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2, I'sychopha,'macology54, 313 314 (1_77) ,t'i_by Spriuger-Verlag 1977 L_[j

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Short Reports

Interaction Between Narcotic Antagonist () and Lysergic Acid Diethylamide (LSD) in the Rat

ALLEN P. FERTZ1GERand ROLAND FISCHER Maryland PsychiatricResearchCenterand Departmentof Pharmacology,The George WashingtonUniversityMedicalCenter, Washington,D.C., U.S.A.

Abstract. LSD administration in rats elicited a diphasic commencedat zerotime(to)withan i.p. injectionof 375_g/kgLSD reaction consisting of a brief excitable period (up to dissolvedin saline. Naloxone-HCIwas administeredi.m.at a dose of 0.2 mg/kgknown to elicitwithdrawalin narcotic-dependentrats 8 rain) followed by a prolonged catalepsy (8 rain- 1 h). (Wei, 1973). Naloxone was administered either 5 min prior to While the cataleptic response was antagonized by a to(t-s) or 30minafterthe LSD injection(ta0).Naloxonecontrols single injection of naloxone (given 30 rain after LSD were i.m. saline injectionsat t-._ or t3o, and LSD controls were administration), pretreatment with naloxone short- saline injectionsat to. All behavioralobservations were made in _ ened the excitable phase and potentiated the catalepsy, a 122-cm square open-field black box divided into four equal isolated compartments that were 46 cm deep. This arrangement, Key words: LSD 'bad trip" - Rats - Cataleptic anal- reported by us previously(Fertziger et al., 1974),facilitatescom- gesia - Narcotic antagonist - Naioxone-LSD antag- parative drug studies in freely moving rats. Observations were onism reported by individualsignorant of the nature of treatment.

RESULTS "['he (Kast and Collins, 1964"1hallucinogen lysergic acid diethylamide (LSD) and the class of At the dose levels described in this study LSD con- narcotic of which is prototypical sistently elicited brief hyperactivity that changed in share the phenylethylamine structural element about 8 min to a hypoactive 'catalepsy' of about 1 h (Fischer, 1974). The spatial disposition of the nitrogen duration. During this state rats became unresponsive atom and the aromatic nucleus of the phenylethyl- to the environment and to noxious stimulation (pinch- amine group in morphine has been shown by Jung et ing); their eyes were wide open and their neuromuscu- al. (1976) to be identical with that present in the nar- lar tone was such that their bodies could be 'shaped' cotic antagonist and other synthetic anal- into atypical positions. This behavior was strikingly gesics. The phenylethylamine pattern is present not similar to the morphine- or -induced cata- only in cyclazocine but also in naloxone, and it is of lepsy described by Ahtee and Kaariainen (1973), interest to note that the latter can block the LSD-like Ayhan and Randrup (1972), and Fog (1970), and the - "ide effects of the former (Fink et al., 1971). Inasmuch -induced 'cataleptic anaesthesia' reported by as there is no known specific antagonist with which Winters et al. (1973). Rats generally remained fixed to treat LSD-induced 'bad trips,' this preliminary in a corner, heads up, eyes wide open, and feet seem- study sought to examine any possible antagonistic ingly fixed to the floor. interaction between LSD and the narcotic antagonist Pretreatment (t-5) with naloxone tended to shorten naloxone, the initial hyperexcitability and prolong and intensify the LSD-induced 'catalepsy,' but the naloxone injec- tions at t30 reversed much of the LSD 'catalepsy." MATERIALS AND METHODS Within minutes of these injections, the immobile rats Experimentswere performed on 16Sprague-Dawleyrats (8 male once again became exploratory and active and soon and 8 female) weighingbetween280 and 320g. Each experiment resembled the LSD-control rats whose behavior remained unremarkable throughout the duration of Address]br offprint requests: Roland Fischer, Ph.D., Port D'es the experiment. Saline injeclion at t30 did not alter the Canonge, Esporles, Mallorca, Spain LSD-induced 'catalepsy.' This naloxone antagonism 314 Psychopharmacology 54 ( !977)

