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Hallucinogenic and Non-Hallucinogenic 5-Ht Agonists: Differences in Subjective Effects Parallel Differences in Receptor Dynamics

Hallucinogenic and Non-Hallucinogenic 5-Ht Agonists: Differences in Subjective Effects Parallel Differences in Receptor Dynamics

5-HT Agonists as Psychoactive Drugs edited by R.H. Rech and GA. Gudelsky

HALLUCINOGENIC AND NON-HALLUCINOGENIC 5-HT AGONISTS: DIFFERENCES IN SUBJECTIVE EFFECTS PARALLEL DIFFERENCES IN RECEPTOR DYNAMICS

l Kathryn A. Cunningham and James B. Appel

Behavioral Pharmacology Laboratory, Department of Psychology University of South Carolina, Columbia, SC 29208, U.S.A.

INTRODUCTION

There is considerable evidence in this volume and elsewhere that multiple receptor subtypes are involved in the activity of neuronal systems and, hence, in the effects of serotonergic drugs. At present, at least four such sUbtypes (5-HTIA, 5-HTIB, 5-HTIC, and 5-HT2) have been differentiated on the basis of anatomical distribution, synaptic localization, and pharmacological profile (Leysen et al., 1981; Middlemiss and Fozard, 1983; Peroutka and Snyder, 1979; Sills et al., 1984a,b). Investigations of 5-HT-stimulated adenylate cyclase (Barbaccia et al., 1983; Fillion et al., 1979; Nelson et al., 1980), 5-HT-modulated release of neurotransmitters (Ennis and Cox, 1982; Gothert, 1982; ganders-Bush, 1982), and ~lectrophysiological responses to serotonergic agents (Boakes et al., 1970; Aghajanian and Wang, 1978; Olpe, 1981; Segal, 1976; Sprouse and Aghajanian, 1986) indicate that each of these subtypes has functional significance. Studies of behavioral responses such as the "5-HT syndrome" and 5-HT-induced "head twitches" provide additional support for this possibility (Green et al., 1983; 1984; Lucki and Frazer, 1982; Lucki et al., 1984); the 5-HT syndrome appears to involve 5-HTI receptors while head twitches involve 5-HT2 receptors (Lucki et al., 1984). Indeed, particular components of the S-HT syndrome may be related to different receptor mechanisms; for example, forepaw treading and flat body posture may be the result of 5-HTIA receptor stimulation (Tricklebank et al., 1985).

The major concern of the present paper is with the role of 5-HT receptor subtypes in the actions of 5-HT agonists that are either hallucinogenic (psychotomimetic) or anxiolytic and the presumably related endogenous states with which the in vivo effects of these compounds are associated (hallucinations and anxiety). More specifically, we will review a series of ex- periments in which one sensitive and specific behavioral assay,

1. Present Address: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77550.

217 218 STIMULUS EFFECTS OF S-HT AGONISTS

drug discrimination (Appel et al., 1982), has been used in an effort to: 1) systematically compare the stimulus effects of several S-HT agonists that are purported to act at different S-HT receptor subtypes and, 2) evaluate pharmacologically the mechanisms that might be subserving them.

By definHion, drug discrimination (DD) makes use of the fact that many centrally-active drugs (or, more accurately, drug effects) can be programmed to act as cues or signals for reinforcement (food, water, escape from shock, etc.), which is delivered conditional on the occurrence of some response (e.g., left or right lever press). Thus, the situation is analogous to the discrimination of "external" stimuli (lights, tones, etc.) except that the discriminative stimulus is the subject's own, drug-induced "internal state" (Overton, 1984). Since all discriminative stimuli are environmentally consequential, the procedure is both reliable and sensitive; that is, subjects respond with relatively little variability to minimal intensities of stimulation (doses). However, its primary value for neuropharmacology is that it is also specific; that is, 1) only drugs that act through similar neuronal mechanisms substitute for (mimic) particular training drugs or, stated in another way, novel drugs do not mimic training compounds solely because they may have similar phenomenological properties (in humans). Moreover, 2) only selective receptor antagonists block drug cues (Appel and Rosecrans, 1984; Rosecrans and Glennon, 1979); that is, a randomly-selected drug will not "mask" the cueing properties of a training compound because of its own psychoactive properties (Overton, 1984).

