Abstract
Ten rats were injected s.c. with THC twice daily for 5 weeks in increasing doses. In the last 3 weeks they received 40 mg/kg THC in each administration. Ten control rats received the same amount of vehicle by the same route for the same period. The comparison of rectal temperatures of the first and fifteenth days showed that a very pronounced tolerance developed to the hypothermic effect of THC.
The administration of naloxone on the 22nd and 31st days precipitated an opiatelike abstinence syndrome. The termination of the drug administration on the 35th day also produced a similar withdrawal syndrome.
The most common signs of abstinence syndrome in THC-treated animals were teeth chattering, defecation, urination, dyspnea, and complete palpebral closure. Although the frequency of the incidence of the following signs were not high, they have been observed only in THC-treated animals: chewing, tremors on the face, escape behavior, jumping, eating of objects, biting of fingers, and sniffing.
During abstinence, an increased locomotor activity was recorded by an activity-meter. Similarly, the total amount of excreted feces and urine was higher in the THC group than in the controls. Both abstinence scores and increased motility exhibited the peak in the 48th h of withdrawal.
Some similarities between the effects of THC and morphine have been reviewed.
Similar content being viewed by others
References
Bhargava, H. N.: Inhibition of naloxone-induced withdrawal in morphine dependent mice by 1-trans-Δ9-tetrahydrocannabinol. Eur. J. Pharmacol. 36, 259–262 (1976)
Blasig, J., Herz, A., Reinhold, K., Zieglgansberger, S.: Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia (Berl.) 33, 19–38 (1973)
Buckett, W. R.: A new test for morphine-like physical dependence (addiction liability) in rats. Psychopharmacologia (Berl.) 6, 410–416 (1964)
Buxbaum, D., Sanders-Buch, E., Efron, D. H.: Analgesic activity of tetrahydrocannabinol (THC) in rat and mouse. Fed. Proc. 28, 735 (1969)
Chesher, G. B., Jackson, D. M.: The effect of withdrawal from cannabis on pentylenetetrazol convulsive threshold in mice. Psychopharmacologia (Berl.) 40, 129–135 (1974)
Davis, W. M., Moreton, J. E., King, W. T., Pace, H. B.: Marihuana on locomotor activity: biphasic effect and tolerance development. Res. Commun. Chem. Pathol. Pharmacol. 3, 29–35 (1972)
Deneau, G. A., Kaymakçalan, Ş.: Physiological and psychological dependence to synthetic Δ9-tetrahydrocannabinol (THC) in rhesus monkeys. Pharmacologist. 13, 246 (1971)
Dewey, W. L., Jenkins, J., O'Rourke, T., Harris, L. S.: The effect of chronic administration of trans-Δ9-tetrahydrocannabinol on behavior and the cardiovascular system of dogs. Arch. Int. Pharmacodyn. Ther. 198, 118–131 (1972)
Fernandes, M., Hill, R.: Morphine-cannabinoid interactions in rats and mice. Naunyn Schmiedebergs Arch. Pharmacol. [Suppl.] 282 R 19 (1974)
Frederickson, R. C. A., Aiken, J. W.: Naloxone-induced withdrawal and the effects of naloxone on isolated ileum from morphinedependent guinea-pig: antagonism by Δ9-tetrahydrocannabinol. Sixth International Pharmacological Congress, Abstract No. 638, Helsinki 1975
Harris, R. T., Waters, W., McLendon, D.: Evaluation of reinforcing capability of delta-9-tetrahydrocannabinol in rhesus monkeys. Psychopharmacologia (Berl.) 37, 23–29 (1974)
Hine, B., Friedman, E., Torrelio, M., Gershon, S.: Morphine-dependent rats: blockade of precipitated abstinence by tetrahydrocannabinol. Science 187, 443–445 (1975a)
