No abstract

Serotonin (5‐HT) applied at 1, 3, and 10 µM into the striatum of halothane‐anesthetized rats by in vivo microdialysis enhanced dopamine (DA) outflow up to 173, 283, and 584% of baseline values, respectively. The 5‐HT effect was partially reduced by 1 or 10 µM GR 125,487, a 5‐HT4 antagonist, and by 100 µM DAU 6285, a 5‐HT3/4 antagonist, whereas the 5‐HT1/2/6 antagonist methiothepin (50 µM) was ineffective. In the presence of tetrodotoxin the effect of 1 µM 5‐HT was not affected by 5‐HT4 antagonists. In addition, tetrodotoxin abolished the increase in DA release induced by the 5‐HT4 agonist (S)‐zacopride (100 µM). In striatal synaptosomes, 1 and 10 µM 5‐HT increased the outflow of newly synthesized [3H]DA up to 163 and 635% of control values, respectively. The 5‐HT4 agonists BIMU 8 and (S)‐zacopride (1 and 10 µM) failed to modify [3H]DA outflow, whereas 5‐methoxytryptamine (5‐MeOT) at 10 µM increased it (62%). In prelabeled [3H]DA synaptosomes, 1 µM 5‐HT, but not (S)‐zacopride (1 and 10 µM), increased [3H]DA outflow. DAU 6285 (10 µM) failed to modify the enhancement of newly synthesized [3H]DA outflow induced by 5‐MeOT or 5‐HT (1 µM), whereas the effect of 5‐HT was reduced to the same extent by the DA reuptake inhibitor nomifensine (1 µM) alone or in the presence of DAU 6285. These results show that striatal 5‐HT4 receptors are involved in the 5‐HT‐induced enhancement of striatal DA release in vivo and that they are not located on striatal DA terminals.

Dopamine (DA) release from nerve terminals of the nigrostriatal DA neurons not only depends on the activity of nigral DA cells but also on presynaptic regulation. Glutamatergic neurons of cortical origin play a prominent role in these presynaptic regulations. The direct glutamatergic presynaptic control of DA release is mediated by N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA) receptors, located on DA nerve terminals. In addition, by acting on striatal target cells, these glutamatergic neurons contribute also to indirect regulations of DA release involving several transmitters such as GABA, acetylcholine and neuropeptides. Diffusible messengers such as nitric oxide (NO) or arachidonic acid (AA) which are particularly formed under the stimulation of NMDA receptors may also participate to the regulation of DA release. In the present study, it will be shown that the co-application of NMDA and carbachol synergistically increases the release of [3H]-DA and that this effect is reduced by mepacrine or 4-bromophenacylbromide (10(-7) M), two inhibitors of PLA2. Therefore endogenously released AA induced by the co-stimulation of NMDA and cholinergic receptors seems to be involved, at least partly, in the release of DA.