EFFECTS OF ANGIOTENSIN-II ON DOPAMINE AND SEROTONIN TURNOVER IN THE STRIATUM OF CONSCIOUS RATS

This study was designed to evaluate the functional significance of ang iotensin II (Ang II) receptors identified by previous receptor autorad iography studies to be located presynaptically on terminals of dopamin ergic neurones projecting to the striatum. Microdialysis was performed in the striatum of conscious freely moving rats and dopamine and sero tonin metabolites measured by HPLC with electrochemical detection. Dur ing perfusion with artificial CSF, the major extracellular dopamine me tabolite identified was DOPAC with smaller concentrations of HVA. When Ang II (1 muM) was introduced into the dialysis perfusion medium, DOP AC output increased markedly, peaking at 219%, and returned to control with vehicle perfusion during the recovery period. This increase in D OPAC output with Ang II was completely blocked by co-administration of the AT1 selective antagonist, Losartan (1 muM). Administration of Los artan alone led to a significant (16%) depression of DOPAC output rela tive to vehicle, suggesting that dopamine release is under a tonic fac ilitatory influence of Ang II via the AT1 receptor subtype. Parallel, but smaller changes were seen with HVA outputs. During Ang II perfusio n the output of HVA was elevated 34-79% of that in vehicle-treated rat s and this effect was completely abolished by concomitant administrati on of Losartan. As was observed with DOPAC output, administration of L osartan alone led to a 13-24% depression of HVA output compared to veh icle perfusion. When nomifensine (10 muM) was included in the infusion fluid, dopamine was clearly measurable. Ang II perfusion increased th e levels of dopamine to 225%. Values returned towards baseline during the recovery period. Ang II administration also increased (by 15% and 55%) the levels of the major serotonin metabolite, 5HIAA. This effect was also abolished by co-administration with Losartan, and Losartan al one depressed basal levels of 5HIAA. Although these results are less d ramatic than those seen with the dopamine metabolites, they suggest th at serotonin turnover may be under the influence of Ang II in the stri atum. The findings of increased DOPAC and HVA output following Ang II infusion, which are blocked by Losartan, together with the decreased b asal output of these dopamine metabolites following Losartan alone, is strong evidence for an in vivo role of Ang II in modulating dopaminer gic transmission, probably via presynaptic Ang II receptors which faci litate dopamine release.