glennon,1986). After pretreatment with ketanserin, however, 5-MeO-DMTengenders complete substitution in 8-OH-DPAT-trained animals(Fozard et al., 1986). As such, it would appear that the 5-HT2Aagonist activity of 5-MeO-DMT is responsible for the behavioraldisruption. There is other evidence that 5-HT2A receptor activationcan disrupt 5-HT1A-mediated stimulus control: response rates areseverely depressed when animals trained to discriminate 8-OH-DPAT are given DOM in combination with the training drug (Arnt,1989). Interestingly, administration of 5-MeO-DMT to animalstrained with ipsapirone results in full drug-appropriate responding(Spencer and Traber, 1987). This observation raises the question ofwhy 5-MeO-DMT disrupts responding in 8-OH-DPAT-trainedanimals but not in ipsapirone-trained animals. Given that ipsapir-one is a less efficacious 5-HT1A agonist than 8-OH-DPAT (Dumuiset al., 1988), the most plausible explanation is that whereas low,


non-disruptive doses of 5-MeO-DMT can fully mimic ipsapirone, 5-MeO-DMT fails to fully mimic 8-OH-DPAT because the dosesrequired to evoke full substitution also induce significant 5-HT2Areceptor activation, leading to behavioral disruption.

There is also evidence that the hallucinogen DPT producesa discriminative stimulus that is mediated by interactions withboth 5-HT2A and 5-HT1A receptors. DPT produces complete gener-alization in rats trained with DOM (Li et al., 2007; Li et al., 2009)and partial generalization in animals trained with LSD (Fantegrossiet al., 2008), effects that are fully blocked byM100,907. However, inanimals trained to discriminate 1.5 mg/kg DPT, pretreatment witha combination of WAY-100,635 and M100,907 was much moreeffective at antagonizing stimulus control than was either antago-nist given alone, indicating that DPT elicits a compound stimulusinvolving both 5-HT1A receptor- and 5-HT2A receptor-mediatedcomponents (Fantegrossi et al., 2008). Likewise, although psilo-cybin-induced stimulus control is mediated primarily by the5-HT2A receptor, with the 5-HT1A receptor playing no apparent role(Winter et al., 2007), the ability of DPT to evoke partial general-ization in animals trained with psilocybin appears to involveinteractions with both 5-HT1A and 5-HT2A receptors (Fantegrossiet al., 2008).

6.2. 5-HT behavioral syndrome

Administration of 8-OH-DPAT to rats produces a 5-HT behav-ioral syndrome that includes flat body posture, reciprocal forepawtreading, hindlimb abduction, and lateral head weaving (Hjorthet al., 1982; Smith and Peroutka, 1986). The behavioral effects of8-OH-DPAT are very similar to those produced by treatment witha 5-HT precursor in combinationwith a monoamine oxidase (MAO)inhibitor (Grahame-Smith, 1971). Indoleamine hallucinogens,including 5-MeO-DMT, LSD, and DPT, can also induce componentsof this behavioral syndrome (Li et al., 2007; Tricklebank et al., 1985;Trulson et al., 1976). By contrast, phenylalkylamine hallucinogensdo not reliably produce the 5-HT behavioral syndrome. The abilityof 8-OH-DPAT and 5-MeO-DMT to induce the 5-HT behavioralsyndrome is blocked by WAY-100,635 and pindolol, and thereforethe syndrome is likely mediated by 5-HT1A receptors (Tricklebanket al., 1984, 1985; Sanchez et al., 1996). It appears that these5-HT1A receptors are located postsynaptically because destructionof central serotonergic projections with 5,7-DHT does not prevent5-MeO-DMT and LSD from inducing the behavioral syndrome(Sloviter et al., 1978; Trulson et al., 1976). Compared to the doses ofLSD and 5-MeO-DMT that inhibit DRN firing, relatively high dosesof those indoleamines are required to induce the 5-HT behavioralsyndrome. For example, although 75 mg/kg (IP) LSD completelyinhibits the firing of serotonergic DRN neurons in rats (Gallager andAghajanian, 1975), much higher doses of LSD (400e1000 mg/kg) arerequired to induce hindlimb abduction, head weaving, and forepawtreading (Trulson et al., 1976). This discrepancy probably reflectsthe fact that for 5-HT1A receptors there is a large receptor reservepresent in the DRN but not in postsynaptic regions (Yocca et al.,1992). Indeed, although the 5-HT1A partial agonists buspirone,ipsapirone, and gepirone inhibit the firing of DRN neurons (andthus behave as full agonists presynaptically), they block the abilityof 8-OH-DPAT and 5-MeO-DMT to induce the behavioral syndrome(Smith and Peroutka, 1986; Scott et al., 1994).

