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A Drug Discrimination Analysis of Lysergic Acid Diethylamide (LSD

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A Drug Discrimination Analysis of Lysergic Acid Diethylamide (LSD f5Jfl.35K5/82/221 1.0206$02.OO/O THY. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUI’Ics Vol. 221, No. I Copyright © 1982 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. A Drug Discrimination Analysis of Lysergic Acid Diethylamide (LSD): In Vivo Agonist and Antagonist Effects of Purported 5-Hydroxytryptamine Antagonists and of Pirenperone, A LSD-Antagon 1st1 FRANCIS C. COLPAERT, CARLOS J. E. NIEMEGEERS and PAUL A. J. JANSSEN Department of Pharmacology, Janssen Pharmaceutica Research Laboratories, B-2340 Beerse, Belgium Accepted for publication January 1 1 , 1982 ABSTRACT Colpaert, Francis C., Carlos J. E. Niemegeers and Paul A. J. mimicked LSD; the maximum LSD-like agonist effect ranged Janssen: A drug discrimination analysis of lysergic acid dieth- from 1 4 (cinanserin) to 86% (methysergide and mianserin). A ylamide (LSD): In vivo agonist and antagonist effects of pur- dose of 40 mg/kg of methysergide or mianserin produced ported 5-hydroxytryptamine antagonists and ofpirenperone, a effects which were similar to those of 40 mg/kg of mescaline LSD-antagonist. J. Pharmacol. Exp. Ther. 221 : 206-214, and the peak agonist activity of methysergide, mianserin and 1982. cyproheptadine exceeded their peak antagonist effects. Stim- ulus generalization of these agents with 0.1 6 mg/kg of LSD An in vivo analysis was conducted of the pharmacological typically was a linear function of dose. LSD-like agonist and interactions of the putative 5-hydroxytryptamine (5-HT) recep- antagonist effects of moderate intensity coexisted at the same tor blocking agents metergoline, methysergide, 2-bromo- lys- dose of the same agent, but strong agonist activity was clearly ergic acid diethylamide (LSD), mianserin, pizotifen, cyprohep- incompatible with strong antagonist activity and vice versa. tadine, metitepine and cinanserin, with LSD. Rats were trained Only pirenperone, a newly synthesized compound, effectively to discriminate i.p. injections of 0.1 6 mg/kg of LSD from saline antagonized LSD. This antagonism of LSD was unique in that injections in a two-lever procedure in which food served as the it occurred at low (0.01 -0.1 6 mg/kg) s.c. and oral doses, reinforcer. Potential antagonists were given as a s.c. pretreat- proceeded along a linear and steep gradient, reached the ment (t = 60 mm) before the injection (t = 1 5 mm) of either 1 00% level of effect and was not associated with any agonist LSD or saline to test for antagonist and LSD-like agonist activity. It is suggested 1 ) that LSDs discriminative stimulus activity, respectively. The 5-HT antagonists produced only a properties in the rat are contingent upon agonist effects at 5- partial antagonism of LSD; their dose-response curve in antag- HT receptor sites in the brain, 2) that the putative 5-HT antag- onizing LSD was invariably curvilinear, reached a ceiling level onists mentioned above act complexly as partial and mixed at 29 (methysergide and metitepine) to 71 % (pizotifen) of agonists/antagonists at these sites and 3) that pirenperone is effect, and assumed a biphasic shape with methysergide, mian- a pure antagonist of LSD. serin and cyproheptadine. In addition, the 5-HT antagonists LSD is among the most powerful agents known to date in Like 5-HT, LSD inhibits the firing rate of neurons in the raphe producing psychotropic effects (e.g., hallucinations and psy- nuclei (Aghajanian et al., 1970, 1973) and in areas receiving choses) in man. Prominent among the pharmacological and identified 5-HT terminals (Aghajanian et al., 1972; Haigler and biochemical properties of LSD is its ability to interact with the Aghajanian, 1974a). LSD also blocks the excitatory effects of 5- receptor sites of 5-HT in the brain. Much of the stereospecific HT in areas in which 5-HT terminals have a sparse distribution binding of d-LSD to brain tissue occurs on 5-HT seceptors (Boakes et al., 1970). (Bennett and Aghajanian, 1974; Peroutka and Snyder, 1979). Research into the mechanism of action of LSD in producing psychotropic effects has been greatly hampered by the paucity of psychophysiological methods through which these physio- Received for publication January 21, 1981. ‘This work was supported by a grant from the Instituut voor Wetenschappelijk logical effects and binding properties can be related to the Onderzoek in Nijverheid en Landbouw. Parts of the present data were presented behavioral action of the drug (Brawley and Duffield, 1972). One at the 12th Collegium Internationale Psychopharmacologium Congress, Gdteborg, June 22-26, 1980 (Abstract No. 130) and at the 8th International Congress of particularly interesting development, therefore, is that of the Pharmacology, Tokyo, July 19-24, 1981 (Abstract No. 1224). drug discrimination technique. Drug discrimination recently ABBREVIATIONS: LSD, lysergic acid diethylamine; 5-HT, 5-hydroxytryptamine; OS, discriminative stimulus; OL, drug lever; SL, saline lever; FR, fixed-ratio; FRF, first reinforcement. 