Articles
Biphasic Effects of Anandamide

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Abstract

Effects of the endogenous cannabimimetic anandamide were assessed over a wide dose range in a series of physiological and behavioral assays. These included the tetrad of tests in mice commonly used to assess cannabinoid-induced effects (motor activity, ring catalepsy, hypothermia, and analgesia tests), as well as a model for agonistic behavior on dyadic interactions of singly housed males with nonaggressive group-housed partners. Anandamide-induced effects on leukocyte phagocytosis were measured in a chemiluminescence assay. Results indicated that the higher doses tested (10–100 mg/kg) produced the well-known inhibitory effects in all of the above parameters as well as inhibition of phagocytosis. The lowest dose of anandamide tested (0.01 mg/kg) stimulated behavioral activities in the open field, on the ring and aggressive behavior in timid singly housed mice. This dose of 0.01 mg/kg, also stimulated phagocytosis. We suggest several possible mechanisms to explain these findings such as a differential involvement of a Gs and a Gi protein activated at low and high doses, respectively, allosteric modulation of the cannabinoid, and activation of presynaptic cannabinoid receptors by low doses of anandamide.

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Animals

Female Sabra mice (6–7 weeks old, Harlan–Sprague–Dawley, Jerusalem) were used for the open-field, ring test, body temperature, and hot-plate tests. Males of albino outbred ICR mice bred at VELAZ, Prague (8 weeks old), were used for the model of agonistic behavior. Female mice of the inbred strain C57BL/10 (8 weeks old) were used for testing of leukocyte phagocytic activity. Animals received food and water ad lib and were maintained at constant temperature (20–22°C) on a 12 L:12 D cycle. Tests

Results

A dose of 0.01 mg/kg of anandamide significantly increased ambulation and rearing, as well as defecation in the open-field (Fig. 1). This dose also decreased the rate of immobility on the ring (Fig. 2A). A nonsignificant tendency to decrease analgesia (Fig. 2B) on a hot plate was also observed, but body temperature was not affected by this dose (data not shown). A dose of 0.1 mg/kg did not elicit significant changes. Ten and 100 mg/kg markedly decreased activity in the open field, increased

Discussion

The inhibitory effects of high doses of anandamide in the various tests are in agreement with previous data 15, 40. In contrast, in most assays performed, a low dose (0.01 mg/kg) of anandamide had effects in the opposite direction to those found after high doses. Thus, we observed stimulated motor activity and rate of defecation in the open field, increased motility on the ring, and aggressive behavior in “timid” mice. Body temperature and analgesia were not significantly affected by low doses.

Acknowledgements

This work was supported by the Grant Agency of the Czech Republic to E. S. (grant No. 309/93/0165) and U.S. National Institute on Drug Abuse to R. M. (Grant Nos. 6481 and 9789).

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