The putative dopamine D3 receptor agonist 7-OH-DPAT: lack of mesolimbic selectivity.
7-Hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), an agonist with relative selectivity for the dopamine D3 receptor, was examined in several electrophysiological assays to determine whether it exhibits preferential effects in the mesolimbic versus nigrostriatal dopamine systems. Extracellular single unit activities of substantia nigra pars compacta (A9) and ventral tegmental area (A10) dopamine neurons, and caudate-putamen and nucleus accumbens neurons, were recorded in male rats anesthetized with chloral hydrate. Intravenous (+/-)-7-OH-DPAT potently and completely inhibited the firing of both A9 and A10 dopamine neurons (ED50's: 3.5 +/- 0.7 micrograms/kg and 3.9 +/- 0.9 micrograms/kg, respectively). The active enantiomer, (+)-7-OH-DPAT, was 2 to 3 times more potent than the racemic drug (ED50's: 1.2 +/- 0.3 micrograms/kg and 1.7 +/- 0.4 micrograms/kg for A9 and A10 cells, respectively). There were no significant differences in potency for either form in inhibiting A9 and A10 dopamine neurons. In other studies, iontophoretically applied (+)-7-OH-DPAT caused current-dependent inhibitions of spontaneously active or glutamate-driven caudate-putamen and nucleus accumbens neurons (I50 values, 6.5 and 7.9 nA, respectively). Again, no difference in potency between cell populations was noted. Finally, in cell-attached patch-clamp recordings from freshly dissociated rat caudate-putamen neurons, an 85 pS K+ channel known to be activated by dopamine and the "D2-like" agonist quinpirole was also observed with (+/-)-7-OH-DPAT (0.2-1 microM) applied in the patch pipette.(ABSTRACT TRUNCATED AT 250 WORDS)
Liu
J C
JC
Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115.
Cox
R F
RF
Greif
G J
GJ
Freedman
J E
JE
Waszczak
B L
BL
D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004873:Ergolines / Q000494:pharmacology; D007275:Injections, Intravenous; D007478:Iontophoresis; D008297:Male; D017072:Neostriatum / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011699:Putamen / Q000187:drug effects; D019257:Quinpirole; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D017557:Ventral Tegmental Area / Q000187:drug effects*
D018491:Dopamine Agonists; D004873:Ergolines; D013764:Tetrahydronaphthalenes; D019257:Quinpirole; C031349:7-hydroxy-2-N,N-dipropylaminotetralin