Drug discrimination has proven to be particularly useful in the analysis of hallucinogenic drug actions, perhaps because the effects of these substances are variable and difficult to analyze with other, less complex procedures (Appel et al., 1982). For example, for several years, it has seemed likely that the discriminative stimulus effects of indolealkylamine (e.g., d-lysergic acid diethylamide, LSD) and phenylalkylamine (e.g., 2,S-dimethoxyphenyl-4-methylphenylisopropylamine, DOM) hallucinogens are related to the interactions of these agents with S-HT2 neuronal systems. The evidence in support of this conclusion includes, but is not limited to, the following:

(1) Antagonists with a high affinity for 5-HT2 receptors (, , ) are the most effective antagonists of the discriminative stimulus properties of LSD (Colpaert et al., 1982, 1983, 1985; Cunningham and Appel, 1987; Nielsen et al., 1985). STIMULUS EFFECTS OF 5-HT AGONISTS 219

(2) The stimulus effects of DOM and the 5-HT2 agonist , both of which mimic LSD in rats (Kuhn et aI, 1977), are blocked by pirenperone (Friedman et al., 1984; Glennon et al., 1983).

(3) The 5-HT2 binding affinities (Ki values) of various phenylisopropylamine derivatives correlate significantly with both DD-derived ED50 values and hallucinogenic potencies (Glennon et al., 1982; Glennon, 1986b).

(4) The extent to which 5-HT antagonists block the quipazine cue correlates highly with the extent to which they inhibit 5-HT2, but not 5-HT1, binding (Friedman et al., 1984).

(5) There is no convincing evidence that any non-serotonergic neurotransmitter system is involved in the stimulus effects of hallucinogens (Appel et al., 1982).

In spite of the evidence implicating 5-HT2 systems in the effects of hallucinogens, LSD has been shown to displace both 5-HT1 and 5-HT2 ligands in vitro (Peroutka and Snyder, 1979). Therefore, the possibility-rhat the in vivo effects of hallu- cinogens are subserved by 5-HT1 in addition to 5-HT2 receptors cannot be dismissed.

Until recently, the stimulus properties of 5-HT precursors and purportedly selective 5-HT1 agonists have not been analyzed and remain less well-understood than those of LSD, DOM and quipazine. However, at least three attempts have been made to describe the mechanisms subserving the discriminable effects of the centrally-active 5-HT precursor 1-5-hydroxytryptophan (5-HTP). In these studies, the 5-HT releaser mimicked, and the 5-HT uptake inhibitor potentiated, the effects of the training drug (Barrett et al., 1982; Friedman et al., 1983); 5-HT2 agonists such as quipazine and LSD also mimicked 5-HTP (Cunningham et al., 1985). Neither classical (non-selective) 5-HT antagonists (, , , methiothepin) nor more selective 5-HT2 antagonists (ketanserin and pirenperone) attenuated the 5-HTP cue (Barrett et al., 1982; Cunningham et al., 1985; Friedman et al., 1983); however, the substitution of LSD for 5-HTP was blocked completely by ketanserin (Cunningham et al., 1985). These data suggest that 5-HTP may either stimulate a 5-HT receptor that is not the same as any identified previously or have complex (presynaptic?) actions at one or more subtypes of 5-HT receptors (5-HT1A, 5-HT1B and 5-HT2) that are not blocked by known 5-HT antagonists. The substitution of LSD for 5-HTP may be related to the mutual ability of these agents to 220 STIMULUS EFFECTS OF 5-HT AGONISTS

stimulate a subset of 5-HT2 receptors (perhaps indirectly) that is antagonized by ketanserin.

The importance of 5-HT2 receptors in mediating the stimulus properties of LSD, DOM and quipazine and the possibility that the 5-HTP cue may involve multiple 5-HT receptors prompted the present comparison of several 5-HT agonists; in particular, we systematically reexamined the discriminative stimulus effects of LSD in comparison with those of the 5-HTIA agonist 8-hydroxy-2(di-n-propylamino) tetralin (8-0HDPAT) and the 5-HTIB agonist l-(m-trifluoromethylphenyl) (TFMPP).

