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Bufotenine (N, N-dimethyl-5-hydroxytryptamine) is a serotonin analog reported to be hallucinogenic. Bufotenine concentrations were measured by liquid chromatography with electrochemical detection after the s.c. injection of bufotenine (1, 30 or 100 mg/kg) into rats. At 1 hr, bufotenine was high in lung, heart and blood and lower in brain and liver. No N-monomethyl-5-hydroxytryptamine was detected, but 5-hydroxyindoleacetic acid (5HIAA) was increased due to bufotenine metabolism. Bufotenine disappeared nearly completely by 8 hr. Bufotenine concentrations were slightly higher in hypothalamus and brain stem than in striatum or cortex; serotonin was slightly decreased, and 5HIAA was increased in these brain regions. Pargyline reduced concentrations of 5HIAA in blood and tissues after bufotenine injection; LY51641 but not deprenyl mimicked pargyline, suggesting type A not type B monoamine oxidase metabolizes bufotenine. Bufotenine injection increased serum corticosterone concentration, an effect not blocked by metergoline at a dose that blocked a similar increase elicited by quipazine. Although only 2% of the serotonin was found in platelet-poor plasma, more than 99% of the bufotenine was found in platelet-poor plasma, indicating that bufotenine is not stored in platelets. These experiments indicate that bufotenine is rapidly eliminated, in part by type A monoamine oxidase, after its injection into rats and that bufotenine penetrates the blood-brain barrier poorly.

Duloxetine, (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine, is an inhibitor of the serotonin and norepinephrine neuronal transporters (Wong et al., 1993). In mice, duloxetine antagonized the depletion of brain serotonin by p-chloroamphetamine (ED50 = 2.5 mg/kg, i.p.) and the depletion of heart norepinephrine by 6-hydroxydopamine (ED50 = 1.1 mg/kg, i.p.). Brain concentrations of 5-hydroxyindoleacetic acid were decreased by duloxetine at 2 hr after doses of 1, 3 and 10 mg/kg and at 1 to 8 hr (but not 24 hr) after a 10 mg/kg i.p. dose of duloxetine. Duloxetine antagonized norepinephrine depletion in frontal cortex, but not dopamine depletion in striatum, after treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In rats, duloxetine decreased brain 5-hydroxyindoleacetic acid dose-dependently for up to 8 hr and decreased serotonin turnover measured by the accumulation of 5-hydroxytryptophan in rat hypothalamus after decarboxylase inhibition. In rats, duloxetine antagonized the depletion of brain serotonin by p-chloramphetamine and the depletion of norepinephrine and epinephrine in hypothalamus after i.c.v. injection of 6-hydroxydopamine. In vitro, duloxetine had little effect on either type A (serotonin as substrate) or type B (phenylethylamine as substrate) monoamine oxidase, IC50 concentrations being above 10(-5) M. These data extend evidence that duloxetine inhibits serotonin and norepinephrine transporters in vivo, actions that may lead to therapeutic efficacy in mental depression.

Although fluoxetine is a highly selective inhibitor of serotonin uptake in vitro and in vivo, some investigators have suggested that dopamine uptake inhibition may contribute to anorectic actions of fluoxetine. The present experiments were done to determine fluoxetine's effects in some animal protocols in which dopamine uptake inhibitors have characteristic actions. Mazindol prevented the depletion of striatal dopamine and its metabolites by amphetamine in iprindole-pretreated rats, but fluoxetine had no effect. Mazindol prevented the depletion of striatal dopamine and its metabolites by 6-hydroxydopamine injected intracerebroventricularly into rats, but fluoxetine had no effect. Mazindol enhanced the elevation of 3,4-dihydroxyphenylacetic acid concentration in rat brain after spiperone injection, but fluoxetine did not cause that effect. Fluoxetine did not mimic amfonelic acid in antagonizing the retention of alpha-methyl-m-tyramine invant striatum after the injection of alpha-methyl-m-tyrosine. These results show that fluoxetine, at doses that are effective in blocking the serotonin uptake carrier and causing anorexia, does not block the dopamine uptake carrier.