The 5-HT1A agonists 8-OH-DPAT, buspirone, ipsapirone, flesi-noxan, and lisuride induce lower lip retraction (LLR) in rats(Marona-Lewicka et al., 2002; Berendsen et al., 1989; Joordens et al.,1998; Berendsen and Broekkamp, 1987). WAY-100,635 blocks LLRinduced by 8-OH-DPAT, demonstrating that this behavioralresponse involves activation of 5-HT1A receptors (Joordens et al.,1998). Microinjection of 8-OH-DPAT directly into the MRN

induces LLR, indicating that 5-HT1A receptors expressed by MRNneurons are responsible for mediating this behavior (Berendsenet al., 1994). Interestingly, 5-MeO-DMT and DPT induce LLR onlyin animals that have been pretreated with a 5-HT2A antagonist(Berendsen et al., 1989; Li et al., 2007). It has also been shown thatDOI and the 5-HT2C agonist m-chlorophenylpiperazine (mCPP) canattenuate lower lip retraction induced by 8-OH-DPAT (Kleven et al.,1997), indicating that 5-HT2A and/or 5-HT2C receptors act toattenuate the behavioral effects of 5-HT1A receptor activation.These findings indicate that the activity of 5-MeO-DMT and DPT at5-HT2 receptors acts to functionally antagonize LLR induced by5-HT1A receptor activation.

6.3. Exploratory and investigatory behavior

Tests of drug effects on locomotor activity have been usedfrequently to assess psychoactive agents for stimulant or depres-sant activity. However, studies examining the effects of hallucino-gens on behavior in an open field produce inconsistent results andfail to distinguish the effects of hallucinogens from those of otherdrug classes (Brimblecombe, 1963; Cohen and Wakeley, 1968;Kabes et al., 1972; Silva and Calil, 1975). Given the complexnature of hallucinogen effects, it is not surprising that the loco-motor paradigm produces inconclusive results because it does notprovide a qualitative assessment of behavior and fails to assesswhether changes in sensitivity to environmental stimuli contributeto the behavioral effect. The Behavioral Pattern Monitor (BPM) isa combination of activity and holeboard chambers that providesquantitative and qualitative measures of unconditioned locomotorand investigatory activity in rats, and can be used to assess forchanges in the response of animals to environmental stimuli (Geyeret al., 1986). Statistical assessment of the geometrical and dynam-ical structures of motor behavior in the BPM has proven very usefulin characterizing drug effects in rats (Geyer, 1982, 1990; Geyer et al.,1986; Gold et al., 1988; Geyer and Paulus, 1992). Using the BPM it ispossible to differentiate statistically the effects of various stimu-lants at doses that produce comparable increases in locomotion butmarked differences in qualitative aspects of behavior involvingspatiotemporal patterns of locomotion and investigatory responsesdirected at specific environmental stimuli (Geyer et al., 1986, 1987;Gold et al., 1989; Geyer and Paulus, 1992, 1996; Geyer and Callaway,1994).

6.3.1. Effects of hallucinogens on exploratory and investigatorybehavior in rats

When phenylalkylamine (mescaline, DOM, DOI, and DOET) andindolealkylamine (psilocin, DMT, 5-MeO-DMT, and 5-methoxy-a-methyltryptamine) hallucinogens are tested in rats in a novel BPMenvironment they produce a characteristic behavioral profile: (1)there is reduced locomotor activity; (2) the frequency of investi-gatory behaviors (rearings and holepokes) is diminished; and(3) avoidance of the center of the BPM chamber is increased (Geyeret al., 1979; Adams and Geyer, 1985a; Wing et al., 1990; Hameleerset al., 2007). Fig. 3 illustrates the behavioral profile of psilocin in theBPM. The effects of hallucinogens are not observed when animalsare tested in a familiar environment, and thus likely reflectpotentiation of the neophobia displayed by rats in a novel envi-ronment. It has been theorized that the diminution of the behav-ioral effects of hallucinogens in a familiar test environment occursbecause hallucinogen-treated animals are more willing to explorethe BPM chambers once the stimuli associated with the test envi-ronment become less threatening due to habituation. LSD hassimilar effects on investigatory behavior and center entries (Adamsand Geyer, 1985b), but it has biphasic effects on locomotor behaviorwith activity initially suppressed and then increasing over time


(Mittman and Geyer, 1991). Mescaline and DOM can also producebiphasic effects on locomotor activity, but this occurs only afterrelatively high doses are administered (100 mg/kg and �5 mg/kg,respectively; Yamamoto and Ueki, 1975; Pálenícek et al., 2008). Theeffects of hallucinogens on investigatory and exploratory behaviorsin the BPM are distinct from those produced by other drug classes,including lisuride (Adams and Geyer, 1985c), 5-HT releasers such as3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenediox-ymethamphetamine (MDMA) (Gold et al., 1988; Callaway et al.,1990; Paulus and Geyer, 1992), 5-HT1 agonists (Mittman andGeyer, 1989; Rempel et al., 1993), psychostimulants (Geyer et al.,1986, 1987), and NMDA antagonists (Lehmann-Masten and Geyer,1991; Bakshi et al., 1999).