EXPERIMENT 1: LSD - SALINE DISCRIMINATION

Methods: The methods were similar to those used previously and are described in detail elsewhere (Cunningham and Appel, 1987). Rats (N=24) were trained (in commercially-available, two-lever chambers) to discriminate intraperitoneal (i.p) injections of LSD (0.08 mg/kg) from saline (0.9% NaCl). A fixed-ratio (FR 20) schedule of water reinforcement for "correct" responding (i.e., pressing the drug-appropriate lever following drug injection and the saline-appropriate lever following saline injection) was used. Once animals demonstrated mean individual accuracies of at least 85% correct over a period of 10 consecutive sessions, testing began. In substitution (transfer, generalization) tests, a wide range of doses of novel serotonergic compounds (putative 5-HT agonists) were given (i.p., in a volume of 1.0 ml/kg) in place of the training drug (LSD). These compounds were: 8-0HDPAT (0.02 - 0.64 mg/kg) , Ru 24969 (0.2 3.2 mg/kg), m-chloro- phenylpiperaz.ine (MCPPj 0.1 1.6 mg/kg), TFMPP (0.1 - 1.6 mg/kg) and quipazine (0.2 3.2 mg/kg). In combination (antagonism) tests, the following 5-HT antagonists were injected 60 min prior to the training drug (0.08 mg/kg of LSD): BC 105 (0.2 3.2 mg/kg), 2-bromolysergic acid diethylamide (BOL; 0.1 - 1.6 mg/kg), Ly 53857 (0.4 3.2 mg/kg), metergoline (0.05 - 0.8 mg!kg), ketanserin (0.2 - 3.2 mg/kg), pirenperone (0.0025 - 0.08 mg/kg) and sp.iperone (0.02 - 0.32 mg/kg).

Results: Of the novel compounds tested, the only substance that mimicked the training drug was quipazine (1.6 and 3.2 mg/kg), the stimulus properties of which appear to be mediated by 5-HT2 receptors (above). No dose of any 5-HTl agonist (5-HTIA or 5-HTIB) induced more than 50% LSD-appropriate responding (higher doses disrupted choice behavior and could not be tested). These effects are shown in Fig. 1. STIMULUS EFFECTS OF 5-HT AGONISTS 221

LSD Ru24969 8-OHDPAT o 100 , , I': 90 0

80 80 I\I 1 I\ ~70 0::.• o 0.60 T \!\J o " \ £ 'I', I , ~ 050 (/) ...J _ 40 '{ \l s ~30 ._.Ki 20 ./111"1.l' ~},,~,~. 20 10 1 ~. 10 o • """;''-1'-",1",.....1._1.....1 o o '.01 ,02 .04 .08 .16 02 0,4 OB 1.6 32 ,02.04 ,08 .16 ,32 ,64 Dose of DrU9 Img/kg)

TFMPP MCPP Quipazine o 100, I T 90 0

80 80

~ 70 T [ 60 T I, il £ o \ ,\ 1q \ T' , \ o 50 , c/) ..J I. \ i 40 \/\, \T ,f" 30 b. . ·-1 . """ «· 20 1.•.• .1\, 20 \ 10 ·1J11 10 1 'r •~"-'{,""-"---.1-..•...... • o o '0.1 0.2 0.4 DB 1.6 0., 0.2 0.4 0.8 1.6 0,2 Q4 0.8 1.6 3.2 Dose of Drug Img/mg)

Fig. 1. Results of dose-response and substitution tests with putatively selective 5-HT agonists in rats trained to discriminate LSD (0.08 mg/kg) from saline. Reprinted from: Cunningham, K. A. and Appel, J. B. Neuropharmacological reassessment of the discrimi- native stimulus properties of d-lysergic acid diethyl- amide (LSD). Psychopharmacology, 91: 67-73, 1987 with the permission of Springer-Verlag, A. G. 222 STIMULUS EFFECTS OF 5-HT AGONISTS

While hampered by an absence of available 5-HTI anta- gonists, combination testing also produced consistent results; both relatively selective 5-HT2 and less selective 5-HT antagonists blocked the LSD cue; indeed, the only substance given in combination with LSD that did not alter the amount of drug-appropriate responding was spiperon~Fig. 2).

ly53857 Metergoline Pirenperone Spiperooe 0 ,. 100 I ~ I T I I1: 90 0 80 1 ~ 80 o 70 r R ~ Iso 0 1 LJ 60i 050 1 ?-'" , ,,T 50$ ..• ,, l''. ' ; \ ~ '"_40 Q 40 § !! , •. s I\~, I. l' . a: ,f30 , " r 30 , '."i 1 \, 20 ,A b 20 , ,:1, 'i i " , 10 10 'r ~. 1 0 0 ~I, o 0.4 Q8 1.6 3.2 .05 U1 Q2 (14 Q8 OO25.oos .Q1 D2 J)4 .08 D2 D4 De .16 .32 Dose of Drug (mg/kg)

Fig. 2. Results of combination tests with Ly 53857, metergoline, pirenperone and in rats trained to discriminate LSD (0.08 mg/kg) from saline. Reprinted from: Cunningham, K. A. and Appel, J. B. Neuropharmacological reassessment of the discrimi- native stimulus properties of d-lysergic diethylamide (LSD). Psychopharmacology, 91: 67-73, 1987 with the permission of Springer-Verlag, A. G.