Nefazodone (2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl- 2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one) has been reported to be effective in the treatment of depression. Antagonism of serotonin type 2A (5HT2A) receptors, as well as inhibition of the serotonin (5HT) uptake carrier, has been suggested to contribute to the antidepressant action of nefazodone in vivo (Eison et al., 1990). Nefazodone weakly antagonized the quipazine-induced rise in rat serum corticosterone levels and the quipazine-induced increase in rat hypothalamic 3-methoxy-4-hydroxy-phenylglycol sulfate, suggesting blockade of 5HT2A receptors in vivo. Nefazodone, however, failed to antagonize the p-chloroamphetamine-induced depletion of mouse or rat brain 5HT, displaying a lack of effect on the 5HT uptake carrier. These data extend previous in vitro and in vivo data (Eison, et al. 1990) reporting nefazodone to be an antagonist at 5HT2A receptors, but fail to show inhibition of the 5HT uptake carrier in the same dose range.

Nefopam antagonized 6-hydroxydopamine-induced depletion of heart norepinephrine in mice with an ED50 value of 12 mg/kg. Nefopam was ineffective in antagonizing p-chloroamphetamine-induced depletion of brain serotonin in our standard assay in mice, apparently due to a short duration of action. Brain concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were decreased after a 32 mg/kg, i.p., dose of nefopam at 1 and 2 hr but not at 4 hr. When nefopam was injected simultaneously with p-chloroamphetamine, it prevented brain serotonin depletion initially, but by 6 hr the protective effect was essentially lost, suggesting that p-chloroamphetamine persisted in mouse brain longer than did nefopam. Nefopam caused a dose-related antagonism of brain serotonin depletion at 2 hr after injection of a low dose of p-chloroamphetamine hydrochloride (10 mg/kg, i.p.), with a calculated ED50 value of 11 mg/kg. The lowering of brain 5-HIAA concentration 2 hr after nefopam injection occurred after a 32 mg/kg dose but not after a 3 or 10 mg/kg dose. These data suggest that nefopam is effective as an inhibitor of norepinephrine and serotonin uptake at doses previously shown to be analgesic in mice, consistent with uptake inhibition being a postulated mechanism important in its analgesic effect. Nonetheless, nefopam is a relatively weak inhibitor of monoamine uptake with a short duration of action in mice.

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.

Norfluoxetine, the N-desmethyl metabolite of fluoxetine, has been reported to resemble fluoxetine in being a potent and selective inhibitor of the serotonin uptake carrier. The enantiomers of norfluoxetine have now been compared as serotonin uptake inhibitors in vivo, based on their antagonism of p-chloroamphetamine-induced depletion of serotonin in brain and their lowering of concentrations of the metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA) in brain. In rats, S-norfluoxetine (ED50 3.8 mg/kg) was more potent than R-norfluoxetine (ED50 > 20 mg/kg) in blocking the depletion of serotonin by p-chloroamphetamine after intraperitoneal administration. The S enantiomer decreased concentrations of 5-HIAA in whole brain after doses of 2.5-20 mg/kg, whereas the R enantiomer did not. The concentrations of both enantiomers in brain increased in proportion to dose and the R enantiomer disappeared from the brain at a slightly slower rate than the S enantiomer. The relative inability of the R enantiomer to block the uptake of serotonin was therefore not a result of smaller concentrations of drug in the brain. In mice, S-norfluoxetine was also more potent than R-norfluoxetine in blocking depletion of serotonin by p-chloroamphetamine (ED50 values 0.82 and 8.3 mg/kg, respectively). Thus, in contrast to the relatively similar potencies of the enantiomers of fluoxetine in blocking the uptake of serotonin, the enantiomers of norfluoxetine have markedly different potencies as inhibitors of the uptake of serotonin.

