Dopamine releasing effect of phenylbiguanide in rat striatal slices

The present study explored the mechanisms underlying the dopamine releasing effect of phenylbiguanide, a compound commonly used as a 5-HT3 receptor agonist. Phenylbiguanide, and also serotonin and 2-methyl-serotonin, enhanced the outflow of radioactivity from superfused rat striatal slices preloaded with [3H]dopamine. The presence of the dopamine uptake blocker nomifensin prevented the increase in outflow. The effect of phenylbiguanide was not antagonized by 5-HT3 receptor antagonists, did not require the presence of Ca2+ in the superfusion buffer, and also occurred in reserpinized preparations with depleted dopamine stores. Phenylbiguanide caused a greater shift in the distribution of superfusate radioactivity from DOPAC to dopamine than did nomifensin. All these results are in agreement with an exchange mechanism by which phenylbiguanide promotes the efflux of dopamine by operation of the uptake carrier in the reversed direction. In consonance, phenylbiguanide, and also serotonin and 2-methyl-serotonin, inhibited the binding of [3H]CFT to dopamine uptake sites, although the rank order for promoting outflow, serotonin greater than phenylbiguanide greater than 2-methyl-serotonin, differed from that for inhibiting [3H]CFT binding to dopamine uptake sites, 2-methylserotonin approximately serotonin greater than phenylbiguanide. The present results raised the possibility that phenylbiguanide has an additional activity in releasing vesicular dopamine into the cytoplasmic pool.