Differences between A 68930 and SKF 82958 could suggest synergistic roles of D1 and D5 receptors.
The isochroman A 68930 and the benzazepine SKF 82958 are two full dopamine D1 receptor agonists. Responses to these compounds are different in several important aspects. When given to rats in a novel environment, A 68930 caused a dose-dependent (0.019-4.9 mg/kg) suppression of locomotion. SKF 82958 had no such effect at any dose studied (0.051-3.3 mg/kg). In animals habituated to the environment, A 68930 had no effect but SKF 82958 increased locomotor activity. Both A 68930 and SKF 82958 caused a decrease in core temperature at early time points. Both agonists increased c-fos and NGFI-A expression in caudate putamen but only SKF 82958 did so in the accumbens nucleus (at 1.6 mg/kg). Quantitative receptor autoradiography showed that A 68930 is 9-13 times more potent than SKF 82958 at displacing the selective dopamine D1 antagonist [3H]SCH 23390. This difference agrees with the difference observed when the agonists were used to stimulate cAMP formation in cells transfected with the D1 receptor. In contrast, SKF 82958 was 5 times more potent than A 68930 in cells transfected with the D5 receptor. We suggest that the balance between signaling via dopamine D1 and D5 receptors determines the functional effects of agonists at D1/D5 receptors.
Nergårdh
R
R
Department of Physiology and Pharmacology, Section of Molecular Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden. Ricard.Nergardh@fyfa.ki.se
Oerther
S
S
Fredholm
B B
BB
D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D002839:Chromans / Q000494:pharmacology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D050641:Receptors, Dopamine D5 / Q000502:physiology*
D001552:Benzazepines; D002839:Chromans; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; C071262:SK&F 82958; C065380:A 68930