P-glycoprotein inhibition and risperidone-induced striatal dopamine release

ALEJANDRA. M. PACCHIONI,; ALISHA. HENDERSON,; AMANDA. GABRIELE,; LINDSAY. DEVANE,; RONALD E. SEE.

Whashington DC, USA

Congreso; 38th Annual Meeting of Neurosciences; 2008

Society for Neuroscience

<!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} @font-face {font-family:Times; panose-1:2 2 6 3 5 4 5 2 3 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-536859921 -1073711039 9 0 511 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; text-autospace:none; font-size:12.0pt; font-family:"Times","serif"; mso-fareast-font-family:"Times New Roman"; mso-bidi-font-family:"Times New Roman";} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; mso-ascii-font-family:Calibri; mso-fareast-font-family:Calibri; mso-hansi-font-family:Calibri;} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.0in 1.0in 1.0in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --> Antipsychotic drugs (APDs) are the mainstay pharmacotherapy for schizophrenia and related psychiatric disorders. While the pharmacokinetic pathways of APDs have been well defined, the role of drug transporters in the disposition and effects of APDs has not been well explored.  P-glycoprotein (P-gp) has an 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.  Previous evidence has shown that APDs act as substrates at the P-gp transporter.  Increased APD entry into the brain via blockade of the P-gp transporter may facilitate drug action on relevant receptor targets.  By increasing available drug concentrations, P-gp inhibition offers a novel means of enhanced drug treatment of schizophrenia.  In the current study, we utilized in vivo microdialysis to test whether P-gp is an important modulator of brain access and pharmacologic effects of the atypical APD, risperidone, on striatal dopamine (DA) release.  Male, Sprague-Dawley rats were implanted with a guide cannula aimed at the caudate-putamen.  Following one week of recovery, microdialysis probes (3 mm) were inserted and basal samples were collected at 20 min intervals for one hour.  Subjects then received either 30 mg/kg of PSC833 (a selective inhibitor of P-gp) or control vehicle by oral gavage.  One hour after pretreatment, rats were administered risperidone (0.01 mg/kg, s.c.).  Samples were analyzed for extracellular levels of DA and DA metabolites (DOPAC and HVA) using HPLC-EC.  Preliminary data indicates that risperidone alone at 0.01 mg/kg significantly increases DA release as compared to baseline or vehicle injection, with a modest increase in DA metabolite levels.  Furthermore, PSC833 alone has no effect on striatal DA release  The combination of PSC833 and risperidone at the currently utilized doses does not appear to further increase DA release. Further studies will evaluate extended dose-response curves of PSC833 and risperidone.