Pretreatment with the 5-HT2 antagonists ritanserin and ketan-serin blocks the effects of DOI, DOM, and mescaline in the BPM(Wing et al., 1990; Mittman and Geyer, 1991). The effects of DOI areblocked by M100,907 but not by the selective 5-HT2C/2B antagonistSER-082, and are therefore likely mediated by the 5-HT2A receptorand not by the 5-HT2C receptor (Krebs-Thomson et al., 1998). Theaction of the indoleamines in the BPM is more complex mecha-nistically. The initial suppression of locomotor activity induced byLSD is blocked by the mixed 5-HT1/b-adrenergic antagonistpropranolol (Mittman and Geyer, 1991) and the selective 5-HT1Aantagonist WAY-100,635 (Krebs-Thomson and Geyer, 1996),whereas ritanserin (Mittman and Geyer, 1991) and M100,907(Ouagazzal et al., 2001) block LSD-induced hyperactivity . Thus,both 5-HT1A and 5-HT2A receptors appear to contribute to thebehavioral effects of LSD in the BPM, and this finding is supportedby the fact that chronic treatment with either 8-OH-DPAT or DOIproduces cross-tolerance with LSD in this behavioral paradigm(Krebs and Geyer,1994). The effects of low doses of 5-MeO-DMTare

Fig. 3. Effect of psilocin on the exploratory and investigatory behavior of rats in the Behav(B) Effect on time spent in the center region of the BPM chamber (in minutes). (C) Effect on t(A) or mean� SEM (BeD). *p< 0.05, **p< 0.01 versus vehicle control (Tukey’s test).

antagonized by WAY-100,635 but not by M100,907 (Krebs-Thomson et al., 2006), and thus are likely mediated by 5-HT1Areceptors. However, when 5-MeO-DMT is administered in combi-nation with a behaviorally inactive dose of an MAOA inhibitor suchas harmaline, clorgyline, or pargyline, it produces LSD-like delayedhyperactivity that is blocked by the 5-HT2A-selective antagonistMDL 11,939 and is sensitive to the novelty of the testing environ-ment (Halberstadt et al., 2008). Thus, both 5-HT1A and 5-HT2Areceptors mediate the effects of LSD and 5-MeO-DMT in the BPM.

6.3.2. Effects of hallucinogens on exploratory and investigatorybehavior in mice

The original BPM was designed for rats, but we have also testedhallucinogens in a mouse version of the BPM (Risbrough et al.,2006; Halberstadt et al., 2009). In mice, DOI, mescaline, DOM,DOET, and DOPR reduce investigatory behavior and produce effectson locomotor activity that follow an inverted U-shaped dos-eeresponse function, with low and moderate doses increasingactivity and higher doses decreasing activity (Halberstadt et al.,2009; Halberstadt et al., unpublished observations). The increasein locomotor activity induced by 1.0 mg/kg DOI or 25 mg/kgmescaline is absent in 5-HT2A receptor knockout mice, suggestingthe involvement of 5-HT2A receptors. Conversely, the reduction inlocomotor activity produced by 10 mg/kg DOI is potentiated in 5-HT2A knockout mice and attenuated by SER-082, indicating that thedecrease in activity is partially mediated by the 5-HT2C receptor.This conclusion is supported by the fact that selective 5-HT2Cagonists decrease locomotor activity in mice (Halberstadt et al.,2009; Fletcher et al., 2009). By contrast to the phenylalkylaminehallucinogens, psilocin, DMT, 5-MeO-DMT, and LSD producedecreases in locomotor activity, investigatory behavior, and time

ioral Pattern Monitor (BPM). (A) Effect on crossings, a measure of locomotor activity.he number of holepokes. (D) Effect on the number of rearings. Data are shown as mean


spent in the center of the mouse BPM chambers (Halberstadt et al.,2010; Halberstadt et al., unpublished observations). The effects ofpsilocin and 5-MeO-DMT are blocked by WAY-100,635 but are notaltered by the selective 5-HT2C antagonist SB 242,084 or by 5-HT2Areceptor gene deletion. Thus, the effects of indoleamines in themouse BPM are mediated by 5-HT1A receptors, whereas the effectsof the phenylalkylamines are mediated by 5-HT2 receptors. Fig. 4compares the effects of DOM and 5-MeO-DMT on locomotoractivity in the mouse BPM. These studies demonstrate that phe-nylalkylamine and indoleamine hallucinogens produce disparateeffects on exploratory and investigatory behaviors in mice, behav-ioral differences that are not readily apparent when these agentsare studied in rats.

