Evidence for 5‐HT autoreceptor‐mediated, nerve impulse‐independent, control of 5‐HT synthesis in the rat brain

To gain further insight into the operation of 5‐HT autoreceptor‐mediated feedback control of 5‐HT biosynthesis in serotonergic nerve terminal areas, the effect of the 5‐HT 1B and the 5‐HT 1A receptor agonists, TFMPP and 8‐OH‐DPAT, respectively, were investigated in the rat central nervous system (CNS) using in vivo and in vitro neurochemical approaches. TFMPP suppressed 5‐HT synthesis (5‐HTP accumulation after decarboxylase inhibition) both in vivo and in vitro. In vivo, the 5‐HT synthesissuppressing effect of the drug (3.0 mg/kg, s.c.) proved resistant to either acute hemitransection or reserpine (5 mg/kg, i.p.; 90 min before) pretreatment. In vitro, in cortical, hippocampal and striatal slice preparations, TFMPP (0.1–10 μM) decreased 5‐HT synthesis under basal and stimulated (30 mM K + ) conditions, an effect which was unaltered by prior in vivo reserpine‐induced 5‐HT depletion but was attenuated in the presence of 5‐HT 1B receptor antagonists such as methiothepin, cyanopindolol or propranolol. The 8‐OH‐DPAT (0.1 mg/kg, s.c.)‐induced decrease of 5‐HT synthesis in vivo was abolished by hemitransection but resistant to acute reserpine pretreatment; 8‐OH‐DPAT (10 μM) did not decrease 5‐HT synthesis in vitro. In conclusion, the present study confirms the importance of 5‐HT autoreceptors in the feedback control of nerve terminal 5‐HT biosynthesis. Specifically, our data indicate: (1) that the reduction of rat brain 5‐HT synthesis after TFMPP is mediated by 5‐HT 1B autoreceptors located on the serotonergic axon terminals, and (2) that the effect is directly mediated and occurs independently of 5‐HT neuronal firing and intact monoamine stores. © 1995 Wiley‐Liss, Inc.