The behavioural and neurochemical profile of the putative dopamine D3 receptor agonist, (+)-PD 128907, in the rat.
The functional relevance of the dopamine D3 receptor is still unresolved, largely because of the absence of selective D3 receptor ligands. In the present study we have examined the in vivo profile of (+)-PD 128907, a potent and functionally selective D3 receptor agonist. Low doses of (+)-PD 128907 reduced spontaneous locomotor activity in the rat (ED50 = 13 +/- 3 micrograms/kg, s.c.) a response which was comparable with the non-selective D2,3 receptor agonist apomorphine (ED50 = 13 +/- 1.6 micrograms/kg, s.c.). In addition (+)-PD 128907 impaired prepulse inhibition of the acoustic startle response, with significant effects observed at doses of 30 micrograms/kg when appropriate prepulse intensities were used. Higher doses reversed gamma-butyrolactone-induced catecholamine synthesis (ED50 = 95 +/- 22 and 207 +/- 37 micrograms/kg in accumbens and striatum respectively) and induced yawning (100-300 micrograms/kg), penile grooming (30-1000 micrograms/kg) and sniffing (> or = 300 micrograms/kg) although doses 3- to 10-fold greater than apomorphine were required to produce maximal effects. In contrast to apomorphine, however, (+)-PD 128907 failed to induce intense stereotyped licking and biting in the rat. In view of the potency and selectivity of (+)-PD 128907 for the D3 receptor, a role in the control of locomotor activity is suggested. In addition, the observation that (+)-PD 128907 disrupts prepulse inhibition, a phenomenon which is also impaired in schizophrenic subjects, may indicate the pathological importance of this receptor subtype.
Bristow
L J
LJ
Merck Sharp, Neuroscience Research Centre, U.K.
Cook
G P
GP
Gay
J C
JC
Kulagowski
J J
JJ
Landon
L
L
Murray
F
F
Saywell
K L
KL
Young
L
L
Hutson
P H
PH
D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D010078:Oxazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001578:Benzopyrans; D018491:Dopamine Agonists; D010078:Oxazines; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; D004295:Dihydroxyphenylalanine; D001058:Apomorphine; D015107:4-Butyrolactone