is similar to the naloxone antagonism of methadone- REFERENCES induced 'catalepsy' reported by Ahtee (I 974). Ahtee, L.: Catalepsy and stereotypies in rats treated with metha- done: relation to striatal dopamine. Eur. J. Pharmacol. 27, 221 - 230 (1974) DISCUSSION Ahtee, L., Kaariainen. I. : The effect of narcotic antagonists on the homovanillic acid content of rat nucleus caudatus. Eur. J. Since low doses of LSD can induce analgesia in man Pharmacol. 22, 2O6-208 (1973) Ayhan, I. H., Randrup, A.: Role of brain noradrenaline in mor- (Kast and Collins, 1964; Kuromaru et al., 1967), the phine-induced stereotyped behavior. Psychopharmacologia higher LSD dose administered to our rats should (Berl.)27,203-212(1972) intensify the analgesic response. Only the post-LSD Belluzzi, J. D., Grant, N., (;arsky, V., Sarantakis, D., Wise, C. D., administration of naioxone antagonized LSD-induced Stein, L.: Analgesia induced in viw_ by central administration 'catalepsy' and presumably the concurrent analgesia; of in rat. Nature 260, 625-626 (1976) Fertziger, A. P., Lynch, J. J., Stein. E.: Modification of morphine therefore, this preliminary report is compatible with withdrawal syndrome in rats. Brain Res. 7g, 331 -334 (1974) the notion that LSD may set free analgesic endorphines Fink, M., Freedman, A. M., Zaks, A. M., Resnick, R. B. : Narcotic (), the latter of which are known to be antagonists: another approach to therapy. Am. J. counteracted by naloxone (Beiluzzi et al., 1976). Nurs. 71, 1359-1364(1971) Fischer. R.: A pharmacological and conceptual reevaluation of Whether this hypothesized LSD-induced enkephalin- hallucinations. Confin. Psychiatr. 17, 143-151 (1974) naloxone interaction is related to the partial structural Fog, R.: Behavioral effects in rats of morphine and similarity between LSD, morphine, enkephalin, and and of a combination of the two drugs. Psychopharmacologia naloxone is a matter of speculation. The literature (Berl.) 16. 305-312(1970) implies that 'analgesic bliss' may be induced by Jung, L, KoheI,J.C.. Toumi, A., Cros. J.: Structure-activit6des analg6sique morphiniques. IV. Importance du groupement , such as , LSD (Kuromaru phenyl6thylamine de la morphine et d6riv6s. Mecanismes et al., 1967), ketamine, the N-substituted isostere of d'action. Eur. J. Med. Chem. II, 426-431 (1976) A9-THC (Villarreal et al., 1974), methoxylated am- Kast, E. C., Collins, V. J.: Lysergic acid diethylamide as an anal- phetamines, and morphine and its antagonists gesic agent. Anesth. Analg. 43, 285-291 (1964) Kuromaru, S., Okada, S.. Hanada, M., Kashara, Y., Sakamoto, K. : (Fischer, 1974). The analgesic and/or anesthetic effect The effect of LSD on the phanton limb phenomenon. The of all these compounds may be a function of the Journal-Lancet87,22-27(1967) endorphine concentration, which they are able to dis- VanNeuten, J. M., Janssen, P. A. J., Fontaine, J. : Naloxone rever- place through interaction with common 'hallucino- ses inhibitory effects or'fatigue and of compounds not related to genie' receptors, narcotic analgesics in the guinea-pig ileum. Archives internatio- hales de Pharmacodynamie et de Therapie 220, 349 (1976) In addition to being a narcotic antagonist, naloxone Villarreal, J. E., Seevers, M. H., Swain, lt. H. : Evaluation of selected possesses other 'fatigue reversing' pharmacological nitrogen analogs for morphine-like physical dependence in the properties (VanNueten et al., 1976) that may mask rhesus monkey. Abstract of 168thACS Mtg., Med. Chem. Div., Sept. 9-12, 1974, No. 6 cataleptic analgesia. In any case, the present prelimi- Wei. E.: Assessment of precipitated in morphine depen- nary results imply that naloxone may counteract LSD- dent rats. Psychopharmacologia (Bed.) 28, 25- 44 (1073) induced analgesia in humans. Winters, W. D., Alcaraz, M., Cervantes, M. Y., Guzman-Flores, C.: The synergistic effect of reduced visual input on ketamine Acknowledgements. LSD and naloxone were obtained through the action: the possible role of the pineal gland. Neuropharma- courtesy of Ms. Jackie Bryant, Program Support Section, Center cology 12. 407-416 (1973) for Studies of Narcotic and Drug Abuse, N.I.DA., Rockville, Maryland and Endo Laboratories, Garden City, New York, re- spectively. Received January 6, 1977