MICE LACKING PRESYNAPTIC DOPAMINE D2 AUTORECEPTORS DISPLAY HYPERACTIVITY AND INCREASED MOTIVATION FOR FOOD REWARD

BELLO GAY, E; NOAÍN, D; GELMAN, D; NEMIROVSKY, S; RUBINSTEIN, M

Huerta Grande, Córdoba, Argentina

Congreso; I Reunión Conjunta SAN - Taller de Neurociencia; 2009

SAN y Taller de Neurociencia

The dopamine D2 receptor (D2R) is expressed postsynaptically in most dopamine (DA) target areas where it participates in the extrapyramidal control of locomotor activity, spatio-temporal organization of goaloriented behaviors and the reinforcing properties of natural rewards. Also, D2Rs are present in DA neurons where they act as autoreceptors controlling cell firing and DA release. Selective in vivo blockade or stimulation of D2 autoreceptors has been hampered by the fact that active compounds on these receptors also interact with those located on postsynaptic non-DA neurons. To circumvent this difficulty, we created transgenic mice lacking D2 autoreceptors by cell-specific conditional gene targeting. Homozygous mutant mice carrying loxP sites flanking Drd2 exon 2 (Drd2flox/flox), overtly indistinguishable from Drd2+/+ mice, were crossed with knockin mice expressing Cre from the dopamine transporter gene Dat+/IresCre. An in situ hybridization analysis performed on compound Drd2flox/flox. Dat+/ IresCre mice (autoDrd2-/-) showed a total loss of Drd2 expression within midbrain dopaminergic neurons while retaining expression in forebrain postsynaptic neurons and pituitary cells. AutoDrd2-/- mice displayed increased locomotor activity and were insensitive to low doses of the D2R agonist quinpirole. Motor coordination on a rotarod, approach/avoidance behavior on an elevated plus maze and conditioned place preference for cocaine were normal in autoDrd2-/- mice. Interestingly, autoDrd2-/- mice showed increased motivation for food reward in a progressive-ratio operant test. Altogether, our results indicate that loss of presynaptic D2 autoreceptors impairs behaviors dependent in locomotor and emotional functions.