6.4. Prepulse inhibition of startle

Prepulse inhibition (PPI) describes the phenomenon where thestartle response is attenuated when preceded by a weak prestimu-lus. PPI has been used as an operational measure of sensorimotorgating andhas been found tobedeficient inpatientswith avarietyofpsychiatric illnesses, including schizophrenia. LSD, DOI, DOB,mescaline, and 5-MeO-DMT disrupt PPI in rats (Rigdon andWeatherspoon, 1992; Sipes and Geyer, 1994; Johansson et al.,1995; Varty and Higgins, 1995; Ouagazzal et al., 2001; Krebs-Thomson et al., 2006; Pálenícek et al., 2008; Halberstadt andGeyer, 2010). The decrease in PPI induced by DOI and LSD isblocked by the highly selective 5-HT2A antagonists M100,907 andMDL11,939but not by the 5-HT2C antagonist SB 242,084, the5-HT2C/2B antagonist SER-082, or the 5-HT1A antagonist (þ)WAY-100,135

Fig. 4. Effects of DOM hydrochloride (A) and 5-MeO-DMT (B) on locomotor activity(distance traveled) in mice. Data are shown as mean� SEM. *p< 0.05, **p< 0.01versus vehicle control (Tukey’s test).

(Sipes and Geyer, 1995a; Ouagazzal et al., 2001; Halberstadt andGeyer, 2010), demonstrating the involvement of 5-HT2A receptors.In comparison with DOI and LSD, the mechanism for the effect of5-MeO-DMT on PPI in rats is more complex: the effect of 5-MeO-DMT is attenuated by pretreatment with either SER-082 or WAY-100,635, but not by M100,907 (Krebs-Thomson et al., 2006). Thenon-hallucinogenic LSD congener lisuride also disrupts PPI in rats,and thus can be considered to be an LSD false-positive (Halberstadtand Geyer, 2010). However, LSD and lisuride disrupt PPI in rats viadistinct mechanisms, and the effect of lisuride is blocked by theselective DA D2/D3 antagonist raclopride but is unaffected bypretreatment with MDL 11,939 (Halberstadt and Geyer, 2010). Thisfinding indicates that the 5-HT2A agonist activity of lisuride does notcontribute to the effects of the drug on PPI.

The effects of DOI on PPI in rats appear to be mediated specifi-cally by actions in the ventral pallidum, since bilateral infusion ofDOI directly into the ventral pallidum but not into the nucleusaccumbens produces disruption of PPI (Sipes and Geyer, 1997). It islikely that the effects of DOI on PPI are mediated by activation of5-HT2A receptors in the ventral pallidum because local infusion ofM100,907 attenuated the effects of systemic DOI on PPI. However,the possibility remains that dopamine receptors in the ventralpallidum or in other brain regions may play a downstream role inthe PPI-disruptive effects of DOI because haloperidol and raclopridecan also block the effect of systemic DOI on PPI (Sipes and Geyer,1994; Halberstadt and Geyer, unpublished observations). It is notcurrently clear whether the ventral pallidum plays a role in medi-ating the ability of LSD and 5-MeO-DMT to disrupt PPI in rats.

Activation of 5-HT1A receptors has opposing effects on sensori-motor gating in rats and mice. In rats, selective 5-HT1A agonistssuch as 8-OH-DPAT, buspirone, gepirone, and ipsapirone decreasePPI (Rigdon and Weatherspoon, 1992; Sipes and Geyer, 1995b).Conversely, in 129/SV and Balb/c mice, treatment with 8-OH-DPATincreases PPI (Dulawa et al., 1998; Dulawa et al., 2000; Gogos et al.,2008). The ability of 8-OH-DPAT to increase PPI is blocked by the5-HT1A antagonist WAY-100,635 and is absent in 5-HT1A knockoutmice. Interestingly, we have found that 5-MeO-DMT and psilocinproduce dose-dependent increases in PPI in 129/SvEv mice (Powellet al., 2003; Fig. 5A and B). The ability of 5-MeO-DMT to increasePPI was partially attenuated by pretreatment with 1.0 mg/kg WAY-100,635, indicating that 5-HT1A receptors are involved in mediatingthis effect (Fig. 5C).

