RT Journal Article
SR Electronic
T1 D<sub>2</sub>, but Not D<sub>1</sub> Dopamine Receptor Agonists Potentiate Cannabinoid-Induced Sedation in Nonhuman Primates
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JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 952
OP 959
VO 292
IS 3
A1 Meschler, Justin P.
A1 Clarkson, Francis A.
A1 Mathews, Patricia J.
A1 Howlett, Allyn C.
A1 Madras, Bertha K.
YR 2000
UL http://jpet.aspetjournals.org/content/292/3/952.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics