Changes in serum tryptophan, tryptophan binding to serum albumin and serum total amino acid concentration after administration of neuroleptic drugs to rats.

It has been shown previously that administration of chlorpromazine to rats leads to a decrease in total serum tryptophan and total amino acids, but an increase in that fraction of tryptophan freely diffusible rather than bound to serum albumin (Bender, 1975~). At the same time, there are changes in brain tryptophan uptake and 5-hydroxytryptamine synthesis, supporting the view that serum diffusible tryptophan and total amino acid concentrations are important determinants of the rate of brain 5-hydroxytryptamine synthesis (Bender, 197%). To determine whether these effects are due solely to chlorpromazine, or whether they are also shown after administration of other neuroleptic drugs, the following have been tested : chlorprothixene, prochlorperazine, thioridazine, haloperidol and pimozide. These compounds are representative of the main classes of currently used anti-psychotic medication. Female Courtauld Institute Wistar rats weighing between 80 and llOg were used; all animals were deprived of food, but not water, for 24h before being killed. They were injected intraperitoneally with solutions of the drugs between 09:Wh and 09:30h, and were killedbetween 13:Whand 14:Wh. Animals were killed by decapitation, blood was collected and allowed to clot for about 60min at room temperature before centrifugation to separate serum, which was used for determination of tryptophan (by a modification of the method of Denckla &Dewey, 1967), tryptophan binding to serum albumin by smallscale equilibrium dialysis (Bender et al., 1975) and total amino acids by a modification of the method of Maeda & Tsuji (1973). Solutions of the drugs were prepared as follows: chlorpromazine in 0.15 M-NaCI ; chlorprothixene and prochlorperazine in 0.1 M-HCI; thioridazine, haloperidol and pimozide in ethanol. All solutions were diluted at least 10-fold to the required concentration with O.lS~-Nacl. Control animals were injected with saline alone. For each drug, a range of concentrations was used, between 0.5 and 6mg/animal; in Table 1 the results obtained for most of the drugs at only a single dose are shown. This is the dose of the drug at which there was first an unequivocal effect on serum tryptophan concentration. It is also the lowest dose at which the animals were obviously sedated or cataleptic, apart from pimozide, which did not appear to lead to obvious sedation at any of the doses tested. Table 1 shows that all the drugs had an effect on serum tryptophan concentration, producing a marked decrease at doses of the same order of magnitude as are used clinically. At the lowest dose to affect tryptophan concentration, all except haloperidol and pimozide also led to a displacement of tryptophan from albumin binding; haloperidol and pimozide only did so at a somewhat higher dose. The effect on serum total amino acids was less clear. Prochlorperazine and pimozide had no effect, haloperidol led to an increase, and the remaining drugs all lowered serum total amino acid concentration. To ensure that none of the effects observed in vivo was due to a direct action of the drug on the assay procedures used, assays were performed on a sample of human serum to which each of the drugs in turn was added to a final concentration of 100pg/ml. This is considerably higher (by at least 10-fold) than would be expected in vivo in any of the experiments described here. Table 2 shows that chlorpromazine, chlorprothixene and thioridazine led to a significant increase in the apparent concentration of tryptophan in the sample used. These three and prochlorperazine also led to an increase in the apparent concentration of total amino acids. Haloperidol and pimozide had no effect on either assay. None of the drugs had any effect on the binding of tryptophan to albumin in vitro. Thus it is clear that none of the effects of administration of these drugs to animals can be