Continuous infusion of clozapine increases Mu and delta opioid receptors and proenkephalin mRNA in mouse brain

• Published in: Biological psychiatry (1969) 1995-04, Vol.37 (8), p.496-503
• Main Authors: Zhang, Sui-Po, Connell, Thomas A., Price, Trevor, Simpson, George M., Zhou, Long-Wu, Weiss, Benjamin
• Format: Article
• Language: English
• Subjects: Animals; Autoradiography; Biological and medical sciences; Brain - drug effects; Clozapine; Clozapine - pharmacology; D 1 and D 2 dopamine receptor mRNA; D 1 and D 2 dopamine receptors; Enkephalins - genetics; Gene Expression - drug effects; Infusion Pumps, Implantable; Male; Medical sciences; Mice; mu and delta opioid receptors; Neuropharmacology; Pharmacology. Drug treatments; proenkephalin mRNA; Protein Precursors - genetics; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D2 - genetics; Receptors, Opioid, delta - genetics; Receptors, Opioid, mu - genetics; RNA, Messenger - genetics; schizophrenia; Transcription, Genetic - drug effects
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/0006-3223(94)00185-6

The biochemical mechanisms involved in the actions of the atypical antipsychotic clozapine are still unclear. Because elevated levels of enkephalin in certain areas of the central nervous system may be necessary for antipsychotic activity, we have examined the effect of clozapine on certain receptors and mRNA transcripts involved in the opioid peptidergic system. Clozapine was infused continuously into mice for 21 days and the density of mu and delta opioid receptors was measured in the brains by quantitative receptor autoradiography, and the level of proenkephalin mRNA and dopamine D 1 and D 2 receptor mRNA were measured by in situ hybridization histochemistry. The results showed that continuous infusion of clozapine increased the density of D 1 but not D 2 receptors. However, it failed to alter the levels of either D 1 or D 2 dopamine receptor mRNA. By contrast, clozapine increased the density of mu and delta opioid receptors and increased the levels of proenkephalin mRNA. These results indicate that continuous treatment with clozapine increases opioid peptidergic activity in mouse brain and suggest that alteration of peptidergic activity as well as alteration of dopaminergic activity may be involved in its antipsychotic action.