The activity of pramipexole in the mouse forced swim test is mediated by D2 rather than D3 receptors.
BACKGROUND
Recent studies have reported antidepressant-like activities of the dopamine D2/D3 agonist pramipexole in the chronic mild stress model and in the forced swim test, suggesting that D3 receptor agonists may represent a new class of antidepressant drugs. However, the relative contribution of D2 or D3 receptors to the activity of pramipexole in these models is unclear.


OBJECTIVE
The aim of the current studies was to explore the role of dopamine D2 and D3 receptors in the activity of pramipexole in the mouse forced swim test.


METHODS
The effect of pramipexole (0.1-3.2 mg/kg) in the mouse forced swim test was examined both in conjunction with D2 and D3 receptor antagonists (haloperidol (0.1-1 mg/kg) and LU-201640 (A-437203, 5.6-17.8 mg/kg), as well as in D3 receptor knockout mice obtained on two different background strains (C57BL/6J and B6129SF2/J). Locomotor activity was also assessed following pramipexole administration. RESULTS. Pramipexole produced dose-dependent reductions in immobility in the forced swim test at doses that did not produce generalized increases in locomotor activity. LU-201640, the D3 selective antagonist, failed to block the antidepressant-like effects of pramipexole. In contrast, the efficacy of pramipexole in the forced swim test was completely blocked by the D2 antagonist, haloperidol. No baseline differences were observed between knockout and wild-type mice from either background strain in locomotor activity or in the forced swim test. Furthermore, in both background strains, pramipexole showed similar efficacy in the forced swim test for both wild-type and knockout mice.


CONCLUSIONS
Taken together, these studies suggest that the D2 receptor rather than the D3 receptor is important for the antidepressant-like activity observed for pramipexole in the mouse forced swim test.
CNS Discovery Research, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. judith_a_siuciak@groton.pfizer.com
Judith A
JA
Siuciak
Remie A
RA
Fujiwara
D000818:Animals; D052160:Benzothiazoles; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D000077487:Pramipexole; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D013045:Species Specificity; D013550:Swimming; D013844:Thiazoles / Q000494:pharmacology*
D052160:Benzothiazoles; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; C493594:Drd3 protein, mouse; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; D000077487:Pramipexole; D006220:Haloperidol