Olanzapine, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-B] [1,5]benzodiazepine (LY170053), antagonized the quipazine-induced elevation of serum corticosterone concentration in rats with an ED50 value of 0.57 mg/kg i.p. LY170053 was less potent in antagonizing the pergolide-induced elevation of serum corticosterone concentration in rats, and increases in corticosterone elicited by olanzapine alone at higher doses complicated the precise estimate of an ED50 value, which was approximately 3 mg/kg. These relative potencies in blocking quipazine and pergolide effects are taken as indices of antagonism of serotonin 5HT2 and of dopamine D2 receptors, respectively. Olanzapine is more potent than clozapine in blocking 5HT2 and D2 receptors, and its ability to block these receptors supports its possible usefulness as an antipsychotic drug.

The effects of L-5-hydroxytryptophan (L-5HTP) and L-5HTP inosinate injection on brain 5-hydroxyindoles in rats were compared. L-5HTP and L-5HTP inosinate caused indistinguishable dose-dependent increases in 5HTP and 5HIAA (5-hydroxyindoleacetic acid) but not serotonin concentrations in whole brain at 1 hr in rats. Our results do not substantiate a previous claim that L-5HTP inosinate is superior to L-5HTP itself in increasing brain serotonin formation.

Fluoxetine, a serotonin uptake inhibitor, is known to inhibit the metabolism of some drugs including desipramine, resulting in increased brain and blood levels of desipramine when the drugs are co-administered to rats. Norfluoxetine, the N-desmethyl metabolite of fluoxetine, was found to be less potent than fluoxetine in increasing brain and blood levels of desipramine in rats. Norfluoxetine was essentially equipotent to fluoxetine in decreasing brain concentrations of 5-hydroxyindoleacetic acid (5-HIAA) as a consequence of serotonin uptake inhibition. After the injection of fluoxetine into rats, brain levels of fluoxetine predominated over those of norfluoxetine at 1 hour, but at longer times (out to 24 hours), norfluoxetine levels were higher in brain (and in liver) than fluoxetine levels. Brain levels of 5-HIAA were decreased for at least 24 hours after fluoxetine injection, due apparently to the persistence of and inhibition of serotonin uptake by norfluoxetine. When desipramine was injected 16 hrs after fluoxetine injection, brain levels of desipramine were no longer elevated. The results suggest that norfluoxetine contributes in a major way to the inhibition of serotonin uptake after fluoxetine administration but contributes less, if at all, to the inhibition of desipramine metabolism.

The serum corticosterone concentration in rats was increased by injection of quipazine, a relatively nonselective serotonin (5-hydroxytryptamine; 5-HT) agonist, or 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT), a serotonin agonist selective for the 5-HT1A subtype of receptor. The quipazine-induced increase in serum corticosterone was antagonized by 17 different serotonin antagonists; of these, MDL 11939, pirenperone, setoperone, mianserin, LY 281067, ketanserin, ritanserin and clozapine have relatively selective affinity for the 5-HT2 subtype of receptor. The 8-OH-DPAT-induced increase in serum corticosterone was not antagonized by metergoline, the most potent antagonist of the quipazine effect, but was antagonized by pindolol or penbutolol, 5-HT1A receptor antagonists. Pindolol did not block the effect of quipazine. The results support earlier evidence that serum corticosterone concentration in rats can be increased by activation of either 5-HT1A or 5-HT2 receptors. Indirect-acting serotonin agonists - fluoxetine, L-5-hydroxytryptophan and p-chloroamphetamine - also increased serum corticosterone concentrations. The increases elicited by those agents, which earlier had been reported not to be blocked by metergoline pretreatment, also were not blocked by pretreatment with pindolol or with the combination of metergoline and pindolol. Thus, an involvement of a specific serotonin receptor subtype in the actions of these indirect agonists has not been established.

