title: P-glycoprotein activity in the blood-brain barrier is affected by virus-induced neuroinflammation and antipsychotic treatment.
abstract: A large percentage of schizophrenic patients respond poorly to antipsychotic treatment. This could be explained by inefficient drug transport across the blood-brain barrier due to P-glycoprotein mediated efflux. P-glycoprotein activity and expression in the blood-brain barrier can be affected by inflammation and pharmacotherapy. We therefore investigated the effect of herpes simplex virus type-1 (HSV-1) induced neuroinflammation and antipsychotic treatment on P-glycoprotein activity. Rats were inoculated with HSV-1 or PBS (control) on day 0 and treated with saline, clozapine or risperidone from day 0 up until day 4 post-inoculation. Positron emission tomography with the P-glycoprotein substrate [11C]verapamil was used to assess P-glycoprotein activity at day 6 post-inoculation. Disease symptoms in HSV-1 inoculated rats increased over time and were not significantly affected by treatment. The volume of distribution (VT) of [11C]verapamil was significantly lower (10-22%) in HSV-1 inoculated rats than in control rats. In addition, antipsychotic treatment significantly affected the VT of [11C]verapamil in all brain regions, although this effect was drug dependent. In fact, VT of [11C]verapamil was significantly increased (22-39%) in risperidone treated rats in most brain regions when compared to clozapine treated rats and in midbrain when compared to saline treated rats. No interaction between HSV-1 inoculation and antipsychotic treatment on VT of [11C]verapamil was found. In this study we demonstrated that HSV-1 induced neuroinflammation increased and risperidone treatment decreased P-glycoprotein activity. This finding is of importance for the understanding of treatment resistance in schizophrenia, and warrants further investigation of the underlying mechanism and the importance in clinical practice.
authors: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. Electronic address: j.doorduin@umcg.nl.
authors: Janine
authors: J
authors: Doorduin
authors: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors: Erik F J
authors: EF
authors: de Vries
authors: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors: Rudi A
authors: RA
authors: Dierckx
authors: University Center of Psychiatry, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
authors: Hans C
authors: HC
authors: Klein
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000276:immunology; D002250:Carbon Radioisotopes; D003024:Clozapine / Q000494:pharmacology; D004195:Disease Models, Animal; D006561:Herpes Simplex / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000276:immunology*; D018259:Herpesvirus 1, Human; D008297:Male; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D011897:Random Allocation; D017208:Rats, Wistar; D018967:Risperidone / Q000494:pharmacology*; D014700:Verapamil
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D014700:Verapamil; D003024:Clozapine; D018967:Risperidone
keywords: Antipsychotics; Herpes simplex virus; Neuroinflammation; P-glycoprotein; Positron emission tomography