D(2), but not D(1) dopamine receptor agonists potentiate cannabinoid-induced sedation in nonhuman primates.
In primates, CB(1) 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 D(1) or D(2) dopamine receptor agonists on spontaneous behavior in three to six cynomolgus monkeys (Macaca fasicularis) alone and after administration of a low dose of the CB(1) agonist levonantradol. Alone, the CB(1) cannabinoid receptor agonist levonantradol (0.01-0. 3 mg/kg) induced sedation, ptosis, and decreased locomotor and general activity. Alone, D(2)-type dopamine agonists quinelorane (0. 001-1.0 mg/kg; n = 4) or pergolide (0.01-1.0 mg/kg) or a D(1) 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), D(2)-type agonists, but not the D(1) agonist, precipitated marked sedation, ptosis, and decreased general activity and locomotor activity. These data inducate the following: 1) D(2,) but not D(1) dopamine agonists, potentiate sedation in monkeys treated with a CB(1) cannabinoid agonist, at doses of agonists that alone do not produce sedation; 2) the threshold dose for cannabinoid-induced sedation is reduced by D(2) agonists, but not by a D(1) dopamine agonist, differentiating D(1) and D(2) dopamine receptor linkage to cannabinoid receptors; and 3) modulation of D(2) 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 D(2) dopamine agonists should be combined with caution.
Meschler
J P
JP
Department of Psychiatry, Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts, USA.
Clarkson
F A
FA
Mathews
P J
PJ
Howlett
A C
AC
Madras
B K
BK
D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010617:Phenanthridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D017448:Receptors, Dopamine D2 / Q000819:agonists*
D002186:Cannabinoids; D018491:Dopamine Agonists; D006993:Hypnotics and Sedatives; D010617:Phenanthridines; D011804:Quinolines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C025490:nantradol; C047726:quinelorane