A peptide-containing fraction in the urine of schizophrenic patients which stimulates opiate receptors and inhibits dopamine uptake

Abstract

A factor in the urine of schizophrenic patients has been investigated for its effects on uptake of monoamines in crude synaptosomal preparations and on behaviour in rats. Urine from seven schizophrenic patients was precipitated with benzoic acid and fractionated on Sephadex G 25, P 2 gels and Fractogel, and characteristic patterns of peptide and protein-associated peptide complexes were found. One factor which showed marked biological activity (factor 3b2) was further studied. This factor strongly inhibited uptake of [ 3H]dopamine into hypothalamic and striatal synaptosomes, and slightly reduced this uptake in hippocampal synaptosomes, uptake of [ 14C]5-hydroxytryptamine was also some-what reduced in synaptosomes from these three structures. When injected intracerebroventricularly in rats factor 3b2 produced a characteristic behavioural syndrome, including transient ‘explosive motor behaviour’, autonomic changes, long-lasting (at least 3 weeks) ‘catalepsy’, rigidity and loss of righting reflexes. Pain sensitivity was greatly reduced, and body temperature initially rose and then it was reduced for several days. Rats with unilateral 6-hydroxydopa-mine-induced lesions of the nigrostriatal dopamine pathway showed turning ipsilateral to the lesion after injections of factor 3b2. Behavioural effects (except the autonomic effects) were partly or completely blocked by pretreatment with the opiate receptor blocker naloxone, and several of the behavioural effects were also blocked by the dopamine receptor blocker haloperidol. Repeated injections of factor 3b2 resulted in the development of tolerance, as well as cross tolerance with morphine. It was concluded that schizophrenic patients excrete in the urine peptides or peptide-like factors which have strong opiate receptor stimulating effects, and which also result in dopaminergic stimulation. The possibility that this factor is of importance in the pathogenesis of schizophrenia is discussed.