Clinical studies have demonstrated that psilocybin can alter PPIin human volunteers. Gouzoulis-Mayfrank et al. (1998) reportedthat psilocybin increases PPI in humans when an interstimulusinterval (ISI) of 100 ms was used for the prepulse trials. However,Vollenweider et al. (2007) found that psilocybin increases PPI atlong ISIs (120e2000 ms) but reduces PPI when shorter ISIs of 30 msare used. Thus, the effects of psilocybin on PPI are dependent on thetesting parameters. The receptor mechanism(s) responsible for theeffects of psilocybin on PPI in humans have not yet been investi-gated. In contrast to the effect of psilocybin, administration of DMTby continuous i.v. infusion (Heekeren et al., 2007) or orally asa component of ayahuasca (Riba et al., 2002) has no effect on PPI inhuman subjects.

6.5. Head twitch response

Corne and Pickering reported in 1967 that a variety of halluci-nogens, including LSD, psilocybin, psilocin, DMT, and mescaline,produce a head twitch response (HTR) in mice consisting ofa paroxysmal rotational movement of the head (Corne andPickering, 1967). This behavior had been observed previously tooccur after systemic administration of the 5-HT precursor5-hydroxytryptophan (Corne et al., 1963). It was subsequently

Fig. 5. Effects of 5-MeO-DMT and psilocin on prepulse inhibition of startle (PPI) in 129/SvEv mice. (A) 5-MeO-DMT dose-dependently increased PPI. (B) Psilocin dose-dependently increased PPI. (C) The ability of 5-MeO-DMT to increase PPI was partiallyreversed by pretreatment with the selective 5-HT1A antagonist WAY-100,635. Data areshown as mean� SEM. *p< 0.05, **p< 0.01 versus vehicle control (Tukey’s test).


demonstrated that LSD, 5-MeO-DMT, DOM, and mescaline alsoinduce the HTR when administered to rats (Yamamoto and Ueki,1975; Bedard and Pycock, 1977). In rats, the HTR often involvesnot only the head but also the neck and trunk of the animal, andthus the behavior has also been referred to as the wet-dog shake inthat species (Bedard and Pycock, 1977).

Evidence linking the HTR to the 5-HT2A receptor emergedalmost immediately after 5-HT2A binding sites were first detectedby radioligand binding studies (Peroutka and Snyder, 1979;Peroutka et al., 1981). Specifically, Leysen reported in 1982 thatthere is a significant correlation (r¼ 0.88) between the 5-HT2Aaffinity of a series of 19 5-HT antagonists and their potency forblocking mescaline-induced HTR in rats (Leysen et al., 1982). It waslater shown that the ability of 5-HT antagonists to block the HTRinduced by DOI is also significantly correlated (r¼ 0.83) with5-HT2A affinity (Schreiber et al., 1995). Studies have also demon-strated that the HTR evoked by DOI in rats is blocked by theselective 5-HT2A antagonist M100,907 but not by the selective

5-HT2C antagonist SB 242,084 or the mixed 5-HT2C/2B antagonist SB200,646A (Schreiber et al., 1995; Vickers et al., 2001). Likewise, HTRinduced by DPT, 5-MeO-DIPT, and TCB-2 in mice is blocked byM100,907 andMDL 11,939 (Fantegrossi et al., 2006, 2008; Fox et al.,2009). It has also been reported that 5-HT2A knockout mice do notdisplay the HTR in response to administration of LSD, DOI, DOM,DOB, mescaline, psilocin, 1-methylpsilocin, DMT, or 5-MeO-DMT(González-Maeso et al., 2007; Keiser et al., 2009; Halberstadt et al.,2010), conclusively linking the HTR to 5-HT2A activation. Further-more, genetic restoration of the 5-HT2A receptor to the cortex of 5-HT2A knockout mice restores the ability of LSD to induce the HTR(González-Maeso et al., 2007).