EXPERIMENT 2: 8-0HDPAT - SALINE DISCRIMINATION

Methods: In this experiment (Cunningham et ale, 1987) rat.s (N-24) were trained to discriminate 8-0HDPAT (0.4 mg/kg) from saline using methods similar to those of Experiment 1. After attaining criterion (85% correct for 10 consecutive sessions), testing began. Compounds given in substitution tests included the 5-HT agonists LSD (0.08-0.24 mg/kg), 5-MeODMT (5-methoxy-N,N-dimethyltryptamine; 0.5-4.0 mg/kg), (0.02-0.32 mg/kg) , quipazine (0.5, 1.0 mg/kg) and TFMPP STIMULUS EFFECTS OF 5-HT AGONISTS 223

(0.25-1.0 mg/kg). the novel anxiolytics (0.5 4.0 mg/kg) and (1.0 - 4.0 mg/kg). both of which have been reported to act at 5-HT1A receptors. and the classic (benzodiazepine) anxiolytic diazepam (0.5 8.0 mg./kg). antagonists tested in combination with 8-0HDPAT were: ketanserin (0.2 - 0.8 mg/kg). metergoline (0.5 8.0 mg/kg). methiothepin (0.125 - 0.5 mg/kg) and pirenperone (0.02 - 0.08 mg/kg). B-OHDPAT LlSURIDE LSD ,. I100 eo , , .0 I (/) W 80 .0 (/) I Ik z 70 a.0 70 ,~ (/) w w 60 I eo ~ a: l- SO 10 ~ a.< ...•. Cl 40 40 ~ J: CI) 0 I 30 co '0 ~a. I- 20 " z . 20 ~ w a: o 10 1<,~--1 10 a: w .1. a. 0 \. 0 , 1"" II II I i I I ( ( i 0 .1 .2 .4 .02 .04 .08 .16 .32 .08 .16 .24

DOSE OF DRUG (MG/KG)

Fig. 3. Results of dose-response and substitution tests with the ergot derivatives lisuride and LSD in animals trained to discriminate 8-0HDPAT (0.4 mg/kg) from saline. Reprinted from: Cunningham. K.A •• Callahan. P.M. and Appel. J.B. Discriminative stimulus properties of 8-hydroxy-2-(di-n-propylamino) tetralin (8-0HDPAT): implications for understanding the actions of novel anxiolytics. Eur. J. Pharmacol. 138: 29-36. 1987, with the permission of Elsevier Bio- medical Press.

Results: As might be predicted from Experiment 1. LSD did not mimic 8-0HDPAT (Fig. 3). nor did the 5-HTIB agonist TFMPP or the 5-HT2 agonists 5-MeODMT and quipazine (data not shown). Drugs that did substitute for 8-0HDPAT included lisuride. which is structurally similar to 8-0HDPAT (Fig. 3). buspirone and ipsapirone (TVX Q 7821; Fig. 4). 224 STIMULUS EFFECTS OF 5-HT AGONISTS

BUSPIRONE TVX a 7821 DIAZEPAM 100 100

10 I 80 :1 rn W 70 .I 70 rn •..1 w z 80 t- O eo :::l Il. \ rn 50 50 ~ w , \ ::E...•. a:: 1\ \ t- 40 " 40 ~ e,4( , I" \ • rn C 30 \\ 30 ~ :I: " " ~"" c, 0 20 20 rn I w co 1 \\ a:: t- 10 10 Z \!i... w 0 0 0 a:: III I I I i I a..W 2 4 2 4 .5 2 4 8 DOSE OF DRUG (MG/KG)

Fig. 4. Results of substitution tests with anxiolytics in animals trained to discriminate 8-0HDPAT (0.4 mg/kg) from saline. Reprinted from: Cunningham, K.A., Callahan, P.M. and Appel, J.B. Discriminative stimulus properties of 8-hydroxy-2- (di-n-propylamino) tetralin (8-0HDPAT): implications for understanding the actions of novel anxiolytics. Eur. J. Pharmacol. (138: 29-36, 1987) with the permis- sion of Elsevier Biomedical Press.

