title: An intra-cerebral drug delivery system for freely moving animals.
abstract: Microinfusions of drugs directly into the central nervous system of awake animals represent a widely used means of unravelling brain functions related to behaviour. However, current approaches generally use tethered liquid infusion systems and a syringe pump to deliver drugs into the brain, which often interfere with behaviour. We address this shortfall with a miniaturised electronically-controlled drug delivery system (20 × 17.5 × 5 mm³) designed to be skull-mounted in rats. The device features a micropump connected to two 8-mm-long silicon microprobes with a cross section of 250 × 250 μm² and integrated fluid microchannels. Using an external electronic control unit, the device allows infusion of 16 metered doses (0.25 μL each, 8 per silicon shaft). Each dosage requires 3.375 Ws of electrical power making the device additionally compatible with state-of-the-art wireless headstages. A dosage precision of 0.25 ± 0.01 μL was determined in vitro before in vivo tests were carried out in awake rats. No passive leakage from the loaded devices into the brain could be detected using methylene blue dye. Finally, the device was used to investigate the effects of the NMDA-receptor antagonist 3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid, (R)-CPP, administered directly into the prefrontal cortex of rats during performance on a task to assess visual attention and impulsivity. In agreement with previous findings using conventional tethered infusion systems, acute (R)-CPP administration produced a marked increase in impulsivity.
authors.affiliation: Institut für Mikro-und Informationstechnik der Hahn-Schickard-Gesellschaft e.V.-HSG-IMIT, Wilhelm-Schickard-Str. 10, 78052 Villingen-Schwenningen, Germany. sven.spieth@hsg-imit.de
authors.forename: Sven
authors.initials: S
authors.lastname: Spieth
authors.forename: Axel
authors.initials: A
authors.lastname: Schumacher
authors.forename: Tahl
authors.initials: T
authors.lastname: Holtzman
authors.forename: P Dylan
authors.initials: PD
authors.lastname: Rich
authors.forename: David E
authors.initials: DE
authors.lastname: Theobald
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Dalley
authors.forename: Rachid
authors.initials: R
authors.lastname: Nouna
authors.forename: Stephan
authors.initials: S
authors.lastname: Messner
authors.forename: Roland
authors.initials: R
authors.lastname: Zengerle
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D016503:Drug Delivery Systems / Q000295:instrumentation* / Q000379:methods; D004867:Equipment Design; D007175:Impulsive Behavior / Q000378:metabolism; D008845:Microinjections; D010879:Piperazines / Q000008:administration & dosage*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid