EFFECTS OF INTRACEREBROVENTRICULAR ADMINISTRATION OF D-FENFLURAMINE AND D-NORFENFLURAMINE, AS A SINGLE INJECTION OR 2-HR INFUSION, ON SEROTONIN IN BRAIN - RELATIONSHIP TO CONCENTRATIONS OF DRUGS IN BRAIN

The effects of d-fenfluramine (DF) and d-norfenfluramine (DNF), administered intracerebroventricularly (i.c.v.) on levels of serotonin (5-HT) in the brain, was assessed in relation to levels of drugs in brain. d-Fenfluramine, as a single injection (500-mu-g/20-mu-l), caused no significant changes in 5-HT in whole brain from 15 to 480 min after injection. When infused intraventricularly for 2 hr, DF and DNF at 500 but not at 125-250-mu-g/hr, markedly reduced concentrations of 5-HT in brain 4 hr after the end of the infusion. At this time levels of DNF in brain were similar (between 4 and 5-mu-g/g) with both compounds, whereas levels of DNF after single intraventricular injections of DF were below 2-mu-g/g at all times after injection. Infusion of 500-mu-g/hr of DNF for 2-hr reduced concentrations of 5-HT in various regions of the brain, with the exception of the brainstem, whereas 250-mu-g/hr of DNF significantly lowered levels of 5-HT only in the cortex. The effect of infusion of 500-mu-g/hr of DNF was specific for 5-HT (no effect on dopamine and norepinephrine) and lasted for at least 168 hr. The results suggest that the effect on 5-HT in brain of intraventricular infusion of DF, but not a single injection, was due to the fact that, only in the former condition were adequate levels of DNF, the active metabolite of DF, reached in the brain. These results are relevant to the interpretation of studies in which biochemical changes in the brain after intraventricular administration, are reported without any measurement of the drug or its active metabolites, in plasma and brain.