Expression of 5-HT2A receptor-induced HTR can be modified byactivity at a variety of receptors, including 5-HT1A. Selective 5-HT1Aagonists, including 8-OH-DPAT, attenuate the HTR induced by DOIin mice and rats (Arnt and Hyttel, 1989; Heaton and Handley, 1989;Darmani et al., 1990a; Schreiber et al., 1995; Willins and Meltzer,1997). Furthermore, although 5-MeO-DMT induces the HTR,pretreatment with 5-MeO-DMT dose-dependently reduces DOI-induced HTR in mice (Darmani et al., 1990a). This finding raises thepossibility that activation of the 5-HT1A receptor by 5-MeO-DMTand other indoleamines may attenuate their ability to induce theHTR. Experiments with LSD, however, demonstrate that theresponse to the drug is not altered by deletion of the 5-HT1Areceptor gene (González-Maeso et al., 2007). Given the especiallypotent 5-HT1A agonist activity of 5-MeO-DMT, additional studiesare needed to determine whether the 5-MeO-DMT doseeresponsefor HTR is altered in 5-HT1A knockout mice. Finally, it is importantto note that some discrepancies exist regarding the interactionbetween 5-HT1A receptors and 5-HT2A-induced HTR; indeed,whereas WAY-100,635 can potentiate DOI-induced HTR in rats(Willins and Meltzer, 1997), it has also been reported that WAY-100,635 can antagonize DPT-induced HTR in mice (Fantegrossiet al., 2008). It is not clear whether this discrepancy reflectsspecies differences or is indicative of pharmacological differencesbetween phenylalkylamines and indoleamines. This issue is furthercomplicated by the fact that 5-HT1A antagonists such as WAY-100,635 and S-(�)-UH-301 can themselves provoke HTR in micethrough a mechanism that purportedly involves elevation of 5-HTrelease and subsequent 5-HT2A receptor activation (Darmani andReeves, 1996; Darmani, 1998).

There is also evidence that the 5-HT2C receptor can regulate theHTR induced by 5-HT2A receptor activation. The 5-HT2 agonist Ro60-0175, which is w30-fold selective for 5-HT2C receptors versus5-HT2A receptors (Martin et al., 1998), does not induce the HTR inrats unless administered in combination with SB 242,084 (Vickerset al., 2001). This finding indicates that the ability of Ro 60-0175to induce the HTR via 5-HT2A receptor activation is suppressed byits interaction with the 5-HT2C receptor. Ro 60-0175 has also beenshown to inhibit the HTR induced by DOI in mice (Fantegrossi et al.,2010). Fantegrossi and colleagues have reported that the HTRinduced by DOI, 2C-T-7, DPT, and 5-MeO-DIPT in NIH Swiss andSwiss-Webster mice typically follows an inverted U-shaped dos-eeresponse function (Fantegrossi et al., 2005, 2006, 2008, 2010).The descending limb of the DOI response is shifted to the right bySB 242,084, indicating that the 5-HT2C receptor is responsible forthe inhibition of HTR that occurs at higher doses (Fantegrossi et al.,2010). By contrast, it has been reported that 5-HT2C knockout micedisplay a significant reduction in DOI-induced HTR (Canal et al.,2010). Although compensatory developmental adaptations in5-HT2C knockout mice may have contributed to these contradictoryfindings, the same investigators found that pretreatment with SB242,084 reduced the magnitude of the HTR to DOI in C57BL/6J andDBA/2J mice (Canal et al., 2010). It is not clear why those two groupsobtained such discrepant results with DOI in animals pretreated


with SB 242,084, but the fact that the studies used different strainsof mice may have been a contributing factor. It has been reportedthat there are strain differences in 5-HT2C receptor mRNA editing(Calcagno and Invernizzi, 2010; Hackler et al., 2006). Editing of5-HT2C receptor mRNA can dramatically alter G-protein coupling(Burns et al., 1997), and thus differences in 5-HT2C editing couldpotentially alter how 5-HT2A and 5-HT2C receptors interact indifferent strains of mice.

6.6. Ear scratch response

Deegan and Cook first reported in 1958 that administration ofmescaline produces stereotypic hindlimb scratching of the headand ears in mice but not in other species (Deegan and Cook, 1958).Later work showed that DOM, DOI, DOET, and the 4-ethoxy analogof mescaline (escaline) also induce the ear scratch response (ESR)(Kulkarni, 1973; Yim et al., 1979; Darmani et al., 1990b; González-Maeso et al., 2007). It appears that the ESR is mediated by 5-HT2Areceptors, because the effect of DOI is blocked by ketanserin andspiperone (Darmani et al., 1990b). It should be noted that the ESR isnot induced by indoleamine hallucinogens (Yim et al., 1979). In fact,LSD and 5-MeO-DMT actually block the ESR induced by mescaline,DOM, and DOI (Chen and Bohner,1960; Borsey et al., 1964; Darmaniet al., 1990b). Based on the finding that the DOI-induced ESR is alsoinhibited by the 5-HT1A/1B agonist RU 24,969 but not by the 5-HT1Aagonist 8-OH-DPAT (Darmani et al., 1990b), it appears that blockadeof the ESR by the indoleamine hallucinogens involves interactionsbetween 5-HT2A and 5-HT1B receptors. This hypothesis needs to beevaluated by testing indoleamine hallucinogens in 5-HT1Bknockout mice or in mice pretreated with a selective 5-HT1Bantagonist.

