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-HT1B and the 5-HT1A 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 synthesis-suppressing 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 microM) 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-HT1B 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 microM) 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-HT1B 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.
Hjorth
S
S
Department of Pharmacology, University of Göteborg, Sweden.
Suchowski
C S
CS
Galloway
M P
MP
D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003714:Denervation; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000096:biosynthesis*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D017660:Autoreceptors; D010879:Piperazines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C018406:1-(3-trifluoromethylphenyl)piperazine; D012701:Serotonin; D012110:Reserpine