5-HT4 receptor involvement in the serotonin-enhanced dopamine efflux from the substantia nigra of the freely moving rat: a microdialysis study.

The functional regulation by serotonin (5-HT) receptors of the 5-HT-enhanced dopamine (DA) release from the rat substantia nigra (SN) was investigated using in vivo microdialysis. Exogenously administered or extracellularly enhanced 5-HT (by means of intranigral citalopram perfusion) (both 1 microM for 1 h) significantly increased nigral DA efflux to 165% and 145%, respectively. Intranigral administration of pindolol (10 microM, 3 h), a 5-HT1A/1B receptor antagonist which is clinically used in order to block 5-HT1A/1B autoreceptors, did not affect DA levels but significantly increased nigral 5-HT levels to 135%. Co-perfusion of this antagonist with 5-HT (1 microM, 1 h) did not abolish the 5-HT-induced DA release from the SN as DA was increased to 166%. Local application of the 5-HT1A/1B receptor agonist, CP 93129 (1 microM, 1 h), increased DA release from the SN to 4770% whereas 5-HT release was significantly decreased to 75%. Co-perfusion of the 5-HT1A/1B receptor antagonist, pindolol, with this agonist only partly abolished the CP 93129-induced DA release whereas the CP 93129-induced decrease in nigral 5-HT release was completely abolished. Administration of the 5-HT2A/2C receptor antagonist, ketanserin (50 microM, 3 h), significantly increased DA to 143% and 5-HT release to 363%. Co-perfusion of this antagonist with 5-HT still caused an increase in nigral DA release to 214%. Intranigral perfusion of the 5-HT4 receptor antagonist, RS 39604 (10 microM, 3 h), did not affect DA levels but significantly decreased nigral 5-HT levels to 74%. Co-perfusion of this antagonist with 5-HT was able to prevent the 5-HT-enhanced DA efflux from the SN. From this study it can be concluded that the 5-HT-enhanced (and possibly the citalopram-induced) nigral DA release is 5-HT4 receptor mediated.