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The i.p. injection of R-fluoxetine into mice at doses of 1-10 mg/kg led to higher concentrations of the desmethyl metabolite, R-norfluoxetine, in whole brain than was true for S-fluoxetine. R-Norfluoxetine, but not S-norfluoxetine, concentrations predominated over those of the parent drug at 7-24 hr after injection of the corresponding fluoxetine enantiomer. The more rapid N-demethylation of R-fluoxetine, and the relative inactivity of R-norfluoxetine as a serotonin uptake inhibitor compared with S-norfluoxetine, may explain the earlier report that R-fluoxetine is less potent than S-fluoxetine in antagonizing p-chloroamphetamine depletion of brain serotonin in mice. In the present study, a 10 mg/kg, i.p., dose of S-fluoxetine completely prevented p-chloroamphetamine given 24 hr later from depleting brain serotonin, whereas R-fluoxetine offered no protection at this time.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a commercially available chemical reagent. Although little has been known about its biological effects, recently MPTP has been reported to cause irreversible Parkinson's disease-like symptoms in humans and in monkeys. We describe here another pharmacologic effect of MPTP, the ability to deplete cardiac norepinephrine in rats and mice. In mice, cardiac norepinephrine concentration decreased within 1 hr, was maximally depleted at 24 hr, and recovered by 4-7 days after i.p. injection of a 32 mg/kg dose of MPTP. The depletion was antagonized by desipramine pretreatment, as was norepinephrine depletion by tyramine. In rats, cardiac norepinephrine depletion by 10-30 mg/kg, i.p., doses of MPTP was accompanied by depletion of cardiac dopamine and of norepinephrine in the mesenteric artery. In rats and in mice, norepinephrine in brain was affected to a smaller degree than was norepinephrine in heart, and dopamine in brain was depleted very little if at all. In spontaneously hypertensive rats, the depletion of cardiac norepinephrine was associated with a marked antihypertensive effect. The p-hydroxy analog of MPTP did not deplete cardiac norepinephrine in rats, indicating that its possible formation as a metabolite of MPTP was not involved in the depletion of cardiac norepinephrine. These findings extend the spectrum of known pharmacologic effects of MPTP.

Amantadine (50 and 100 mg/kg IP) did not change basal levels of DOPAC (3,4-dihydroxyphenylacetic acid) or HVA (homovanillic acid) in rat brain and did not alter the increase in DOPAC levels resulting from dopamine receptor blockade by spiperone. The increase in HVA levels produced by spiperone was significantly, but only slightly, enhanced by amantadine at these doses. In contrast, amfonelic acid at a dose of 5 mg/kg increased DOPAC and HVA levels and enhanced several-fold the spiperone-induced elevation of DOPAC and HVA levels. Amfonelic acid at at 2.5 mg/kg dose enhanced the turnover of dopamine (measured by the decline in dopamine concentration after inhibition of tyrosine hydroxylation with alpha-methylytyrosine) in spiperone-treated rats, whereas amantadine (100 mg/kg) had a smaller and not statistically significant effect. Neither compound affected significantly dopamine levels in a alpha-methyltyrosine-treated rats not given spiperone. Although amantadine has been observed by earlier workers to enhance the stimulated release of dopamine, it does not appear to act in a manner similar too amfonelic acid.

1-(m-Trifluoromethylphenyl)-piperazine inhibited the specific binding of tritiated serotonin to membranes from rat brain in vitro at lower concentrations than did quipazine or MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine). In rats 1-(m-trifluoromethylphenyl)-piperazine decreased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) without altering the concentration of serotonin in whole brain. The decrease in 5-HIAA was apparently due to a decrease in serotonin turnover, since 1-(m-trifluoromethylphenyl)-piperazine caused a slower decline in serotonin concentration after synthesis inhibition by alpha-propyldopacetamide and a slower accumulation of 5-HIAA after probenecid injection to block its efflux from brain. The decrease in serotonin turnover is an expected result of stimulating serotonin receptors in brain and has earlier been reported to occur with quipazine. Thus all of the results are compatible with the idea that 1-(m-trifluoromethylphenyl)-piperazine acts as a serotonin receptor agonist in rat brain.