D-2, but not D-1 dopamine receptor agonists potentiate cannabinoid-inducedsedation in nonhuman primates

In primates, CB1 cannabinoid receptor agonists produce sedation and psychom otor slowing, in contrast to behavioral stimulation produced by high doses of dopamine receptor agonists. To investigate whether dopamine agonists att enuate the sedative effects of a cannabinoid agonist in monkeys, we compare d the effects of D-1 or D-2 dopamine receptor agonists on spontaneous behav ior 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 sed ation, ptosis, and decreased locomotor and general activity. Alone, D-2-typ e 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-[H-1]-3-benzazepine (0.3-3.0 mg/kg) produced either n o 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 genera l activity and locomotor activity. These data inducate the following: 1) D- 2, but not D-1 dopamine agonists, potentiate sedation in monkeys treated wi th a CB1 cannabinoid agonist, at doses of agonists that alone do not produc e sedation; 2) the threshold dose for cannabinoid-induced sedation is reduc ed 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) modulati on 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 agonist s and D-2 dopamine agonists should be combined with caution.