5-HT1A agonist alleviates serotonergic potentiation of extrapyramidal disorders via postsynaptic mechanisms

- Fluoxetine potentiated haloperidol-induced extrapyramidal symptoms (EPS).
- 8-OH-DPAT reversed the fluoxetine-enhancement of EPS by stimulating 5-HT1A receptor.
- Intra-striatal injection of 8-OH-DPAT diminished the fluoxetine-enhancement of EPS.
- Intra-cortical injection of 8-OH-DPAT also reduced the fluoxetine-enhanced EPS.
- Intra-raphe injection of (±)-8-OH-DPAT failed to affect the EPS induction.

We previously demonstrated that 5-HT stimulants, including selective serotonin reuptake inhibitors (SSRIs), potentiated antipsychotic-induced extrapyramidal symptoms (EPS) by stimulating 5-HT2A/2C, 5-HT3 and 5-HT6 receptors. Here, we studied the effects of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin ((±)-8-OH-DPAT) on the fluoxetine enhancement of EPS (i.e., bradykinesia and catalepsy) to determine if the 5-HT1A agonist can counteract the serotonergic potentiation of EPS. Fluoxetine did not induce EPS signs by itself, but significantly potentiated haloperidol-induced bradykinesia in mice. (±)-8-OH-DPAT (0.1-1 mg/kg, i.p.) significantly attenuated the fluoxetine enhancement of haloperidol-induced bradykinesia in a dose-dependent manner. A selective 5-HT1A antagonist (s)-WAY-100135 completely reversed the anti-EPS action of (±)-8-OH-DPAT. Microinjection studies using rats revealed that local application of (±)-8-OH-DPAT into the dorsolateral striatum or the motor cortex significantly diminished fluoxetine-enhanced catalepsy. In contrast, (±)-8-OH-DPAT injected into the medial raphe nucleus failed to affect EPS induction. The present results illustrate that 5-HT1A agonist can alleviate the SSRI enhancement of EPS by activating postsynaptic 5-HT1A receptors in the striatum and cerebral cortex.