P-glycoprotein inhibition potentiates the behavioural and neurochemical actions of risperidone in rats.
Antipsychotic drugs are the mainstay pharmacotherapy for schizophrenia and related psychiatric disorders. While the metabolic pathways of antipsychotic drugs have been well defined, the role of drug transporters in the disposition and effects of antipsychotic drugs has not been systematically explored. P-glycoprotein has ubiquitous expression in brain endothelial cells and plays a protective role by effluxing substrates for elimination and by limiting their accumulation in the central nervous system. Risperidone and several other antipsychotic drugs are substrates of P-glycoprotein. Increased antipsychotic drug entry into the brain via blockade of the P-glycoprotein transporter may facilitate the amount of available drug to its targets, particularly dopamine receptors. By increasing available antipsychotic drug concentrations, P-glycoprotein inhibition offers a novel means of enhanced drug delivery. This study evaluated whether selective P-glycoprotein transporter inhibition would increase the effects of risperidone on relevant indices of behaviour (catalepsy and locomotion) and neurochemistry (dopamine release and metabolism as measured by in-vivo microdialysis). We administered the P-glycoprotein inhibitor, PSC 833 (100 mg/kg p.o.), to rats prior to administration of risperidone at varying doses (0.01-4.0 mg/kg s.c.). P-glycoprotein inhibition significantly increased risperidone-induced cataleptic effects, blockade of amphetamine-induced locomotion, and effects on dopamine turnover as seen by increased striatal dopamine metabolite levels. These results provide functional evidence concordant with prior data for increased brain levels of risperidone following PSC 833 treatment.
Pacchioni
Alejandra M
AM
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Gabriele
Amanda
A
Donovan
Jennifer L
JL
DeVane
C Lindsay
CL
See
Ronald E
RE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D003524:Cyclosporins / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000008:administration & dosage*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D018967:Risperidone; C070272:valspodar; D004298:Dopamine