When given in combination with 8-0HDPAT, none of the 5-HT antagonists tested significantly attenuated the 8-0HDPAT cue; when administered alone, none of these agents mimicked the training drug (data not shown).

EXPERIMENT 3: TFMPP - SALINE DISCRIMINATION

Methods: Rats (N=24) were trained to discriminate TFMPP (0.8 mg!kg) from saline using methods similar to those of Experiment 1 and described in detail elsewhere (Cunningham and Appel, 1986). Compounds given in substitution tests included LSD (0.01 - 0.16 mg/kg), fenfluramine (0.8 mg/kg - 1.6 mg/kg), MCPP STIMULUS EFFECTS OF 5-HT AGONISTS 225

(0.1 - 1.6 mg/kg), Ru 24969 (0.1 - 1.6 mg/kg), 8-0HDPAT (0.02 - 0.32 mg/kg) and quipazine (0.2 - 3.2 mg/kg). Compounds tested in combination with TFMPP were: BC 105 (1.6 - 12.8 mg/kg), BOL (0.8 - 1.28 mg/kg), ketanserin (0.8 - 6.4 mg/kg) , Ly 53857 (0.2 1.6 mg/kg), metergoline (0.4 - 6.4 mg/kg), pirenperone (0.08 - 0.64 mg/kg) and spiperone (0.08 - 1.28 mg/kg).

Results: In marked contrast to Experiment 1, MCPP and Ru 24969 (as well as TFMPP) mimicked the training drug (as did the 5-HT releaser fenfluramine). Quipazine and 8-0HDPAT elicited saline- lever responding. The results with LSD were difficult to interpret; while all doses tested (0.01 0.16 mg/kg) induced at least some responding (10 50%) on the drug appropriate lever, LSD could not be said to substitute reliably for TFMPP. The effects of putative 5-HTIA (8-0HDPAT), 5-HTIB (Ru 24969), and 5-HT2 (LSD) agonists in animals trained to discriminate TFMPP from saline are shown in Fig. 5.

Ru24969 LSD 8-0HDPAT 0, 100 , go' I': 0 80 80 r, T 11\ 0 0 70 0- I\ I"\ ~ £80 I 60 I 1 0- I '\J :i !iso I SO<;; u, 51 0 ~40 TI \',1 408. ~ & \ ~ ~30 \ 3Oe:: 0- \ 20 1 20 10 10 ~ 1 0 .JiV' 0 , 0"#'(l1 ' Q2 <1' M 1.6 .01 .02 .04 DB 16 .02 .04 .08 :16 .32 Dose of Drug (mg/kg)

Fig. 5. Results of dose-response and substitution tests with Ru 24969, LSD, and 8-0HDPAT in rats trained to discriminate TFMPP (0.8 mg/kg) from saline. Reprinted from: Cunningham, K. A. and Appel, J. B. Possible 5-hydroxytryptamine-l (5-HTl) receptor in- volvement in the stimulus properties of l-(m-tri- fluoromethylphenyl) piperazine (TFMPP). J. Pharmacol. Exp. Ther. 237: 369-377, 1986 with the permission of Williams & Wilkins, Inc. 226 STIMULUS EFFECTS OF 5-HT AGONISTS

The results of combination tests also contrast markedly with those of Experiment 1. No dose of any 5-HT2 antagonist had any effect on the TFMPP cue; typical data are shown in Fig. 6. While spiperone and metergoline reduced drug appropriate responding somewhat (40-50%), even relatively high doses of these compounds did not antagonize TFMPP completely.

Spiperone Metergoline BC105 BOl 0 100 : 1 I': 900 eo eo "c '"70 J ~ 70 & 0 .!l 60 ~ = r--~\I 1 1 60i I\ I a: 50 I\ 'j \ I u,:Ii ! I [\ '! I [1 I I \ ;40 I \ 1l. \ :t c ~30 1 \"11' \ }\ 1"1 30 20 I l"t> ~ 1 20 "- .L 1 " '0 10

0 0 ">f'1, 1 1 0.. o .08 .16 .32 .641.28 0.8 1.6 3.2 6.' 1.6 3.2 6A 12.8 0.8 16 3.2 6A Dose of Drug (mg/kg)

Fig. 6. Results of combination tests with spiperone, metergoline, BC 105 and BOL in rats trained to discriminate TFMPP (0.8 mg/kg). Reprinted from: Cunningham, K. A. and Appel, J. B. Possible 5-hydroxy- -l (5-HT1) receptor involvement in the sti- mulus properties of l-(m-trifluoromethylphenyl) piper- azine (TFMPP). J. Pharmacol. Exp. Ther. 237: 369-377, 1986 with the permission of Williams & Wilkins, Inc.

