Rd. Spealman, DOPAMINE D-3 RECEPTOR AGONISTS PARTIALLY REPRODUCE THE DISCRIMINATIVESTIMULUS EFFECTS OF COCAINE IN SQUIRREL-MONKEYS, The Journal of pharmacology and experimental therapeutics, 278(3), 1996, pp. 1128-1137
Dopamine agonists and antagonists varying in affinity and selectivity
at the D-3 subtype of D-2-like receptors were studied in squirrel monk
eys trained to discriminate cocaine from vehicle in a two-lever choice
procedure. In drug substitution experiments, all dopamine agonists en
gendered dose-related increases in the percentage of cocaine-lever res
ponses, reaching average maxima of 61 to 85%. The order of potency of
the drugs for engendering cocaine-like stimulus effects [(+)-4-propyl-
9-hydroxynaphthoxazine > (R)-(-)-propylnorapomorphine > (+/-)-2-diprop
ylamino-7-hydroxy- 1,2,3,4-tetrahydronaphthalene greater than or equal
to PD 128907 greater than or equal to quinpirole > bromocriptine] app
roximated their reported order of potency in both functional (agonist-
stimulated mitogenesis) and radioligand ([I-125]iodosulpiride) binding
assays in cells expressing cloned human D-3 receptors but not in cell
s expressing cloned human D-2 or D-4 receptors. In antagonism studies,
the cocaine-like stimulus effects of the most selective of the D-3 ag
onists, PD 128907, were attenuated by D-2-like receptor antagonists wi
th an order of potency (nemonapride > eticlopride > YM-43611) that cor
responded more closely to their reported order of affinity at cloned h
uman D-3 than either D-2 or D-4 receptors, The effects of PD 128907 we
re not attenuated by the D-1-like receptor antagonist SCH 39166. In a
final series of experiments, the discriminative stimulus effects of co
caine were enhanced in a largely additive manner by PD 128907, (+/-)-2
-dipropylamino-7-hydroxy- 1,2,3,4-tetrahydronaphthalene and quinpirole
. The results support a role for D-3 receptor mechanisms in the cocain
e-like stimulus effects of D-3-preferring agonists and suggest that si
milar mechanisms may contribute to the effects of cocaine.