Vol. 292, Issue 3, 952-959, March 2000

D₂, but Not D₁ Dopamine Receptor Agonists Potentiate Cannabinoid-Induced Sedation in Nonhuman Primates^1,2

Justin P. Meschler³, Francis A. Clarkson, Patricia J. Mathews, Allyn C. Howlett³ and Bertha K. Madras

Department of Psychiatry, Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts

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 CB₁ cannabinoid 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) D_2, but not D₁ dopamine agonists, potentiate sedation in monkeys treated with a CB₁ cannabinoid 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 D₁ dopamine agonist, differentiating D₁ and D₂ dopamine 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.