Selective D3 receptor agonist effects of (+)-PD 128907 on dialysate dopamine at low doses.
An involvement of the D3 dopamine receptor in the modulation of extracellular dopamine concentrations is suggested by pharmacological studies. However, recent studies using D3 receptor knock out mice indicated that several functions previously attributed to the D3 receptor are mediated by other receptor types. In the present study, we used the no-net flux microdialysis technique to characterize: (i) basal dopamine dynamics in the ventral striatum of D3 knock out and wild type mice and (ii) the effects of the putative D3-receptor selective agonist (+)-PD 128907. Neither the extracellular dopamine concentration nor the in vivo extraction fraction, an indirect measure of basal dopamine uptake, differed between D3 knock out and wild type mice. Moreover, no differences in potassium (60 mM) or cocaine (5 or 20 mg/kg i.p.) evoked dopamine concentrations were detected between the two genotypes. However, intra-striatal or systemic administration of doses of (+)-PD 128907 that failed to modify dopamine concentrations in knock out mice significantly decreased dialysate dopamine concentrations in the wild type. Comparison of the concentration-response curve for (+)-PD 128907 revealed IC(25) values of 61 and 1327 nM in wild type and knock out mice, respectively, after intra-striatal infusions. Similar differences were obtained after systemic administration of the D3 preferring agonist (IC(25) 0.05 and 0.44 mg/kg i.p. in wild type and knock out mice, respectively). We conclude that the activation of the D3 receptor decreases extracellular dopamine levels and that, at sufficiently low doses, the effects of (+)-PD 128907 on extracellular dopamine are selectively mediated by the D3 receptor.
Zapata
A
A
Integrative Neuroscience Unit, Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. azapata@intra.nida.nih.gov
Witkin
J M
JM
Shippenberg
T S
TS
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001921:Brain / Q000033:anatomy & histology; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D010078:Oxazines / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics; D050637:Receptors, Dopamine D3
D001578:Benzopyrans; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; C493594:Drd3 protein, mouse; D010078:Oxazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; D003042:Cocaine; D011188:Potassium; D004298:Dopamine