Antidepressant-like effect of D(2/3) receptor-, but not D(4) receptor-activation in the rat forced swim test.
Dopamine plays a role in the pathophysiology of depression and therapeutic effects of antidepressants but the contribution of individual D(2)-like receptor subtypes (D(2), D(3), D(4)) to depression is not known. We present evidence that activation of D(2)/D(3), but not D(4) receptors, can affect the outcome in the rat forced swim test (FST). Nomifensine, a dopamine uptake inhibitor (7, 14, and 28 micromol/kg); quinpirole, a D(2)-like receptor and agonist (0.4, 1.0, and 2.0 micromol/kg); PD 12,8907, a preferential D(3) receptor agonist (0.17, 0.35, and 0.7 micromol/kg); PD 168077 (0.1, 0.3, and 1.0 micromol/kg) and CP 226269 (0.3, 1.0, and 3.0 micromol/kg), both selective D(4) receptor agonists, were administered s.c. 24, 5, and 0.5/1 h before testing. Nomifensine, quinpirole at all doses and PD 128907 at the highest dose decreased immobility time in FST. PD 168077 and CP 226269 had no effect on the model. To further clarify what type of dopamine receptors were involved in the anti-immobility effect of quinpirole, we tested different antagonists. Haloperidol, a D(2)-like receptor antagonist (0.27 micromol/kg), completely blocked the effect of quinpirole; A-437203 (LU-201640), a selective D(3) receptor antagonist (17.46 micromol/kg), showed a nonsignificant trend to attenuate the effect of the low dose of quinpirole, and L-745,870, a selective D(4) receptor antagonist (1.15 micromol/kg), had no effect. The pharmacological selectivity of the compounds tested suggests that the antidepressant-like effects of quinpirole are most likely mediated mainly by D(2) and to a lesser extent by D(3) but not D(4) receptors.
Basso
Ana M
AM
Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Park, IL 60064, USA. Ana.basso@abbott.com
Gallagher
Kelly B
KB
Bratcher
Natalie A
NA
Brioni
Jorge D
JD
Moreland
Robert B
RB
Hsieh
Gin C
GC
Drescher
Karla
K
Fox
Gerard B
GB
Decker
Michael W
MW
Rueter
Lynne E
LE
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009627:Nomifensine / Q000494:pharmacology; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D050637:Receptors, Dopamine D3; D013550:Swimming; D013997:Time Factors
D000928:Antidepressive Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; C493595:Drd3 protein, rat; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D009627:Nomifensine