The effects of two anorectic drugs, CM 57227 (4-amino-1-[6-chloropyrid-2-yl]piperidine) and CM 57373 (its 6-bromo analog), on brain serotonin metabolism in rats were studied. Both compounds dose-dependently decreased brain concentrations of 5-hydroxyindoleacetic acid (5-HIAA) for several hours while causing little or no change in brain concentrations of serotonin. Both compounds antagonized the depletion of brain serotonin by p-chloroamphetamine, an agent whose depletion requires the serotonin uptake carrier, with ED(50) values of about 7 mg/kg. The data suggest these compounds affect brain serotonin neurons primarily by inhibiting the membrane uptake carrier, which may be the mechanism by which they produce anorexia.

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.

Nisoxetine, 3-(o-methoxyphenoxy)-3-phenyl-N-methyl-propyl-amine, is a new inhibitor of norepinephrine uptake. Nisoxetine antagonized 6-hydroxydopamine-induced depletion of norepinephrine in mouse heart with an ED50 of 0.9 mg/kg but had no effect on p-chloroamphetamine-induced depletion of serotonin in mouse brain at doses up to 32 mg/kg. Using the antagonism of these depleting agents to estimate inhibition of uptake into noradrenergic and serotoninergic neurons, we compared nisoxetine to several known amine uptake inhibitors. The order of effectiveness in antagonizing 6-hydroxydopamine action was protriptyline greater than desmethylimipramine greater than EXP 561 greater than nisoxetine greater than nortriptyline greater than chlorpheniramine greater than desmethylchlorimipramine greater than imipramine greater than doxepin greater than amitriptyline greater than chlorimipramine, with fluoxetine and its N-demethylated metabolite (103947) having no effect. In blocking p-chloroamphetamine, the order of effectiveness was EXP 561 greater than fluoxetine greater than 103947 greater than chlorpheniramine greater than chlorimipramine, with desmethylchlorimipramine, protriptyline, and nortriptyline having marginal effects and nisoxetine and the other drugs no effect at the highest dose tested, 32 mg/kg. Nisoxetine is thus one of the more potent and specific inhibitors of norepinephrine uptake, differing remarkably from fluoxetine to which it is related structurally.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased the concentration of 5-hydroxyindoleacetic acid (5HIAA), the deaminated metabolite of serotonin, in rat brain. 8-OH-DPAT was much more potent when injected subcutaneously than when injected intraperitoneally, the potency difference being approximately 17-fold. The important influence of route of administration on the potency of 8-OH-DPAT must be considered in interpreting the various functional effects that have been reported with it.

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.

(+/-)p-Chloroamphetamine hydrochloride, at doses of 1-8 mg/kg i.p. in rats, caused a dose-related increase in serum corticosterone concentration. The increase occurred rapidly, within 30 min, and was over within 4 h. Evidence that the increase was mediated by serotonin release consisted of the following findings: (1) a similar increase did not occur with (+/-)o-chloroamphetamine or (+/-)p-chloro-alpha-methylbenzylamine, analogs of p-chloroamphetamine lacking its ability to deplete serotonin; (2) the increase was prevented by prior treatment with p-chlorophenylalanine, which reduced the brain stores of serotonin available for release by p-chloroamphetamine; (3) the increase was prevented by prior treatment with fluoxetine, an inhibitor of the uptake pump on serotonin neurons, which blocks serotonin release by p-chloroamphetamine, and (4) the increase was mimicked by fenfluramine and norfenfluramine, agents known to release brain serotonin in a manner similar to the action of p-chloroamphetamine. These findings strengthen earlier evidence that brain serotonin neurons have a stimulatory influence on pituitary-adrenocortical function in rats.

m-Chlorophenyl-piperazine dihydrochloride injected i.p. into rats caused a rapid increase and a subsequent decrease in whole brain concentration of 3,4-dihydroxyphenylacetic acid (DOPAC), a metabolite of dopamine. The increase in DOPAC at 30 min and the decrease at 3 hrs were dose-related and occurred after doses as low as 5 mg/kg of m-chlorophenyl-piperazine dihydrochloride.

