Mice lacking dopamine D2 autoreceptors reveal their fundamental role on dopamine neurotransmission.

BELLO, EP; MATEO, Y; GELMAN, DM; NOAÍN, D; SHIN, JH; ALVAREZ, VA; LOVINGER, D; RUBINSTEIN, M

Huerta Grande, Córdoba, Argentina

Congreso; XXVI Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia; 2011

Sociedad Argentina de Investigación en Neurociencias

Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors)exert a negative feedback regulation that reduces DA neuron firing, DAsynthesis and DA release. Since D2 receptors are mostly expressed inpostsynaptic neurons, pharmacological and genetic approaches have beenunable to definitively address the in vivo contribution of D2 autoreceptorsto DA-mediated behaviors. To circumvent this difficulty, we generated micedeficient in D2 receptors in midbrain DA neurons (Drd2loxP/loxP; Dat+/IRES-cre, referred to as autoDrd2KO mice), as we could confirm by an insitu hybridization analysis. AutoDrd2KO mice showed elevated DA synthesisand release and displayed hyperlocomotion and supersensitivity to thepsychomotor effects of cocaine whereas showed normal motor reactionswhen challenged on a rotarod or in approach/avoidance conflict tests.Interestingly, these mice also exhibited increased place preference forcocaine and enhanced motivation for food reward. Our results highlight theimportance of D2 autoreceptors in the regulation of DA neurotransmissionand demonstrate that D2 autoreceptors are important for normal motorfunction, food-seeking behavior, and sensitivity to the locomotor andrewarding properties of cocaine.