The effect of tryptophan depletion on the action of haloperidol in MK-801-treated rats.

We investigated the effect of tryptophan depletion (tryptophan-free mixture) on locomotor activity in an animal model of schizophrenia, induced by acute administration of 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801), and the influence of the tryptophan-free mixture on the action of the typical antipsychotic haloperidol. Male rats were pre-treated with haloperidol 60 min after receiving the tryptophan-free mixture (or water). We measured total distance travelled in an open field during a 90-min period. Administration of the tryptophan-free mixture resulted in decreased levels of tryptophan, serotonin and its metabolite 5-hydroxyindolacetic acid in the frontal cortex. Serotonin depletion increased the total distance travelled by MK-801-treated rats, modified the inhibitory effect of haloperidol and normalized the locomotor activity pattern in the model of schizophrenia-like behaviour. The effect of the tryptophan-free mixture combined with the classical antipsychotic haloperidol in MK-801-treated rats indicates the possibly important role of the serotonergic system in the action of antipsychotics.

Age- and sex-dependent effects of ethanol on hippocampal hemicholinium-3 sensitive choline carriers during postnatal development of rats.

Vulnerability of hippocampal hemicholinium-3 (HC-3)-sensitive carriers to ethanol was evaluated in vitro during rat postnatal development. The high-affinity uptake of [3H]choline (HACU) and the specific binding of [3H]HC-3 were measured on synaptosomes from 7-, 14-, and 60-day-and 3-month-old male and female Wistar rats. Marked increases of basal (between 7 and 60 days of age) and of stimulated HACU levels via K(+)-depolarization (between 14 days and 3 months) but only a mild elevation in [3H]HC-3 binding (between 7 days and 3 months) associated with alterations in the binding site number were found. On the mature tissue, ethanol at high concentrations (5%) moderately inhibited the choline transport under basal conditions but totally eliminated depolarization effects. However, both age- and sex-dependent alterations in basal HACU mediated by high or low pharmacologically relevant alcohol concentrations (50-100 mM) were observed in the immature tissue. Namely, the dose- and incubation time-dependent inhibition of HACU associated with changes in the transport velocity was found in postnatal male but not female tissue. [3H]HC-3 binding site was not markedly sensitive to ethanol actions. Anisotropy measurements in the region of the hydrophilic heads of phospholipid bilayers and in the membrane hydrocarbon core indicated penetration of 100 mM ethanol to immature female but not male tissue. Our results suggest the noncompetitive binding of alcohol to choline carriers from immature male tissue and correspond with data reporting significant sexual dimorphism of postnatal hippocampal neurons. The direct effects of ethanol on male choline carriers can contribute to the inhibition of acetylcholine synthesis and to sex-dependent neurotoxic effects of alcohol applied in vivo during early and late postnatal period.