The ability of L-5-hydroxytryptophan (L-5HTP), a serotonin precursor, to elevate plasma levels of corticosterone in rats was confirmed. Pretreatment of the rats with 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenyl-propylamine hydrochloride (Lilly 110140) markedly enhanced the elevation of corticosterone levels by L-5HTP. Since Lilly 110140 is a specific inhibitor of serotonin uptake, these results support the hypothesis that L-5HTP elevates corticosterone by enhancing neurotransmission through a serotoninergic pathway influencing ACTH release.

Norepinephrine concentration was higher in guinea-pig liver than in rat or mouse liver and evidence was obtained that the norepinephrine was present within nerves. In guinea pigs, norepinephrine in liver was depleted by reserpine, 6-hydroxydopamine and metaraminol. The depletion by 6-hydroxydopamine and metaraminol was antagonized by prior treatment with desipramine, an inhibitor of uptake into norepinephrine neurons. Guinea-pig liver concentrated metaraminol to a greater extent than did rat liver; the concentration of metaraminol was lowered by desipramine pretreatment and, within three tissues of the guinea pig (heart greater than liver greater than muscle), paralleled the concentration of endogenous norepinephrine. These findings constitute pharmacological evidence for noradrenergic innervation of guinea-pig liver to a greater extent than in other species. Histofluorescence studies confirmed the existence of norepinephrine-containing nerve terminals in guinea-pig liver. Norepinephrine-containing varicosities were seen adjacent to the hepatic artery, portal vein and bile duct in the portal spaces and adjacent to sinusoid capillaries and hepatocytes in the liver parenchyma. These findings strengthen the evidence for sympathetic innervation of liver and suggest the guinea pig as a useful species in exploring physiological roles of noradrenergic innervation of liver.

Fourteen dopamine antagonists were compared for their ability to antagonize the elevation of the concentration of serum corticosterone in rats by pergolide, a dopamine agonist. Clozapine did not antagonize the effect of pergolide at the largest dose (10 mg/kg) that could be tested without alteration of basal levels of corticosterone. For the other antagonists, calculation of ED50 values [dose antagonizing by 50% the elevation of corticosterone caused by a 0.3 mg/kg (i.p.) dose of pergolide mesylate] revealed the following order of potency: spiperone greater than loxapine greater than fluphenazine greater than perphenazine greater than flupentixol greater than haloperidol greater than cyclophenazine greater than zotepine greater than flumezapine greater than molindone greater than metoclopramide greater than chlorpromazine greater than sulpiride. All of these compounds caused increases in the concentration of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the brains of rats. The dose that increased the concentration of DOPAC to 200% of the control value (ED200) was calculated for each compound. The ratio of the ED50 value for antagonism of the elevation of corticosterone induced by pergolide to the ED200 value for the elevation of DOPAC in brain varied, probably related to differing selectivity for pre- versus postsynaptic dopamine receptors between the compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

The aearance of tritium in plasma water was measured after i.p. injection of 2-tritio-L-alanine as an index of alanine transamination in rats. L-Cycloserine (10 mg/kg) and D-cycloserine (150 mg/kg) inhibited tritium release, whereas theophylline (100 mg/kg) stimulated tritium release.

After injection of fenfluramine into guinea-pigs, the N-dealkylated metabolite norfenfluramine was present in brain at higher concentrations and persisted longer than the parent drug, fenfluramine. Contrary to a claim in previous literature, the guinea-pig does metabolize fenfluramine to norfenfluramine, hence the ability of fenfluramine to cause acute and long-term depletion of brain 5-hydroxytryptamine in this species does not prove that fenfluramine, instead of nonfenfluramine, can produce these effects.

Two antipsychotic drugs, flumezapine and zotepine, resembled clozapine, not spiperone, in not acting synergistically with amfonelic acid to elevate striatal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in rats. Since flumezapine, zotepine and clozapine antagonize 5-hydroxytryptamine (5-HT) receptors with potency similar to their potency in antagonizing dopamine receptors, the possibility that 5-HT receptor blockade prevented their synergism with amfonelic acid was considered. Methiothepin, a potent 5-HT antagonist and dopamine antagonist, mimicked spiperone in causing a marked increase in striatal DOPAC in amfonelic acid-treated rats, indicating that 5-HT antagonism is not involved in the lack of synergism of flumezapine and zotepine with amfonelic acid.

