Vol. 273, No. 1 Printed in U.S.A. 0022-3565/95/2731-0138$OO.OO/O THE JoURNAL o Pa*iu&cowGY *rm ExpaRwxwrL Tiias.i’aurics Copyright C 1995 by The American Society for Pharmacology and Experimental Therapeutics JPET 273:138-145, 1995 Pharmacological Analysis of the Scratching Produced by Dopamine D2 Agonists in Squirrel Monkeys RICARDO PELLON1, PILAR FLORES2, KEN ALLING, JEFFREY M. WIThIN and JONAThAN L KATZ Psychobiology Section, Predinica! Pharmacology Laboratory, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland Accepted for publication December 9, 1994 ABSTRACT Several dopamine agonists, administered i.m., produced per- sistent, excessive and non-localized scratching in squirrel mon- keys (Saimiri sciureus). Studies were Conducted with a series of drugs to determine the pharmacological mechanisms respon- sible for this effect. All of the dopamine D2 agonists studied prOduCed dose-related increases in scratChing, whereas say- eral dopamine D1 receptor agonists, indirect dopamine ago- fists and drugs acting on other receptors failed to produce dose-related increases in scratching. The scratching produced by D2 agonists was stereospecific; (-)-NPA produced scratch- ing whereas its (+)-enantiomer was inactive up to doses 300- fold higher. Scratching induced by quinpirole was attenuated by both D2 and D1 antagonists, and this antagonism was ste- reospecific, with the D2 antagonist (-)-eticlopnde, but not its enantiomer, active. Sensitivity developed to the effects of D2 agonists with the quinpirole dose-effect curve shifting to the left by a factor of approximately 64. Two partial D2 receptor ago- nists (SDZ 208-91 1 and SDZ 208-912) had limited efficacy in producing scratching, however, one partial D2 receptor agonist (tergunde) was fully efficacious, suggesting that there are spare receptors for this effect. The peripherally active dopamine an- tagonist domperidone and the histamine antagonist diphenhy- dramine also reduced the scratching induced by 02 agonists, but not to the same extent as centrally acting D2 antagonists. Scratching in squirrel monkeys is an effect that appears to be due to agonist actions at 02 receptors, and may be mediated by a release of histamine. This behavioral activity may be useful as an in vivo indication of D2 receptor activity in primates. Several distinct dopamine receptor subtypes have been identified with biochemical methods. Two of these dopamine receptors, D1 and D2, have been differentiated for their abil- ity to stimulate adenylyl cyclase activity and they have re- ceived extensive study (ci. Kebabian and Calne, 1979; Clark and White, 1987). Selective agonists at D1 receptors stimu- late adenylyl cyclase activity, whereas D2-receptor agonists have either no effect, or decrease this activity. Differences in other pharmacological effects ofD1 and D2 agonists have also been described. For example, D2 agonists produce a hypo- thermia in rats and mice whereas D1 agonists produce a hyperthermia (Barnett et at. , 1972; Sanchez, 1989). Differences in the behavioral effects of D1 and D2 agonists have been best described in rodents. Dopamine D2 agonists Received for publication May 25, 1994. 1 Present address: Departamento de Psicologla Basica, Universidad Nacio- nal de Educaci#{243}n a Distancia, (P.O. Box) Apartado n.#{176} 50.487, 28040-Madrid, Spain. 2 Supported by a grant from the Ministerio de Educaci#{243}n y Ciencia (Madrid, Spain). Present address: Departamento de Psicologla B#{225}sica, Universidad Pontificia de Conillas, 28040-Madrid, Spain. produce locomotor hyperactivity, and at higher doses, stereo- typies, including gnawing and sniffing (e.g. , Arnt et at. , 1988; Braun and Chase, 1986). Seaman (1980) suggested on the basis of correlations between binding affinity and in vivo potency that these effects were due to actions at D2 receptors. Studies of D1 receptor agonists have suggested that the be- havioral effects of these drugs are distinct from those of D2 agonists. One prominent effect of D1 receptor agonists in rodents is a stimulation ofgrooming behavior (see Clark and White, 1987, for a review). In primates, Elsworth et at. (1991) have shown that both D1 and D2 agonists dose-dependently increased eye-blink rate, and that these increases were blocked by both selective D1 and D2 antagonists. In another study, Loschmann et at. (1991) showed that the dopamine agonists, quinpirole and apomorphine, produced dose-dependent increases in motor activity and stereotypies in marmosets; in contrast, the D1 agonist, SKF 38393, only decreased motor activity. Code and Tang (1991) reported that some D2 agonists, but not the D1 agonist, SKF 38393, produced yawning in rhesus monkeys. ABBREVIAT1ONS: j3-CCE: frcarboline-3-carboxylic acid ethyl ester HCI; CL confidence limits; (-)-NPA R(-)-propyl-norapomorphine HCI; (+)-PHNO: (+)-4-propyl-9-hydroxynaphthoxazine; Ru 24213: N-n-propyl-N-phenylethyl-p(3-hydroxyphenyl)ethylamine HCI; SCH 23390: R(+)-7- chloro-8-hydroxy-3-methyl-1 -phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine HCI; SCH 39166: (-)-trans-6,7,7a,8,9,13b-hexahydro-3chloro-2-hy- droxy-N-methyl-5H-benzo(d)naphtho-(2,1-b)azepine; SDZ 208-91 1: N-[(8-cr)-2,6-dimethylergoline-8-yl)-2,2-dimethylpropanamide; SDZ 208-912: N-[(8-a)-2-chloro-6-methylergollne-8-yl]-2,2-dimethylpropanamide; SKF 38393: (±)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tet- rahydro-1 H-3-benzazepine HCI; SKF 75670: 3-methyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine HBr; SKF 82958: (±)-6- chloro-7,8-dihydroxy-3-allyl-1 -phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine HBr. 138