Abstract
In primates, CB1 cannabinoid receptor agonists produce sedation and psychomotor slowing, in contrast to behavioral stimulation produced by high doses of dopamine receptor agonists. To investigate whether dopamine agonists attenuate the sedative effects of a cannabinoid agonist in monkeys, we compared the effects of D1 or D2 dopamine receptor agonists on spontaneous behavior in three to six cynomolgus monkeys (Macaca fasicularis) alone and after administration of a low dose of the CB1 agonist levonantradol. Alone, the CB1cannabinoid receptor agonist levonantradol (0.01–0.3 mg/kg) induced sedation, ptosis, and decreased locomotor and general activity. Alone, D2-type dopamine agonists quinelorane (0.001–1.0 mg/kg;n = 4) or pergolide (0.01–1.0 mg/kg) or a D1 dopamine agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3-benzazepine (0.3–3.0 mg/kg) produced either no effect or promoted hyperactivity. Thirty minutes after administration of a threshold dose of levonantradol (0.03 mg/kg), D2-type agonists, but not the D1 agonist, precipitated marked sedation, ptosis, and decreased general activity and locomotor activity. These data inducate the following: 1) D2, but not D1 dopamine agonists, potentiate sedation in monkeys treated with a CB1cannabinoid agonist, at doses of agonists that alone do not produce sedation; 2) the threshold dose for cannabinoid-induced sedation is reduced by D2 agonists, but not by a D1dopamine agonist, differentiating D1 and D2dopamine receptor linkage to cannabinoid receptors; and 3) modulation of D2 dopamine receptor activity by a nonsedating dose of a cannabinoid agonist has implications for the pathophysiology and treatment of dopamine-related neuropsychiatric disorders and drug addiction. Cannabinoid agonists and D2 dopamine agonists should be combined with caution.
Footnotes
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Send reprint requests to: Bertha K. Madras, Ph.D., Division of Neurochemistry, New England Regional Primate Research Center, 1 Pine Hill Dr., Box 9102, Southborough, MA 01772-9102. E-mail:bertha_madras{at}hms.harvard.edu
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↵1 This work was supported by Grants DA09462, DA11558, and DA00304 (to B.K.M.); RR00168 (to New England Regional Primate Research Center); and DA03690 and DA05806 (to A.C.H.). Animals used in this study were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and the “Guide for Care and Use of Laboratory Animals” of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education and Welfare Publication No. (NIH)85–23, revised 1985. Research protocols were approved by the Harvard Medical School Institutional Animal Care and Use Committee.
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↵2 This work was presented in abstract at the International Union of Pharmacology, Munich, Germany, 1998. Meschler JP, Clarkson FA, Mathews PJ, Howlett AC and Madras BK (1998) Cannabinoid and dopamine agonists interact to produce paradoxical behavioral effects in nonhuman primates. Naunyn-Schmiedeberg's Arch Pharmacol358:R58.
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↵3 Current address: Department of Pharmacological and Physiological Science, Saint Louis University, 1402 S. Grand Blvd., St. Louis, MO 63104.
- Abbreviations:
- SKF 81297
- 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3-benzazepine
- EtOH
- ethanol
- Received August 11, 1999.
- Accepted November 24, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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