Trazodone, 2-[3-[4-(m-chlorophenyl)-1-piperazinyl]propyl]-s- triazolo[4,3-a]pyridin-3(2H)one, was evaluated as an inhibitor of uptake into serotonin neurons in vivo in the brains of mice and rats by determining its ability to antagonize the depletion of brain serotonin by p-chloroamphetamine. In mice, trazodone was inactive under conditions in which many antidepressant drugs and other inhibitors of uptake are potent antagonists of the depletion of serotonin in brain induced by p-chloroamphetamine. Weak inhibition of uptake into serotonin-containing neurons in brain in vivo was demonstrated early after the injection of trazodone in rats, especially when the dose of p-chloroamphetamine was reduced to facilitate competitive inhibition of its effects. However, the effects of trazodone were short-lasting. Trazodone did not potentiate the elevation of serum corticosterone by L-5-hydroxytryptophan, in contrast to the effect of fluoxetine, a potent and selective inhibitor of the uptake of serotonin. Instead, trazodone antagonized a response mediated by a serotonin receptor, i.e. elevation of serum corticosterone by a serotonin agonist, quipazine, in rats. Trazodone also antagonized the serotonin-induced contraction of the rat jugular vein in vitro (a response mediated by 5-HT2 receptors), the pA2 being 8.79. These findings agree with previous reports that trazodone is a potent antagonist of serotonergic function. These data, together with earlier evidence, suggest it is unlikely that the inhibition of uptake of serotonin contributes to the clinical antidepressant effects of trazodone.

1-(1-Naphthyl)piperazine (1-NP) had high affinity for tritiated serotonin, tritiated LSD (lysergic acid diethylamide) and tritiated spiperone binding sites in rat brain cortex in vitro. 1-NP at doses of 3-30 mg/kg i.p. decreased 5-hydroxyindoleacetic acid (5-HIAA) concentration in whole brain of rats in vivo. The 30 mg/kg dose caused a significant increase in serum corticosterone concentration. At doses of 3-30 mg/kg i.p., 1-NP reduced the accumulation of 5-hydroxytryptophan following decarboxylase inhibition by NSD 1015 in rat hypothalamus and striatum. Reduced serotonin turnover and elevated serum corticosterone concentrations are interpreted as evidence of central serotonin receptor activation by compounds of this structural class. 1-NP has previously been reported to antagonize vascular serotonin receptors, suggesting that it, like 1-(m-trifluoromethylphenyl)piperazine, behaves as an antagonist at peripheral (vascular) serotonin receptors despite being an agonist at central serotonin receptors.

Two chemical analogs of pergolide were examined to test further the idea that pergolide elevates serum corticosterone concentration in rats by activation of brain dopaminergic receptors. LY116467, which contains an N-methyl substituent in place of the N-n-propyl substituent in pergolide, was less potent than pergolide in lowering brain levels of 3,4-dihydroxyphenylacetic acid (Dopac), the metabolite of dopamine. LY116467 increased serum corticosterone concentration in rats at a dose of 3 mg/kg (a higher dose than is required for pergolide), and the effect was prevented by spiperone pretreatment. LY141865, which has been reported to differ from pergolide in not activating dopamine-sensitive adenylate cyclase and which was found in this study to have much less affinity for serotonin receptors than does pergolide, increased serum corticosterone in much the same manner as pergolide, only slightly higher doses being required. The effect of LY141865 was prevented by pretreatment with haloperidol but not domperidone. Both haloperidol and domperidone increased serum prolactin concentration when given alone or in combination with LY141865, indicating they were both capable of blocking peripheral (pituitary) dopamine receptors. In contrast, haloperidol but not domperidone caused a marked elevation in brain levels of Dopac and of homovanillic acid and prevented the lowering of these brain dopamine metabolites by LY141865. The ability of LY141865 to increase serum corticosterone concentration was attenuated in rats that had received four daily injections of pergolide mesylate, indicating corss-tolerance had occurred. These results strengthen the hypothesis that activation of brain dopaminergic receptors leads to increased serum corticosterone concentration in rats.