Hine, B., Torrelio, M., Gershon, S.: Attenuation of precipitated abstinence in methadone-dependent rats by Δ9-THC. Psychopharmacol. Commun. 1, 275–284 (1975b)
Hirschhorn, I. D., Rosecrans, J. A.: Morphine and Δ9-tetrahydrocannabinol: tolerance to the stimulus effects. Psychopharmacologia (Berl.) 36, 243–253 (1974)
Jones, R. T., Benowitz, N.: The 30-day trip—clinical studies of cannabis tolerance and dependence. In: The pharmacology of marihuana, M. C. Braude and S. Szara, eds., pp. 627–642. New York: Raven Press 1976
Jones, R. T., Benowitz, N., Bachman, J.: Clinical studies of cannabis tolerance and dependence. Ann. N.Y. Acad. Sci. 282, 221–239 (1976)
Kaymakçalan, Ş.: Physiological and psychological dependence on THC in rhesus monkeys. In: Cannabis and its derivatives, W. D. M. Paton and June Crown, eds., pp. 142–149. London: Oxford University Press 1972
Kaymakçalan, Ş.: Tolerance to and dependence on cannabis. Bull. Narc. 25, 39–47 (1973)
Kaymakçalan, Ş.: Potential dangers of cannabis. Int. J. Addict. 104, 721–735 (1975)
Kaymakçalan, Ş., Deneau, G. A.: Some pharmacologic properties of synthetic Δ9. Acta Med. Turcica [Suppl. 1], 19–27. Ankara: Güzel Istanbul Press 1972
Kaymakçalan, Ş., Türker, R. K., Türker, M. N.: Analgesic effect of Δ9-tetrahydrocannabinol in the dog. Psychopharmacologia (Berl.) 35, 123–128 (1974)
Kaymakçalan, Ş., Woods, L. A.: Nalorphine-induced “abstinence syndrome” in morphine-tolenrant albino rats. J. Pharmacol. Exp. Ther. 117, 112–116 (1956)
Leite, J. R., Carlini, E. A.: Failure to obtain “cannabis-directed behaviour” and abstinence syndrome in rats chronically treated with cannabis sativa extracts. Psychopharmacologia (Berl.) 36, 133–145 (1974)
McMillan, D. E., Harris, L. S., Frankenheim, J. M., Kennedy, J. S.: 249-9 in pigeons: tolerance to the behavioural effects. Science 169, 501–503 (1970)
Moreton, J. E., Davis, W. M.: Electroencephalographic study of effects of Δ9- and Δ8-tetrahydrocannabinol and cannabis extract on sleep in the rat. Pharmacologist 13, 246 (1971)
Noyes, R., Brunk, S. F., Avery, D. H., Canter, A.: The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin. Pharmacol. Ther. 18, 84–89 (1975)
Pirch, J. H., Osterholm, K. C., Cohn, R. A., Barratt, E. S.: Studies on EEG tolerance to marijuana in the rat. Arch. Int. Pharmacodyn. Ther. 203, 213–220 (1973)
Sjöden, P. O., Jarbe, T. U. C., Henrikson, B. G.: Effects of longterm administration and withdrawal of tetrahydrocannabinol (Δ8-THC and Δ9-THC) on open field behavior in rats. Pharmacol. Biochem. Behav. 1, 243–249 (1973)
Stadnicki, S. W., Schaeppi, U., Rosenkrantz, H., Braude, M. C.: Crude marihuana extract: EEG and behavioral effects of chronic oral administration in rhesus monkeys. Psychopharmacologia (Berl.) 37, 225–233 (1974)
Wei, E.: Assessment of precipitated abstinence in morphine-dependent rats. Psychopharmacologia (Berl.) 28, 35–44 (1973)
Wei, E., Horace, H. L., Way, E. L.: Quantitative aspects of precipitated abstinence in morphine-dependent rats. J. Pharmacol. Exp. Ther. 184, 398–403 (1973)
Wilson, R. S., May, E. L.: Analgesic properties of the tetrahydrocannabinols, their metabolites, and analogs. J. Med. Chem. 18, 700–703 (1975)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kaymakçalan, Ş., Ayhan, I.H. & Tulunay, F.C. Naloxone-induced or postwithdrawal abstinence signs in Δ9-Tetrahydrocannabinol-Tolerant rats. Psychopharmacology 55, 243–249 (1977). https://doi.org/10.1007/BF00497855
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00497855