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Permissive Role of Dopamine D2 Receptors in the Hypothermia Induced by Δ9-Tetrahydrocannabinol in Rats

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Abstract

Cannabinoids produce analgesia, hypomotility, catalepsy, cognitive deficits and positive reinforcement. Moreover, Δ9-tetrahydrocannabinol (9-THC) and synthetic cannabinoids stimulate dopaminergic neurons and increase dopamine release in different brain areas. In order to clarify the role of endogenously released dopamine in the hypothermic response to cannabinoids, the effect of D1 and D2 dopamine receptor agonists and antagonists on Δ9-THC–induced hypothermia was studied in rats. Δ9-THC (2.5 and 5 mg/kg intraperitoneally [IP]) decreased body temperature in a dose-related manner. This effect was antagonized not only as expected by the CB1 cannabinoid receptor antagonist SR 141716A (0.5 mg/kg, IP) but also, unexpectedly, by the dopaminergic D2 receptor antagonists S(-)-sulpiride (5 and 10 mg/kg, IP) and S(-)-raclopride (1 and 3 mg/kg, IP). Conversely, the hypothermic effect of Δ9-tetrahydrocannabinol was potentiated by the D2 dopamine receptor agonists (-)-quinpirole (0.025 and 0.500 mg/kg, SC) and (+)-bromocriptine (0.5 and 1 mg/kg, IP). In contrast, the Δ9-THC–induced hypothermic effect was not modified by either by the D1 dopamine agonist SKF 38393 (10 mg/kg SC) or by the D1 dopamine antagonist SCH 23390 (0.5 mg/kg SC). These results suggest that the D2 dopamine receptors have a permissive role in the hypothermic action of cannabinoids.

Section snippets

Animals

Male Sprague-Dawley rats weighing 125 to 150 g were used (Charles River, Calco, Como, Italy). Prior to experiments they were housed in group cages and kept at a temperature of 22° ± 1°C at 55% of humidity. Food and water were freely available and animals were maintained under an artificial 12/12 h light/dark schedule with light on from 0800 to 2000 h.

The experiments were carried out in accord to the recommendations of the declaration of Helsinki and to the European Communities Council Directive

Results

The administration of Δ9-THC caused a dose-dependent reduction in body temperature (Fig. 1). The maximum decrease obtained at doses of 2.5 and 5 mg/kg, respectively was 2.42 ± 0.42 and 2.92 ± 0.24°C, and occurred 60 min after treatment. The dose of 1 mg/kg had no effect (Fig. 1). As expected, and consistent with previous results (19), the hypothermic response to Δ9-Tetrahydrocannabinol (5 mg/kg) was totally antagonized by the CB1 cannabinoid receptor antagonist SR 141716A (0.5 mg/kg), given 20

Discussion

The results of the present study confirm previous observations showing that Δ9-THC reduces body temperature 7, 10, 11, 12, 19 and that this effect is reversed by the CB1 cannabinoid receptor antagonist SR 141716A 5, 19. Moreover, our results indicate that Δ9-THC–induced hypothermia is antagonized by the D2 dopamine receptor antagonists S(-)-sulpiride and S(-)-raclopride and, conversely, is potentiated by the D2 dopamine receptor agonists (-)-quinpirole and (+)-bromocriptine. When given alone at

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