Cerebrospinal fluid kynurenic acid in male and female controls - correlation with monoamine metabolites and influences of confounding factors.

The concentrations of the tryptophan metabolite kynurenic acid (KYNA) and the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were determined in the cerebrospinal fluid (CSF) from 43 healthy volunteers (30 males and 13 females). Healthy female controls displayed higher CSF concentration of KYNA (1.91nM+/-0.20) compared to healthy male controls (1.06nM+/-0.07) and lower CSF levels of HMPG (39.2nM+/-2.0 and 43.4+/-1.2, respectively). CSF levels of HVA and 5-HIAA did not differ between females (181.3nM+/-21.9 and 93.7nM+/-11.4, respectively) and males (138.9nM+/-12.6 and 74.8nM+/-5.9, respectively). Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA while CSF content of HMPG did not correlate with KYNA or the other monoamine metabolites in CSF. A negative correlation was found between back length and CSF concentrations of KYNA, HVA and 5-HIAA and also between CSF KYNA levels and body height. The results of the present study suggest that concentrations of KYNA and the monoamine metabolites in CSF from healthy controls are dependent on gender and back length, which must be taken in consideration when analysing mixed groups of men and women. The higher KYNA concentration found in female controls compared to male might be attributed to a shorter back in women compared to men. Furthermore, these findings suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover.

Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms.

The major brain noradrenergic nucleus locus coeruleus (LC) has long been thought to be involved in states of alertness and cognitive processes. These functional characteristics make this nucleus interesting with regard to the signs of schizophrenia, especially the negative symptoms of the disease. In the present in-vivo electrophysiological study we analyse a putative interaction between endogenous kynurenic acid (KYNA) and the antipsychotic drugs clozapine and haloperidol on noradrenergic LC neurons. Previous studies have shown that systemically administered antipsychotic drugs increase the neuronal activity of LC noradrenaline (NA) neurons. In line with these findings, our results show that clozapine (1.25-10 mg/kg i.v.) and haloperidol (0.05-0.08 mg/kg i.v.) increased the firing rate of LC NA neurons in anaesthetized rats. Pretreatment with PNU 156561A (40 mg/kg i.v., 3 h), a potent inhibitor of kynurenine 3-hydroxylase, produced a 2-fold increase in rat brain KYNA levels. This treatment prevented the increase in firing rate of LC NA neurons induced by haloperidol (0.05-0.08 mg/kg i.v.) and clozapine in high doses (2.5-10 mg/kg i.v.). However, the excitatory action of the lowest dose of clozapine (1.25 mg/kg i.v.) was not abolished by elevated levels of brain KYNA. Furthermore, pretreatment with L-701,324 (4 mg/kg i.v.) a selective antagonist at the glycine site of the NMDA receptor prevented the excitatory effects of both clozapine and haloperidol. The present results suggest that the excitation of LC NA neurons by haloperidol and clozapine involves a glutamatergic component.