Thomas Keck

Physiology & Pharmacology

T. M. Keck, K. L. Suchland, D. K. Grandy

Microarray analysis of methylphenidate administration to N20 dopamine D4 receptor-deficient mice reveals differential gene expression associated with behavioral sensitization

Previously, we have shown that mice lacking dopamine D4 receptors

(D4R) are highly sensitive to the psychostimulant methylphenidate

(MPD), the most widely prescribed treatment for attention

deficit-hyperactivity disorder. MPD induces behavioral sensitization—a

condition in which MPD exposure causes a progressive increase in the

psychomotor stimulant and positive-reinforcing effects of future MPD

doses—to a greater degree in D4R receptor-null (D4R -/-) mice than

wild-type (D4R +/+) littermates (our unpublished results). The purpose

of the present study was to examine the genetic changes that may

underlie behavioral sensitization in these mice. Three-week old male

D4R -/- and +/+ C57BL/6J littermates were given daily intraperitoneal

injections of MPD at 5mg/kg or saline vehicle for a period of 14 days.

After three weeks, the mice received a challenge dose of 5mg/kg MPD or

saline vehicle. Locomotor activity following injection was measured on

Day 1, 8, 15, and following the challenge dose, similar to the

paradigm described in Kruzich et al. (2004), to demonstrate

the development of drug-induced behavioral sensitization.

Immediately following challenge dose behavioral evaluation, brains were removed and dissected into prefrontal cortex, dorsal striatum and nucleus

accumbens. Affymetrix microarray analysis of prefrontal cortex samples

from MPD-treated and saline control animals identified several genes

of interest that may underlie D4R-mediated behavioral sensitization,

including genes involved in dopamine signaling, synaptic plasticity,

vesicle fusion, and cell adhesion.