Similarities between Δ9-tetrahydrocannabinol (Δ9-THC) and reserpine-like drugs

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<ul><li><p>BEHAVIORAL BIOLOGY 17, 313-332 (1976), Abstract No. 5276 </p><p>S imi lar i t ies between A9-Tet rahydrocannab ino l </p><p>(A 9 -THC) and Reserp ine- l i ke Drugs I ,2 </p><p>BROOKS CARDER 3 and STUART M. DEIKEL </p><p>Department of Psychology, 402 Hilgard Avenue, </p><p>University of California, Los Angeles, California 90024 </p><p>Similarities between the behavioral and biochemical effects of Ag-THC and reserpine are reviewed. This interpretation is further supported by several experimental results. Pretreatment with a monoamine oxidase inhibitor (MAO-I) followed by 0.5 mg Ag-THC, produced straub-tail and excitatory effects on intracranial self-stimulation behavior. The identical dose of THC, without MAO-I pretreatment impaired self-stimulation. It was demonstrated that these effects were probably not due to nonspecific excitatory effects of the MAO-I. Further, rats made tolerant to A9-THC exhibited cross-tolerance to the hypothermic effects of the reserpine- congener tetrabenazene (TBZ). Postmortem examination suggested that these effects were probably not due to ineffective absorption of TBZ from the injection site. Finally, behavioral cross-tolerance between A9-THC and TBZ, in an unlearned swimming-escape task, was demonstrated. These data suggest further similarities between the effects of A 9-THC and reserpine. The possible role of monoamine disposition in the mechanism of cannabis action is discussed. </p><p>Similarities between selected behavioral and physiological effects of Ag-Tetrahydrocannabinol (A9-THC) and other compounds, particularly morphine and anticholinergics, have been noted by several investigators (Lomax, 1971a, 1971b; Mechoulam, 1973 p. 258; Brown, 1971). While there are indeed selected areas of comparison between cannabis and both morphine </p><p>and antimuscarinics, it is doubtful that marijuana shares a mechanism of action common to either of these classes of compounds. </p><p>1This work was supported by Public Health Service Grant Number DA-00288 to Brooks Carder. </p><p>2The authors would like to thank Dr. Larry L. Butcher and Konrad Talbot for advice on the design of the experiments and preparation of the manuscript, and Michelle Black for assistance in carrying out the research. </p><p>3Address reprints to this author at Syanon Foundation, Marshall, California 94940. </p><p>313 </p><p>Copyright 1976 by Academic Press, Inc. All rights of reproduction in any form reserved. </p></li><li><p>314 CARDER AND DEIKEL </p><p>The chemical property of cannabis which has been suggested to domin- ate its pharmacological actions (Paton et al., pp. 50-76, 1972) is its extreme lipophilicity; morphine, in contrast, is readily soluble in water. The pharmaco- logical action of A 9-THC has also been described as far more specific than the general depressant effects which characterize the opiates (Loewe, 1945). While the addiction liability of morphine is well documented, no definitive evidence of physical dependence following the extended use of cannabis has yet been offered (Carlini et al., p. 154, 1972). Furthermore, while cross-tolerance between THC and morphine has been suggested (Kaymakcalan, p. 75, 1972), no data demonstrating that effect have yet been reported. Finally, cannabis is unaffected by opiate antagonists (McMillan et al., 1971). </p><p>It has recently been reported that THC may attenuate the symptoms of naloxone-precipitated morphine (Hine et al., 1975a) and methadone (Hine et al., 1975b) abstinence; on the basis of these data Hine et al. reassert the potential similarities between cannabis and opiate derivatives. However, these speculations should be regarded as tentative due to serious methodological limitations of the work (Carder, 1975; Deikel and Carder, 1975). Further- more, these data failed to represent a similarity between THC and either morphine or methadone since a variety of non-narcotic agents will suppress naloxone-precipitated indices of opiate abstinence (Kamei et al., 1973). Hirschborn and Rosecrans (1974) have demonstrated naloxone-induced abstinence following the chronic administration of Ag-THC. However, these investigators rightly conclude that naloxone-precipated abstinence may be produced following the chronic administration of a variety of substances. </p><p>The behavioral and pharmacological effects of A 9-THC also differ from the antimuscarinics in several important respects. First cannabinols exhibit paradoxical effects on general activity, some of which characterize the anticholinergics (Brown, 1971), while other actions are similar to anti- cholinesterases (Brown, 1972). Furthermore, unlike Ag-THC or reserpine, the typical anticholinergics, atropine sulfate and scopolamine, are water soluble (Innes and Nickerson, 478, 1970). Hypothermic responses accompanying the administration of Ag-THC have been widely described (Abel, pp. 120-142, 1972); however, opposite effects are observed after treatment with Belladonna alkaloids (Innes and Nickerson, p. 533, 1970). Finally cannabis, unlike antimuscarinics, fails to disrupt