Cis and trans isomers of 1-amino-2-(p-chlorophenyl)cyclohexane, conformationally restricted analogs of p-chloroamphetamine, did not decrease brain serotonin and 5-hydroxyindoleacetic acid concentrations at i.p. doses of .05 and .1 mmole/kg in rats, doses at which p-chloroamphetamine itself decreased the concentrations of these 5-hydroxyindoles to half or less of their initial values. These analogs of p-chloroamphetamine, unlike several others studied previously, apparently lack the ability of the parent compound to inhibit serotonin uptake or synthesis or to release serotonin from intraneuronal granular stores.

1-(m-Trifluoromethylphenyl)-4-(p-aminophenylethyl)piperazine (LY 156163), reported previously to have selective affinity for the 5-HT1A subtype of serotonin receptor in vitro, was studied at doses of 1.25 to 20 mg/kg i.p. in rats to determine if it had properties characteristic of centrally acting serotonin agonists. LY 165163 decreased whole brain concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid, but not of serotonin itself, decreased the rate of accumulation of 5-hydroxyindoleacetic acid after probenecid administration to block its efflux from brain, decreased the rate of decline in serotonin concentration after inhibition of serotonin synthesis with alpha-propyldopacetamide and decreased the accumulation of 5-hydroxytryptophan after decarboxylase inhibition by m-hydroxybenzylhydrazine. LY 165163 also decreased 5-hydroxyindoleacetic acid concentrations in two specific brain regions, striatum and hypothalamus. Serum concentrations of corticosterone and prolactin were increased by doses of LY 165163 that reduced serotonin turnover. These effects are all consistent with evidence from other studies that LY 165163 is a centrally acting serotonin agonist. LY 165163 also increased the concentrations of two dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, measured in whole brain as well as in striatum and hypothalamus, but did not alter dopamine concentration. The accumulation of dopa after decarboxylase inhibition was accelerated by LY 165163. The increases in hormone concentrations in serum and of dopamine metabolite concentrations in brain were not antagonized by pretreatment with metergoline, a serotonin antagonist. The mechanisms of those effects require further study.

d-Fenfluramine is an anorectic drug believed to act by enhancement on serotonergic function in the brain. d-Fenfluramine (or the racemate) releases serotonin through a carrier-dependent mechanism, and serotonin release is the mechanism usually thought to produce its serotonergic effects. However, d-fenfluramine also inhibits serotonin uptake in vitro, and serotonin uptake inhibition is sometimes suggested to contribute to its mechanism of anorectic activity. Neurochemical experiments were done to examine serotonin release and serotonin uptake inhibition as mechanisms of action of d-fenfluramine in rats and to compare d-fenfluramine to fluoxetine, a serotonin uptake inhibitor. d-Fenfluramine decreased serotonin concentration in rat brain as early as 1 hr; at 1 hr 5-hydroxyindoleacetic acid (5HIAA) concentration was slightly increased, but at later times 5HIAA was also decreased. Fluoxetine, in contrast, did not change serotonin concentration in whole brain but decreased 5HIAA concentration at all time points. At all time intervals studied, the 5HIAA/serotonin ratio was increased by d-fenfluramine (and by Ro 4-1284, a nonspecific serotonin releaser) but was decreased by fluoxetine, a serotonin uptake inhibitor. No decrease in 5HIAA concentration or in the 5HIAA/serotonin ratio was apparent at any time or after any dose of d-fenfluramine studied. The possibility that doses of d-fenfluramine below those needed for serotonin release might inhibit serotonin uptake was tested by determining whether d-fenfluramine could block the acute depletion of brain serotonin by p-chloroamphetamine, or the long-term neurotoxic effect of p-chloroamphetamine on brain serotonin neurons.(ABSTRACT TRUNCATED AT 250 WORDS)