GENERAL DISCUSSION

The results of the LSD Saline experiment extend and support those reported previously. Of the many, diverse psychoactive compounds that have now been analyzed, only other indolealkylamine and phenylalkylamine hallucinogens, putatively hallucinogenic beta-carbolines, structural congeners of LSD (most of which are not hallucinogenic) and S-HT agonists that have at least some affinity for 5-HT2 receptors, substitute completely for LSD (Table 1); the only compounds that block the LSD cue significantly are 5-HT2, and non-selective 5-HT antagonists (Table 2). STIMULUS EFFECTSOF 5-HT AGONISTS 227

TABLE 1: Results of substitution tests in rats trained to discriminate LSD from saline.

Complete Substitution (> = 80%)

HALLUCINOGENS:

DOB (2,5-Dimethoxy-4-bromo- phenyl)-2-aminopropane Silverman and Ho, 1979 DOM Silverman and Ho, 1979 Cameron and Appel, 1973 MDA Shannon et al., 1984 5-MeODMT Rosecrans and Glennon, 1979 2,5-Dimethoxy-4-ethoxyphenyl isopropylamine Oberlender et al., 1984 2,4-Dimethoxy-5-ethoxyphenyl isopropylamine Oberlender et al., 1984 4,5-Dimethoxy-2-ethoxyphenyl isopropylamine Oberlender et al., 1984 Schechter and Rosecrans, 1972 2,4.5- Silverman and Ho, 1979

(TETRA-HYDRO-)BETA-CARBOLlNES: 6-MeO-THBC Nielsen et al., 1982 THBC Nielsen et al., 1982

STRUCTURAL CONGENERS (): Lisuride White and Appel, 1982 N(6)-ethyl norlysergic acid-N,N-diethylamide Hoffman and Nichols, 1985 N(6)-allyl norlysergic acid-N,N-diethylamide Hoffman and Nichols, 1985 N(6)-propyl norlysergic acid-N,N-diethylamide Hoffman and Nichols, 1985

5-HT2 AGONISTS: BL-3912 (2,5-dimethoxy-4-methyl- alpha-ethyl-phenethylamine) Winter, 1980 MK-212 (6-chloro-2-(1-piperizinyl) -pyrazine) White and Appel, 1982 Quipazine Colpaert et al., 1979

OTHERS: Colpaert, 1984

------228 STIMULUS EFFECTS OF 5-HT AGONISTS

TABLE 1: Results of substitution tests in rats trained to discriminate LSD from saline (continued).

Partial Substitution (60 - 79%)

5-HT ANTAGONISTS: Cyproheptadine Colpaert et al., 1979 Methysergide Colpaert et al., 1979 Colpaert et al., 1979

PHENYLETHYLAMINES: 1-(2, 5-Dimethoxy-4-(2-butyl) phenyl -2-aminopropane) Oberlender et al., 1984 Fenfluramine Winter, 1980 PMA (alpha-methyl-4-methoxphenyl ethylamine) Winter, 1984 Sch 12679 (N-Methyl-1- phenyll-7,8-dimethoxy -2, 3,4,5-tetrahydro -3-benzazepine) Winter, 1980

OTHERS: Clonidine Colpaert, 1984 DPI (3,4-Dihydroxphenyl amino)-2-imidazoline) Appel et al., 1980 Scopolamine Cameron and Appel, 1973 Delta-9 THC Hirschhorn and Rosecrans, 1976 Xylazine Colpaert, 1984

No Substitution «- 59%)

DOPAMINE AGONISTS: Schechter and Rosecrans, 1972 Kuhn et al., 1978 Holohean et al., 1982 Holohean et al., 1982

5-HTl AGONISTS: MCPP Cunningham and Appel, 1987 8-0HDPAT Cunningham and Appel, 1987 Ru 24969 Cunningham and Appel, 1987 TFMPP Cunningham and Appel, 1987 STIMULUSEFFECTS OF 5-HT AGONISTS 229

TABLE 1: Results of substitution tests in rats trained to discriminate LSD from saline (continued)o

No Substitution (continued; < = 59%)