passive avoidance learning in rats (Miller and Drew, 1974). A more comprehensive review by Miller and Drew (1974) clearly outlines further inconsistencies implicit in an anticholinergic model of A 9-THC action. </p><p>Various findings, both from our laboratory and elsewhere, emphasize the similarities between Ag-THC and reserpine (Sofia and Dixit, 1971; Englert et al., 1973; Carder and Deikel, 1975). Table 1 depicts a comparison of selected effects of Ag-THC, reserpine, antimuscarinic agents such as atropine and scopolamine, and morphine. There is a very close correspondence between the </p></li><li><p>THC AND RESERPINE-LIKE DRUGS </p><p>TABLE 1 </p><p>Comparison for Selected Effects of A 9 -THC, Reserpine, Anticholinergics, and Morphine a </p><p>315 </p><p>Atropine/ Effect Ag-THC Reserpine scopolamine Morphine References </p><p>Increased barbiturate + + -* + 46, 69, 83, 40 sleeping time Biphasic motor + + -* + 15, 18, 75, 52 </p><p>Response Blood pressure + + + + 24, 4, 22, 5 decreased Decreased CER + + -* + 29, 18, 19, 58 Catalepsy + + -* + 15, 18, 39, 44 Increased excitability + + -* -** 73, 69, 39, 3 </p><p>to External Stimuli Hypothermia + + -* + 49, 18, 39, 84 Decreased respiration + + -* + 45, 69, 40, 2 </p><p>at high doses Increased respiration + + -* -** 6, 69, 40, 80 </p><p>at low doses Decreased responding + + -* + 56, 18, 19, 20 </p><p>for food Decreased responding + + -* + 81, 65, 19, 64 </p><p>or increased thresh- old for self-stimu- lation </p><p>Spontaneous activity + + + - 14, 69, 39, 72 Reduced Spontaneous activity + + ? -** 73, 7, 40 Increased after MAO-I Lipophilic + + -* -** 61, 18, 39, 40 Straub-tail + + - + 10, 18, 53 </p><p>aDifferenees are denoted between the effects of A 9-THC and atropine/scopolamine (*) or morphine (**). </p><p>effects of cannabis and reserpine; much closer than that between A 9-THC and either morph ine or the antichol inergics. The disparity between these latter compounds and cannabis wi th regard to " Increased Excitabi l i ty to External </p><p>St imul i " and " Increased Respi rat ion at Low Doses" reflects the dose-specific s t imulant effects which are evident after the administ rat ion of either A 9-THC </p><p>or reserpine; these exc i tatory effects are not detected fol lowing the admin- </p><p>istrat ion of e i ther morph ine or antimuscarinics. Also, the increase in spon- taneous activity noted after A9-THC or reserpine administrat ion, fol lowing </p><p>pret reatment with a monoamine oxidase inhib i tor (MAO-I) , fur ther suggests similarit ies between the act ion of cannabis and the Rauwol f ia alkaloid. </p></li><li><p>316 CARDER AND DEIKEL </p><p>Hardman, Domino, and Seevers (197l) described, on the basis of their similar effects on cardiovascular responses, the marked consistencies between the actions of synthetic cannabinoids and reserpine. Indeed Sofia et al. (1971) reported that THC administration attenuated the subsequent action of reserpine and suggested that the two compounds may have a similar site of action. </p><p>Finally Englert et al. (1973) have demonstrated that the prior admin- istration of either THC or reserpine attenuated the hypothermic effects of the other compound; these data further suggest that these agents may bear similarities in their respective mechanisms of action. </p><p>Biochemical investigations, especially with regard to the catecholamines, further support the similarities between cannabis and reserpine. Several researchers report that cannabinols increase turnover and decrease endogenous levels of central catecholamines (Holtzman, et al. 1969; Schildkraut and Efron, 1971; Maitre et al., 1970). Maitre et al. (1973) have reported that increased utilization of catecholamines is especially marked in the hypo- thalamus, a region prominently involved in the mediation of many cannabis effects (Paton and Pertwee, pp. 222-225, 1973). Howes and Osgood (1974) have reported that THC, like amphetamine, blocks uptake of dopamine into striatal synaptosomes. However, conflicting data have been obtained, as a number of investigators report varying effects of A9-THC on central cate- cholamine levels (Ho et al., 1972). The controversial nature of reports reflecting the biochemical effects of cannabinols in animals suggested to us that a somewhat different approach to the problem might prove useful. Thus, we began our investigation by examining the behavioral effects of A9-THC. With this perspective we have attempted to demonstrate further similarities between Ag-THC and other compounds known to facilitate the increased turnover of central neurotransmitter substances. </p><p>EXPERIMENT 1 </p><p>The depressant behavioral effects accompanying the administration of compounds which facilitate the release of monoamines (e.g., Rauwolfia alkaloids and related benzoquinolizines) are markedly reversed when subjects are pretreated with a monoamine oxidase inhibitor (MAO-I)(Carlsson, 1966). Reserpine alone, for example, has marked depressant effects on self- stimulation (Olds and Travis, 1960). However, following the administration of an MAO-I, reserpine has prolonged excitatory effects (Carlsson, 1966). Sabelli et al. (1974), using relatively gross