206 1982 LSD and 5-HT Antagonists 207 has evolved as a method to determine and quantify stimulus (21 ± 1#{176}C;relative humidity 65 ± 5%). Tap water was available freely. properties of drugs which are not directly accessible to an Access to dry powdered standard laboratory food was limited to 2 hr a outside observer (Colpaert and Rosecrans, 1978; Ho et al., 1978; day, as specified below. A total of 93 rats were used in the experiments described here. The Lal, 1977). The technique typically involves training laboratory sample of animals participating in any given experiment was selected animals to discriminate the perceived stimulus effects ofa given from the pool of trained rats which were available at that point of time drug from those of its vehicle, and there is considerable evidence during the 37-month period it took to conduct the study. to suggest that the DS properties of at least some drugs in Apparatus. Six identical small animal test cages were used as animals are closely related to their subjectively perceived effects experimental chambers. They were programed by solid-state logic in humans (for review, see: Colpaert, 1978; Weissman, 1978). programing equipment and fitted with a house light and two levers. That rats can discriminate LSD from saline was originally Between the two levers, a food pellet receptacle was mounted 2 cm reported by Hirschhorn and Winter (1971). Subsequent drug above the cage floor. discrimination work on LSD has reached two important con- Discrimination training procedure. The drug discrimination pro- clusions. First, studies of cross-generalization involving LSD cedure used here has been described in detail elsewhere (Colpaert et aL, 1976). Daily discrimination training started after habituation to the (Cameron and Appel, 1973; Kuhn et al., 1978; Schechter and experimental conditions and initial acquisition of the lever press re- Rosecrans, 1972; White et al., 1977, 1979; Winter, 1979) have sponse. Fifteen minutes before it was placed in the test cage, the rat indicated that stimulus generalization with LSD in the rat was injected i.p. with either the 0.16 mg/kg training dose of d-LSD represents a necessary, albeit perhaps not sufficient, condition tartrate or physiological saline. The injection volume of saline, LSD or for prediction of hallucinogenic activity of the indole/pheneth- any other drug solution was 1 ml/100 g b. wt. Depending on whether ylamine type in man (Winter, 1975a, 1980; Kuhn et al., 1977). the rat was injected with LSD or saline, it obtained food by pressing A second conclusion is that the DS properties of LSD are either the DL or the SL, respectively. After every 10th lever press (FR contingent upon agonist effects of the drug at 5-HT receptor 10) on the correct lever, a 45-mg food pellet was delivered by a food sites in the brain. The evidence in support of this conclusion dispenser. Responses on the incorrect lever (i.e., the SL after LSD and consists mainly of data showing that purported 5-HT receptor the DL after saline) had no consequences. The lever assignments were DL: left, SL: right in about half of the animals and SL: left, DL: right blocking agents antagonize the DS produced by LSD (Kuhn et in the other half. These assignments remained unchanged throughout al., 1978; Winter, 1978) as well as that of mescaline (Browne the study. The number of responses made on either lever before the and Ho, 1975; Winter, 1975b, 1978) and quipazine (White et al., FRF was obtained (and, thus, when 10 responses were made on the 1977, 1979; Winter, 1979). correct lever) was recorded. Fifteen minutes after the rat was put in The following considerations have led us to examine in some the experimental chamber, the session was terminated and all correct detail the interactions of purported 5-HT receptor blocking and incorrect responses made in the course of the 15-mis session were agents with the DS produced by LSD. First, an effective antag- recorded. After the session, the animal was returned to its living cage. onism of the LSD-DS by cinanserin, metitepine, methysergide One hour later it was allowed to feed freely for 2 hr. On week-end days and some related compounds would be difficult to reconcile no sessions were run and the animals were given free access to food with the hypothesis that LSD acts by mimicking 5-HT at 5-HT between 10 AM. and 12 noon. Every week, each rat was run once a day on 5 consecutive days. receptor sites in the brain. This is because these agents essen- Daily training drug (D) or saline (S) injections were given according to tially fail to block the inhibition of firing rate of brain neurons two monthly alternating sequences, i.e., 1) D-S-S-D-S, S-D-D-S-S, S- induced by 5-HT (Haigler and Aghajanian, 1974b).
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