7. Conclusions

Despite the structural differences between indoleamine andphenylalkylamine hallucinogens, these agents evoke a nearlyidentical spectrum of behavioral effects in rats and provoke similarmental and subjective states in humans. As summarized in thisreview, it is clear that activation of the 5-HT2A receptor playsa primary mechanistic role in mediating the behavioral effects ofthe indoleamine and phenylalkylamine classes of serotonergichallucinogens. Indeed, there is a wide consensus that administra-tion of 5-HT2A antagonists blocks the effects of hallucinogens onHTR, drug discrimination, exploratory and investigatory behavior,and sensorimotor gating in rats. Most importantly, clinical inves-tigations have shown that 5-HT2A antagonists block most, althoughcertainly not all, of the subjective and behavioral effects of psilo-cybin (Vollenweider et al., 1998; Carter et al., 2005, 2007). Recentexperiments have also demonstrated 5-HT2A involvement in thediscriminative stimulus effects of hallucinogens in non-humanprimates (Li et al., 2008). Lastly, there tends to be a strong corre-lation between the behavioral potencies of hallucinogens inanimals and humans and 5-HT2A binding affinity (Glennon et al.,1984; Titeler et al., 1988; Sadzot et al., 1989). Thus, over the lasttwo decades, most research focusing on the mechanism of actionfor the unitary pharmacological effects of serotonergic hallucino-gens has concentrated primarily on effects mediated by 5-HT2Areceptors.

It is currently accepted that extremely potent phenylisopropyl-amine (“amphetamine”) hallucinogens such as DOB and DOI arehighly selective for 5-HT2 sites, and it thus follows quite logicallythat the behavioral effects of those compounds are likely to beexclusively 5-HT2-mediated. By contrast, the indoleamine halluci-nogens are not 5-HT2 selective and bind to a much larger set ofmonoamine receptors. Although the two classes of hallucinogens

produce similar effects, it is likely that the ancillary receptorinteractions of indoleamine hallucinogens modulate their overalleffects on perception, cognition, and behavior. Consistent with thecomplexity of the binding profiles of indoleamine hallucinogens,there is evidence that the behavioral profiles of these compoundsare more complex than those of their phenylalkylaminecounterparts.

A large amount of evidence demonstrates that both 5-HT1A and5-HT2A receptors are responsible for the behavioral effects ofindoleamine hallucinogens. This conclusion is derived extensivelyfrom drug discrimination studies and from studies on the explor-atory and investigatory behaviors of rats in the BPM. Additionally,indoleamine hallucinogens elicit behavioral components of the5-HT syndrome (lateral head weaving, hindlimb abduction, back-ward locomotion, and lower lip retraction) and direct inhibitoryeffects on the firing of serotonergic DRN neurons that are rarely, ifever, induced by phenylalkylamine hallucinogens. There is alsoevidence that 5-HT1 receptor activation by indoleamines acts tosuppress expression of HTR, ESR, and other 5-HT2A-mediatedbehavioral effects, a conclusion that is supported by some clinicaldata (Strassman, 1996).

For LSD, DA receptors appear to play an additional role inmediating certain aspects of the behavioral effects of the drug,especially in the drug discrimination paradigm. Freedman hasnoted that in humans there seems to be a secondary temporalphase of LSD action that involves ideas of reference or paranoidideation, effects not seen with indolealkylamines or phenylalkyl-amines (Freedman, 1984). Based on that observation, Nichols andcolleagues (Marona-Lewicka et al., 2005) have theorized that theparanoid stage of the LSD intoxication may be related to the(delayed) dopaminergic discriminative stimulus effects of LSD andthe delayed hyperactivity produced by LSD in the rat BPM. Nicholshas also suggested that secondary non-5-HT2A receptor-effects ofLSD may be at least partially responsible for the exquisitely highbehavioral potency of that drug relative to other serotonergichallucinogens (Nichols, 1997).

In addition to LSD, other hallucinogens have been found toproduce biphasic behavioral effects. In rats, the combination of5-MeO-DMT and an MAO inhibitor produces an initial decrease inlocomotor activity followed by a gradual increase in activity that ismediated by 5-HT2A receptors (Halberstadt et al., 2008). Similarfindings have been reported for high doses of DOM and mescaline(Yamamoto and Ueki, 1975; Pálenícek et al., 2008), although thereceptor mechanisms responsible for the biphasic effects of thoseagents have not been elucidated. We have also found that admin-istration of high doses of phenylalkylamine hallucinogens to micecan produce biphasic locomotor effects. Thus, both indoleamineand phenylalkylamine hallucinogens can produce effects in thedrug discrimination and locomotor activity paradigms that occur indiscrete temporal phases. Further studies are needed to determinewhether pharmacokinetic or pharmacodynamic factors areresponsible for the biphasic behavioral profiles displayed by certainhallucinogens.

