title: Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors.
abstract: Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in vivo contribution of D2 autoreceptors to DA-mediated behaviors. We found that midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2(loxP/loxP); Dat(+/IRES-cre), referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine.
authors: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
authors: Estefanía P
authors: EP
authors: Bello
authors: Yolanda
authors: Y
authors: Mateo
authors: Diego M
authors: DM
authors: Gelman
authors: Daniela
authors: D
authors: Noaín
authors: Jung H
authors: JH
authors: Shin
authors: Malcolm J
authors: MJ
authors: Low
authors: Verónica A
authors: VA
authors: Alvarez
authors: David M
authors: DM
authors: Lovinger
authors: Marcelo
authors: M
authors: Rubinstein
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001418:Baclofen / Q000494:pharmacology; D002755:Choice Behavior / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D005502:Food; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D006948:Hyperkinesis / Q000188:drug therapy / Q000503:physiopathology; D066298:In Vitro Techniques; D018782:Maze Learning / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009042:Motivation / Q000502:physiology*; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000502:physiology; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000172:deficiency*; D012055:Reinforcement Schedule; D012201:Reward; D013469:Sulpiride / Q000494:pharmacology
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D058786:GABA-B Receptor Agonists; D006834:Hydrazines; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D004295:Dihydroxyphenylalanine; D013469:Sulpiride; C004297:3-hydroxybenzylhydrazine; D001418:Baclofen; D003042:Cocaine; D004298:Dopamine