8-OH-DPAT, but not deramciclane, antagonizes the anxiogenic-like action of paroxetine in an elevated plus-maze

Abstract.

Objective: To investigate whether a 5-hydroxytryptamine (5-HT) reuptake inhibitor (paroxetine) has an anxiogenic-like effect and what possible pharmacological mechanism underlies that action. Methods: We used the rat elevated plus-maze paradigm followed by measurement of locomotor activity. Some of the rats were subjected to handling and adaptation to the experimental situation, while the rest were naive to the test situation. Paroxetine was administered as a single treatment and in combination with the 5-HT_1A receptor agonist (8-OH-DPAT) or 5-HT_2A/2C receptor antagonist (deramciclane). Results: The administration of paroxetine induced an anxiogenic-like action in rats adapted to handling, but not in handling naive animals. Treatment with paroxetine (0.1–2 mg/kg) reduced the number of open arm visits and time spent in open arms, and the ratio between open and total arm entries in the elevated plus-maze. Paroxetine also decreased the number of line crossings and head-dips. Paroxetine caused the strongest anti-exploratory action at a dose of 0.5 mg/kg. Paroxetine did not suppress the locomotor activity of rats, showing that the described anti-exploratory effect was behaviourally specific to the plus-maze. Pretreatment with 8-OH-DPAT (0.05 mg/kg) completely reversed the anxiogenic-like action of paroxetine, whereas treatment with deramciclane (2 mg/kg) affected only the number of closed arm visits. Deramciclane (0.5–2 mg/kg) and 8-OH-DPAT (0.01–0.1 mg/kg) changed neither exploratory behaviour nor locomotor activity if given as single treatments to the habituated rats. Conclusion: The 5-HT reuptake inhibitor, paroxetine, at a low dose (0.5 mg/kg) induces an anxiogenic-like action in handling adapted rats. The effectiveness of 8-OH-DPAT against paroxetine probably supports a role of both pre- and postsynaptic 5-HT-ergic mechanisms in the anxiogenic-like action of paroxetine.