5-HTPRECURSORS and UPTAKE INHIBITORS: Chlorimipramine Kuhn et al., 1978 Fluoxetine Kuhn et al., 1978 5-HTP Cunn.ingham et al., 1985 l.- Kuhn et al., 1978

STRUCTURAL CONGENERS (ERGOLINES) ; BOL Colpaert et al., 1982 I-LSD Cameron and Appel, 1973 LY-53857 (6-methyl-l-(1- methyl ethyl) -8- carboxylic acid, 2-hydroxy- 1-methylpropyl ester (z)-2-butenedioate)(1:1) Cunningham and Appel, 1987

NEUROTRANSMITTER ANTAGONISTS: BC 105 () Colpaert et alo, 1982 Cameron and Appel, 1973 Colpaert et alo, 1982 White and Appel, 1982 Ketanserin Nielsen et a1., 1985 Metergoline Colpaert et al., 1982 Methiothepin Co1paert et alo, 1982 Ritanserin Colpaert et alo, 1985 Spiperone Colpaert .et al., 1982 Cunningham and Appel, 1987

OPIATES: Meperidine Hirschhorn and Rosecrans, 1974 Methadone Hirschhorn and Rosecrans, 1976 Morphine Hirschhorn and Rosecrans, 1976 Nalorphine Hirschhorn and Rosecrans. 1976 Pentazocine Hirschhorn and Rosecrans, 1976

OTHERS: Barbital Hirschhorn and Winter, 1975 Ditran Kuhn et al., 1977 Harmaline Nielsen et al., 1982 Harmane Nielsen et al., 1982 5-MeOT (5-methoxytryptamine) White and Appel, 1982 PCP (Phencyclidine) Kuhn et al., 1977 230 STIMULUS EFFECTS OF 5-HT AGONISTS

TABLE 2: Results of combination tests in rats trained to discriminate LSD from saline.

Drugs that antagonize LSD « = 30% drug-appropriate responding)

5-HT2 ANTAGONISTS: Ketanserin Nielsen et ale, 1985 Ly-53857 Cunningham and Appel, 1987 Pirenperone Colpaert and Janssen, 1983 Ritanserin Colpaert et al., 1985 Trazodone Cunningham and Appel, 1987

NON-SELECTIVE 5-HT ANTAGONISTS: BC 105 Holohean et al., 1982 BOL Colpaert et al., 1982 Metergoline Cunningham and Appel, 1987

Partial (incomplete) antagonism (31 < = 60% drug-appropriate responding)

NON-SELECTIVE 5-HT ANTAGONISTS:

Cinanserin Colpaert et al., 1982 Cyproheptadine Colpaert et al., 1982 Methiothepin Colpaert et al., 1982 Methysergide Colpaert et al., 1982 Mianserin Colpaert et al., 1982

Drugs that do not antagonize LSD (> = 61% drug-appropriate responding)

DA ANTAGONISTS: Kuhn et al., 1978 Chlorpromazine Kuhn et al., 1978 Kuhn et al., 1978 Haloperidol Kuhn et al., 1978 Sulpiride Appel et al., 1980 Trifluoperizine Kuhn et al., 1978 Spiperone Colpaert et al., 1982

NE ANTAGONISTS: Phentolamine Kuhn et al., 1978 Propranalol Kuhn et al., 1978 STIMULUS EFFECTSOF 5-HT AGONISTS 231

TABLE 2: Results of combination tests in rats trained to discriminate LSD from saline (continued).

Drugs that do not antagonize LSD (continued; > = 61% drug-appropriate responding)

5-HT UPTAKE INHIBITORS: Chlorimipramine Kuhn et al,, 1978 Citalopram Kuhn et al., 1978 Fluoxetine Kuhn et al,, 1978

OTHERS:

Atropine Kuhn et aI, 1978 8-0HDPAT Cunningham and Appel, 1987 Naloxone Kuhn et al., 1978 Kuhn et al., 1978 Xylamidine Kuhn et al,, 1978

Because 8-oHDPAT is a potent inhibitor of 5-HT1A binding (Hamon et al., 1984; Middlemiss and Fozard, 1983) and there is Iitt Le evidence to suggest that this compound acts through non-serotonergic systems (Cunningham et al., 1987; Hjorth et al., 1982; Glennon, 1986a), 5-HT1A neuronal systems have been said to playa role in the actions of atypical anxiolytics (See Glennon, this volume). The results of Experiment 2 support this possibility, at least indirectly, by demonstrating the following: 1) neither 5-HTIB (Ru 24969, TFMPP) nor 5-HT2 agonists (LSD, quipazine) mimic 8-0HDPAT; 2) 5-HT2 antagonists (ketanserin, methiothepin and pirenperone) do not block the 8-DHDPAT cue. However, the result that is most important to the present discussion is that the discriminable (subjective) effects of atypical anxiolytics are unlike those of LSD and related hallucinogens.

