Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia.

Schizophrenia is characterized by complex and dynamically interacting perturbations in multiple neurochemical systems. In the past, evidence for these alterations has been collected piecemeal, limiting our understanding of the interactions among relevant biological systems. Earlier, both hyper- and hyposerotonemia were variously associated with the longitudinal course of schizophrenia, suggesting a disturbance in the central serotonin (5-hydroxytryptamine (5-HT)) function. Using a targeted electrochemistry-based metabolomics platform, we compared metabolic signatures consisting of 13 plasma tryptophan (Trp) metabolites simultaneously between first-episode neuroleptic-naive patients with schizophrenia (FENNS, n=25) and healthy controls (HC, n=30). We also compared these metabolites between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. N-acetylserotonin was increased in FENNS-BL compared with HC (P=0.0077, which remained nearly significant after Bonferroni correction). N-acetylserotonin/Trp and melatonin (Mel)/serotonin ratios were higher, and Mel/N-acetylserotonin ratio was lower in FENNS-BL (all P-values<0.0029), but not after treatment, compared with HC volunteers. All three groups had highly significant correlations between Trp and its metabolites, Mel, kynurenine, 3-hydroxykynurenine and tryptamine. However, in the HC, but in neither of the FENNS groups, serotonin was highly correlated with Trp, Mel, kynurenine or tryptamine, and 5-hydroxyindoleacetic acid (5HIAA) was highly correlated with Trp, Mel, kynurenine or 3-hydroxykynurenine. A significant difference between HC and FENNS-BL was further shown only for the Trp-5HIAA correlation. Thus, some metabolite interactions within the Trp pathway seem to be altered in the FENNS-BL patients. Conversion of serotonin to N-acetylserotonin by serotonin N-acetyltransferase may be upregulated in FENNS patients, possibly related to the observed alteration in Trp-5HIAA correlation. Considering N-acetylserotonin as a potent antioxidant, such increases in N-acetylserotonin might be a compensatory response to increased oxidative stress, implicated in the pathogenesis of schizophrenia.

Amphetamine behavioral toxicity: rotational behavior after chronic intrastriatal infusion.

The behavioral "reverse tolerance" to d-amphetamine in rats has not been clearly established for the high-dose, sustained d-amphetamine exposure relevant to human behavioral toxicity, especially the amphetamine psychosis. We have looked for alterations in the d-amphetamine response following pretreatment by a newer pharmacologic intervention, the continuous chronic unilateral infusion of highdose d-amphetamine into the caudate-putamen. We found that the circling response to a subsequent intraperitoneal injections of d-amphetamine is consistently ipsilateral compared to saline controls, suggesting tolerance development. This finding, and that of minimal apomorphine-induced rotation in these animals, is discussed in terms of a functional imbalance of right and left nigrostriatal dopamine activity, possibly due to dopamine depletion.

gamma-Butyrolactone effects on behavior induced by dopamine agonists.

gamma-Butyrolactone (GBL) potently inhibits stereotyped behavior induced by indirect (amphetamine and methylphenidate) and direct (apomorphine) dopamine agonists. Amphetamine induces a dose-response partial reversal of the GBL effect. The GABA antagonist, bicuculline, only partially reverses the GBL inhibition of apomorphine activity, indicating that GBL may be acting through mechanisms in addition to effects on GABA.

Anorexia nervosa in treated gonadal dysgenesis: case report and review.

The 12th reported case of anorexia nervosa in association with the 45,XO genotype and Turner's phenotype is presented. This patient received hormonal treatment but had a poor psychological outcome. Reasons for a possible increased coincidence of the two disorders, and the relationships among hormonal treatment, onset of puberty, and development of anorexia nervosa, are discussed in light of this and previous cases.

The effect of reserpine on concurrent repeated administration of d-amphetamine.

The augmentation of the rat stereotypy response with repeated amphetamine doses, put forward as a model of human amphetamine psychosis, was examined during concurrent reserpinization. The effects of reserpinization, amphetamine treatment, and amphetamine dose on four dependent variables representing the time course of stereotypy ratings after a post-treatment amphetamine dose, were tested by three-way MANOVA. An earlier onset of stereotypy , as occurred in nonreserpinized rats, was not detected in reserpinized rats, but an earlier offset of stereotypy with repeated amphetamine occurred in these rats when high amphetamine doses were used.

Influence of gamma-butyrolactone on behavior due to dopaminergic drugs.

Gamma-butyrolactone (GBL) is well known to reduce dopamine neuronal impulse flow, but the effects of the drug on dopamine-dependent behavioral states is not well studied. Qualitative and quantitative data are presented, detailing the influence of GBL on stereotypy when this drug is given after administration of the indirectly-acting dopamine mimetics amphetamine and methylphenidate, and the direct dopamine agonist apomorphine. GBL reversed the stereotypy produced by all three drugs, given at moderate doses producing comparable intensities of stereotypy. GBL unexpectedly proved effective in reversing stereotypy after higher-dose apomorphine while producing a rather weak influence on that of higher-dose amphetamine and methylphenidate. The results are discussed in terms of the dopamine impulse flow, and possible GABA-potentiating, effects of GBL, and the sedative effects of apomorphine.

Anorexia nervosa: review of current treatment practices.

The etiology of anorexia nervosa has defied elucidation for over 100 years and no systematic treatment has yet been developed for the illness. We have reviewed some current findings that relate to both neuroendocrinologic and psychologic defects. Review of current treatment practices reveals that a variety of approaches are used, alone or in combination. Special attention is directed to the rationale for the use of certain neuropharmacologic agents that influence eating behavior. We advocate a flexible, multimodal approach to treatment of this illness, the understanding of which is still in its early stage.