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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.

After the injection of N-cyclopropyl-p-chloroamphetamine (N-cyclopropyl-PCA) into rats, p-chloroamphetamine (PCA) was identified in brain by high performance liquid chromatography with UV detection and was quantitated by that method and by spectrofluorometric analysis involving reaction with fluorescamine. The identity of PCA in brains of rats treated with N-cyclopropyl-PCA was confirmed by mass spectrometry. The peak concentrations of PCA in brain occurred 4 hrs after N-cyclopropyl-PCA injection. Brain concentrations of PCA and of N-cyclopropyl-PCA were measured at 1 or 4 hrs, respectively, after the injection of various doses of PCA or of N-cyclopropyl-PCA into rats. The depletion of brain serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was measured 1 week after injection of those same doses of PCA or N-cyclopropyl-PCA. Comparing peak concentrations of PCA with the degree of depletion of brain serotonin supported the interpretation that PCA formed metabolically accounted for the long-term depletion of brain 5-hydroxyindoles after injection of N-cyclopropyl-PCA in rats.

Dopamine concentration in rat heart is normally very low, only a few percent of the concentration of norepinephrine. After treatment of rats with a dopamine beta-hydroxylase inhibitor, 1-cyclohexyl-2-mercapto-imidazole (CHMI), there was a rapid increase in dopamine concentration even before norepinephrine concentration had decreased perceptibility. This accumulation of dopamine was readily measured by liquid chromatography with electrochemical detection. Since the percentage change in dopamine was much greater than the percentage change in norepinephrine, especially at early times, measurement of dopamine accumulation rather than norepinephrine decline was considered as a useful measure of norepinephrine turnover. Drugs that act on noradrenergic receptors and are known to alter norepinephrine turnover were found to alter the rate of dopamine accumulation. Clonidine and guanabenz decreased dopamine accumulation after CHMI, whereas piperoxan (but not prazosin) increased dopamine accumulation after CHMI. Pergolide, a dopamine agonist whose lowering of blood pressure and cardiac rate has been suggested to be due to suppression of neurogenic release or norepinephrine, also decreased dopamine accumulation after CHMI. The results suggest that measuring dopamine accumulation may have advantages over measuring norepinephrine disappearance after dopamine beta-hydroxylase inhibition as an indicator of norepinephrine turnover in heart.

Ketanserin and ritanserin antagonized with similar potency the pressor response to serotonin in pithed rats, a measure of antagonism of vascular 5HT2 receptors. Both compounds also antagonized the elevation of serum corticosterone concentration by quipazine, a centrally acting serotonin agonist; higher doses of both antagonists were needed, but ketanserin was not less potent than ritanserin. Earlier suggestions that ketanserin mainly blocks peripheral serotonin receptors and that ritanserin mainly blocks central serotonin receptors seem unfounded.

Molindone at a dose of 3 mg/kg i.p. in rats prevented pergolide-induced decreases in brain DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid), causing instead significant increases in these dopamine metabolites when given in combination with pergolide. Molindone alone at 3 mg/kg caused two-fold or greater increases in DOPAC and HVA and at doses as low as 0.3 mg/kg caused significant increases in these metabolites. However, molindone at 3 mg/kg and lower doses was without effect on pergolide-induced elevation of serum corticosterone, though a higher dose of molindone, 10 mg/kg, significantly antagonized this increase in corticosterone. These data support earlier findings with molindone, suggesting it has greater affinity for presynaptic dopamine autoreceptors than for postsynaptic dopamine receptors.