The stimulus properties of TFMPP (Experiment 3) appear to be subserved by mechanism(s) similar to those of the novel 5-HTIB agonists MCPP and Ru 24969. The effects of these compounds can be differentiated from those of some (e.g., LSD and quipazine) but not all (e.g.,8-0HDPAT) 5-HT agonists on the basis of the fact that they are not attenuated by putative 5-HT2 antagonists (Cunningham and Appel, 1986) and that, like 8-DHDPAT, they are clearly different from those of hallucinogens (Cunningham et al., 1987).

In conclusion, the results of all of these experiments, along with those appearing elsewhere in this volume, indicate that subtypes of 5-HT receptors, identified originally by 232 STIMULUS EFFECTS OF 5-HT AGONISTS

radioreceptor binding assays (Peroutka and Snyder, 1979; Sills et al., 1984a,b) are indeed functionally significant and appear to selectively mediate different effects of important psychoactive substances. While it is true that LSD, 8-0HDPAT, and TFMPP have been characterized as 5-HT agonists, these compounds have discriminably different properties (induce different "subjective" states) that involve different (serotonergic) neuronal mechanisms. Because 8-0HDPAT inhibits 5-HT1A binding preferentially (Middlemiss & Fozard. 1983) while TFMPP, MCPP, and RU24969 inhibit 5-HT1B binding (Sills et. al., 1984b) and antagonists that block the LSD cue (ketanserin. pirenperone, BC lOS, LY 53857~ metergoline) displace 5-HT2 binding (Cunningham and Appel, 1987), we have concluded that the mechanisms subserving the 8-0HDPAT, TFMPP and LSD cues are mediated by 5-HT1A, 5-HT1B and 5-HT2 receptors, respectively.

However, these conclusions must be tempered by at least three considerations: 1) While neither the 8-0HDPAT nor the TFMPP cues could be blocked by any of the substances used, selective 5-HT1A or 5-HT1B antagonists have not yet been developed. Without such "tools," direct pharmacological proof of the importance of these receptor subtypes in the actions of 8-0HDPAT, TFMPP or, for that matter, any putative "agonist" must remain speculative. 2) Although a common interaction with one neurotransmitter system or even a subtype of one system may serve as one site of action for a complex effect such as a drug cue, all drugs have many effects which may be the result of interactions with many neuronal systems. Thus, -although the stimulus properties of TFMPP, for example, appear to depend primarily on 5-HTIB systems, an interaction of TFMPP with catecholaminergic systems could modulate these effects considerably (Cunningham and Appel, 1986). However, it should be noted that, when and norepinephrine agonists and antagonists were tested, no significant substitutions or antagonisms were observed in animals trained to discriminate LSD (White and Appel, 1982). 8-0HDPAT (Cunningham et al., 1987) or TFMPP (Cunningham and Appel, 1986). 3) Finally, the results, as always, depend upon particular parameters of the assay used. Just as in radioreceptor assays, lC50's are dependent upon both the ligand used and its concentration in the tissue being studied (Enna, 1978), DD results depend upon the dose of the drug used during training (White and Appel, 1982). Since each of the present experiments involved only one such dose, further interpretations should be withheld until research using additional doses of the various training drugs has been conducted. STIMULUS EFFECTS OF 5-HT AGONISTS 233

ACKNOWLEDGEMENTS

This research was supported by USPHS Grant 2 ROI DA02543, from the National Institute on Drug Abuse and by an Advanced Predoctoral Fellowship from the Rhude M. Patterson Foundation. In addition, we thank the following companies for their gifts of various drugs: Bristol-Myers (Evansville, IN); Farmitalia (Milan, Italy); Hoffman-LaRoche (Nutley, NJ); Janssen Pharmaceutica (Piscataway, NJ); Eli Lilly (Indianapolis, IN); Pfizer (Groton, CT); Robins (Richmond, VA); Roussel (Romainville, France); Sandoz (East Hanover, NJ); Schering, A. G. (Berlin, FRG); Smith, Kline and French (Philadelphia, PA); Tropenwerke (Cologne, FRG).

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