BEHAVIORAL BIOLOGY 17, 313-332 (1976), Abstract No. 5276
S imi lar i t ies between A9-Tet rahydrocannab ino l
(A 9 -THC) and Reserp ine- l i ke Drugs I ,2
BROOKS CARDER 3 and STUART M. DEIKEL
Department of Psychology, 402 Hilgard Avenue,
University of California, Los Angeles, California 90024
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.
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
and antimuscarinics, it is doubtful that marijuana shares a mechanism of action common to either of these classes of compounds.
1This work was supported by Public Health Service Grant Number DA-00288 to Brooks Carder.
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.
3Address reprints to this author at Syanon Foundation, Marshall, California 94940.
Copyright 1976 by Academic Press, Inc. All rights of reproduction in any form reserved.
314 CARDER AND DEIKEL
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).
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.
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.
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
THC AND RESERPINE-LIKE DRUGS
Comparison for Selected Effects of A 9 -THC, Reserpine, Anticholinergics, and Morphine a
Atropine/ Effect Ag-THC Reserpine scopolamine Morphine References
Increased barbiturate + + -* + 46, 69, 83, 40 sleeping time Biphasic motor + + -* + 15, 18, 75, 52
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
to External Stimuli Hypothermia + + -* + 49, 18, 39, 84 Decreased respiration + + -* + 45, 69, 40, 2
at high doses Increased respiration + + -* -** 6, 69, 40, 80
at low doses Decreased responding + + -* + 56, 18, 19, 20
for food Decreased responding + + -* + 81, 65, 19, 64
or increased thresh- old for self-stimu- lation
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
aDifferenees are denoted between the effects of A 9-THC and atropine/scopolamine (*) or morphine (**).
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
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
or reserpine; these exc i tatory effects are not detected fol lowing the admin-
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
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.
316 CARDER AND DEIKEL
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.
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.
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.
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 mo