The finding that hallucinogens are agonists at the 5-HT2Creceptor has confounded the hypothesis that these agents act viaa 5-HT2A-dependent mechanism. There is a growing consensus,however, that the effects of hallucinogens are not mediated by the5-HT2C receptor, and it appears that activity at the 5-HT2C receptoractually serves to attenuate many of the behavioral effects ofhallucinogens. The ability of DOI to reduce prepulse inhibition inrats is significantly attenuated by treatment with the 5-HT2C-selective agonist WAY-163,909 (Marquis et al., 2007). We haveshown that 5-HT2A and 5-HT2C receptors exert opposing effects onlocomotor activity in mice (Halberstadt et al., 2009). Similar find-ings have been reported for HTR (Vickers et al., 2001; Fantegrossi


et al., 2010). Importantly, recent clinical trials with the selective 5-HT2C agonist lorcaserin for weight loss have shown that thiscompound does not produce any hallucinogen-like effects (Smithet al., 2009, 2010). Given the lack of significant neuropsychiatriceffects of lorcaserin, it appears highly unlikely that hallucinogenbinding to 5-HT2C receptors contributes to hallucinogenesis.

Recently, evidence has emerged that there are sometimessubstantial differences between the effects of serotonergic anddopaminergic drugs on behaviors in rats and mice that cannot beascribed to cross-species differences in the behavioral paradigms perse. As an example, PPI studies with DA agonists have shown thatpharmacological antagonists and KO mice reveal diametricallyopposite effects in mice versus rats (Ralph-Williams et al., 2002;Doherty et al., 2008). Similar species differences have been notedfor PPI studies with hallucinogens, with indolealkylamine hallucino-gens disrupting PPI in rats but increasing PPI inmouse strains. Indeed,for PPI themouse resultsmay actually bemore predictive of effects ofhallucinogens on PPI in humans (Gouzoulis-Mayfrank et al., 1998),although the effects observed in human volunteers are heavilydependent on the testing parameters used (Vollenweider et al., 2007).

We have recently reported evidence that indoleamine and phe-nylalkylamine hallucinogens evoke distinct effects on exploratoryand investigatory behaviors inmice. Thisfinding contrastswith datafromrats,which showed that the two classes of hallucinogens evokesimilar behavioral profiles. In mice, moderate doses of DOI(Halberstadt et al., 2009) and mescaline produce increases in loco-motor activity that aremediated by the 5-HT2A receptor. By contrast,indoleamine hallucinogens such as psilocin and 5-MeO-DMTproduce decreases in locomotor activity that are mediated by the5-HT1A receptor (Halberstadt et al., 2010). These findings demon-strate that it is possible to differentiate these two classes of hallu-cinogens behaviorally. Furthermore, in light of the PPI data, itappears that mice may be highly sensitive to the 5-HT1A-mediatedbehavioral effects of indoleamine hallucinogens. Thus, in contrast torats, mice may serve as a useful rodent species to probe the contri-bution of 5-HT1A receptors to indoleamine-induced behavioraleffects. It is important to note that evidence has been reportedpreviously that phenylalkylamine and indoleamine hallucinogenscan be distinguished by their behavioral effectse the former but notthe latter class of agents induce the ESR inmice. However, the recentevidence from the mouse BPM is among the first to demonstratethat the two structural classes of hallucinogens can induce distinctbehavioral profiles. Additional studies, both in rodents and humans,are necessary to determine the significance of these behavioraldifferences and to explore whether there are subtle behavioraldifferences in thehumanpsychopharmacologyof these compounds.More generally, there is a need for clinical trials that directlycompare the behavioral and subjective effects of a variety of phe-nylalkylamine and indoleaminehallucinogens in humanvolunteers.Given the recent resurgence in human testing of hallucinogens, itmay be possible to conduct these trials in the near future.

Acknowledgements

This work was supported by National Institute on Drug AbuseAwards R01DA002925 and F32DA025412, and the Veterans AffairsVISN 22Mental Illness Research, Education, and Clinical Center. Wewould like to thank Dr. Susan Powell for her helpful comments onthe manuscript, and Dr. Kirsten Krebs-Thomson for data collection.

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