The serotonin (5-HT)1A agonist, LY 165,163, induces contralateral rotation in unilateral substantia nigra-lesioned rats via dopamine receptors

The serotonin (5-HT)_1A agonist, LY 165,163 (1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine), also known as PAPP, has been suggested to exert effects via an interaction with dopamine receptors. Thus, in this study, we examined its ability to induce rotation in rats sustaining unilateral 6-hydroxy-dopamine lesions of the substantia nigra, an in vivo model of dopaminergic activity. In analogy to the direct dopamine (mixed D₁/D₂) agonist, apomorphine, (0.01–0.63 mg/kg), LY 165,163 (0.16–10.0 mg/kg) dose-dependently elicited robust and substained contralateral rotation. Its maximal effect was comparable to that of apomorphine and its duration of action more extended. Rotation elicited by LY 165,163 (10.0 mg/kg) was resistant to the 5-HT_1A antagonist, (−)-alprenolol. It was also unaffected by the selective D₁ antagonist, SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,tetraphydro-1H-3- benzazepine) (2.5 mg/kg) or the selective D₂ antagonist, raclopride (10.0 mg/kg) when each was administered alone. However, upon joint administration they clearly diminished the effect of LY 165,163. The dopamine antagonist, haloperidol (D₂ > D₁) also reduced the action of LY 165,163. This profile of partial antagonism by mixed D₁ and D₂ receptor blockade has been reported previously for apomorphine and contrasts to that seen with selective D₁ or D₂ agonists, the actions of which are completely blocked by D₁ or D₂ antagonists, respectively. In conclusion, the present data demonstrate that LY 165,163 exerts pronounced rotation in nigral-lesioned rats: this reflects a mixed D₁/D₂ action rather than an activation of 5-HT_1A sites. Thus, in addition to an agonist action at 5-HT_1A receptors, dopaminergic effects contribute to the pharmacological profile of LY 165,163.