observational techniques, reported that pretreatment with Nialamide caused an increase in the motor activity and general excitability of rats administered A 9-THC. </p><p>Prior work on self-stimulation indicated that A9-THC is an effective </p></li><li><p>THC AND RESERPINE-LIKE DRUGS 317 </p><p>inhibitor of this behavior (Wayner, 1974). These data are, of course, com- patible with a hypothesis that A9-THC interferes with the central cate- cholamines, the significant neural transmitters in the mediation of self- stimulation (German and Bowden, 1974). This disruption may reflect a facilitation of the utilization in CAs systems in a manner similar to reserpine; an hypothesis which would predict that pretreatment of rats with MAO-I should result in a stimulant action of THC, rather than the depressant effect typically observed. Our first studies then investigated the joint influence of THC and MAO-I on intracranial self-stimulation with a view toward further investigation of similarities between THC and reserpine. </p><p>Method </p><p>Subjects </p><p>Subjects were 20 male, Sprague-Dawley rats acquired from Simonsen Breeding Laboratories, Gilroy, California. All subjects were at least 90 days old and weighed between 300 and 350 g at the beginning of the experiment. Each subject was housed individually with food and water freely available at all times. </p><p>Five to nine days prior to the beginning of the experiment subjects were anesthetized with Pentobarbital Sodium (35 mg/kg) and implanted bilaterally with bi-polar, Teflon coated, stainless steel electrodes directed at the lateral hypothalamic region (DeGroot coordinates: anterior from interaural axis: 5.5; lateral: 1.6; vertical from dura: 7.5). </p><p>Apparatus </p><p>Training and testing for self-stimulation were conducted in two Gerbrands Operant Conditioning Chambers. Each bar press delivered a 500 msec train of 60 Hz current of adjustable intensity. </p><p>Procedure </p><p>Following recuperation from surgery subjects were tested for self- stimulation. Current intensities were adjusted to yield response rates of 1500 to 3600 responses per hour and remained constant for each subject through- out the experiment. Intensities ranged from 130 to 220/~A RMS. Each subject was allowed 4 hr of practice prior to the initiation of the experiment. Subjects were allowed 2 days of training during which they were each allowed to respond for l hr. Beginning on the evening of the second day, and continuing on throughout the experiment, 12 subjects were administered 100rag Nialamide/kg, while the remaining animals were administered 1 ml saline/kg. During the drug test session, conducted on the fifth day of the experiment, </p></li><li><p>318 CARDER AND DEIKEL </p><p>subjects were allowed to respond for 40 min after which they were admin- istered either 0.5 mg Ag-THC/kg, 24 mg Nembutal/kg, or 1 ml propylene glycol/kg. </p><p>At the beginning of each session on Days 1-4 subjects were placed in the chamber and allowed to respond for 1 hr; response totals were recorded at 20 rain intervals. During the drug test session, conducted on the fifth day of the experiment, after 40 min of responding subjects were dosed with the appropriate drug and immediately returned to the experimental chamber. Response totals were recorded for the following 2 hr at 20 rain intervals. </p><p>A9-THC was supplied by NIMH as a solution in dehydrated alcohol with 1000 rag/5.3 ml. This was diluted in propylene glycol to yield a solution of 0.5 mg Ag-THC/ml. Nialamide was supplied by Charles Pfizer, Incorporated. This compound was dissolved in 1 M HC1 and diluted in distilled water to yield a concentration of 80 mg/ml. Sodium bicarbonate was used to adjust the solution to a pH of approximately 4. Nembutal was used in a concentration of 50 mg/ml. Propylene glycol and physiological saline were prepared in sealed and sterile injection vials. All drug solutions were prepared prior to the beginning of the experiment and refrigerated throughout. All drugs were administered by intraperitoneal injection. </p><p>Following the completion of the experiment all subjects were sacrificed with Pentobarbital-sodium, perfused with 10% formalin, and frozen sections prepared to locate the electrode tips. Placements were located in the lateral regions of the lateral hypothalamic area at the approximate level of the ventromedial nucleus. </p><p>Results </p><p>Table 2 presents the mean response rate per hour for the entire session before and after each drug treatment. The data indicate that pretreatment with saline followed by Ag-THC administration induced a suppression of responding. However, animals pretreated with Nialamide prior to the admin- istration of THC exhibited a significant increase in response rate IF(5, 3) = 9.33, P&lt; 0.05]. Subjects treated with Nialamide and then dosed with Nembutal (25 mg/kg) also demonstrated a marked reduction in responding, much greater than that exhibited by subjects administered saline prior to Nembutal injection [F(5, 6)=5.81, P</p></li><li><p>THC AND RESERPINE-LIKE DRUGS </p><p>TABLE 2 </p><p>Mean Self-Stimulation,...</p></li></ul>

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