Antidepressant-like properties of the anti-Parkinson agent, piribedil, in rodents: mediation by dopamine D2 receptors.
The dopamine D2/D3 receptor agonist and alpha2 adrenergic receptor antagonist, piribedil, is used clinically as monotherapy and as an adjunct to L-3,4-dihydroxyphenylalanine in the treatment of Parkinson's disease. As it appears to improve mood, we examined its actions in rodent models of antidepressant properties, in comparison with the prototypical anti-Parkinson agent, apomorphine, the D2/D3 receptor agonist, quinpirole, and the antidepressants, imipramine and fluvoxamine. In the mouse forced-swim test, acute administration of imipramine, fluvoxamine, apomorphine or quinpirole decreased immobility time, actions dose dependently mimicked by piribedil (2.5-10.0 mg/kg, subcutaneously). In rats, acute and subchronic administration of piribedil similarly reduced immobility (0.63-10.0 mg/kg, subcutaneously) and apomorphine, quinpirole and imipramine were also active in this test, whereas fluvoxamine was inactive. Both in mice and in rats, the D2/D3 receptor antagonist, raclopride, and the D2 receptor antagonist, L741,626, dose dependently blocked the antidepressant properties of piribedil, whereas the selective D3 receptor antagonists, S33084 and SB277,011, were ineffective. In a chronic mild stress model in rats, piribedil (2.5-40.0 mg/kg, subcutaneously) restored sucrose intake in stressed animals exerting its actions more rapidly (by week 1) than imipramine. Imipramine, fluvoxamine, apomorphine, quinpirole and piribedil dose dependently (0.63-10.0 mg/kg, subcutaneously) suppressed aggressive and marble-burying behaviour in mice. In the latter procedure, raclopride and L741,626, but not S33084, attenuated the actions of piribedil. Over a dose range (0.63-10.0 mg/kg, subcutaneously) equivalent to those active in models of antidepressant activity, piribedil did not stimulate locomotor behaviour. In conclusion, principally via recruitment of D2 receptors, piribedil exerts robust and specific antidepressant-like actions in diverse rodent models.
Brocco
Mauricette
M
Psychopharmacology Department, Servier Research Institute, Croissy Research Center, Paris, France. mauricette.brocco@fr.netgrs.com
Dekeyne
Anne
A
Papp
Mariusz
M
Millan
Mark J
MJ
D000374:Aggression / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002908:Chronic Disease; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D016666:Fluvoxamine / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010891:Piribedil / Q000494:pharmacology*; D019257:Quinpirole / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000187:drug effects*; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors; D012934:Social Isolation / Q000523:psychology; D013315:Stress, Psychological / Q000523:psychology; D013395:Sucrose / Q000494:pharmacology; D013550:Swimming / Q000523:psychology
D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D019257:Quinpirole; D020891:Raclopride; D013395:Sucrose; D010891:Piribedil; D016666:Fluvoxamine; D007099:Imipramine