NMDA Receptors on Dopaminoceptive Neurons Are Essential for Drug-Induced Conditioned Place Preference.
Plasticity of the brain's dopamine system plays a crucial role in adaptive behavior by regulating appetitive motivation and the control of reinforcement learning. In this study, we investigated drug- and natural-reward conditioned behaviors in a mouse model in which the NMDA receptor-dependent plasticity of dopaminoceptive neurons was disrupted. We generated a transgenic mouse line with inducible selective inactivation of the NR1 subunit in neurons expressing dopamine D1 receptors (the NR1(D1CreERT2) mice). Whole-cell recordings of spontaneous EPSCs on neurons in the nucleus accumbens confirmed that a population of neurons lacked the NMDA receptor-dependent component of the current. This effect was accompanied by impaired long-term potentiation in the nucleus accumbens and in the CA1 area of the ventral, but not the dorsal, hippocampus. Mutant mice did not differ from control animals when tested for pavlovian or instrumental conditioning. However, NR1(D1CreERT2) mice acquired no preference for a context associated with administration of drugs of abuse. In the conditioned place preference paradigm, mutant mice did not spend more time in the context paired with cocaine, morphine, or ethanol, although these mice acquired a preference for sucrose jelly and an aversion to naloxone injections, as normal. Thus, we observed that the selective inducible ablation of the NMDA receptors specifically blocks drug-associated context memory with no effect on positive reinforcement in general.
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Magdalena
0000-0001-9653-6579
M
Sikora
Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Krzysztof
K
Tokarski
Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Bartosz
B
Bobula
Cell Biology, Department of Clinical and Experimental Medicine, Linköping University , SE-581 83 Linköping, Sweden.
Joanna
0000-0002-6662-7709
J
Zajdel
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Kamila
0000-0002-4083-0020
K
Jastrzębska
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Przemysław Eligiusz
0000-0002-0543-8445
PE
Cieślak
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Magdalena
M
Zygmunt
Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Joanna
0000-0001-7017-539X
J
Sowa
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Magdalena
M
Smutek
Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Katarzyna
K
Kamińska
Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Krystyna
K
Gołembiowska
Cell Biology, Department of Clinical and Experimental Medicine, Linköping University , SE-581 83 Linköping, Sweden.
David
0000-0001-6501-9077
D
Engblom
Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Grzegorz
G
Hess
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland; Department of Neurobiology and Neuropsychology, Institute of Applied Psychology, Jagiellonian University, 30-348 Krakow, Poland.
Ryszard
R
Przewlocki
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences , 31-343 Krakow, Poland.
Jan
0000-0003-0367-2331
J
Rodriguez Parkitna
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D013287:Illicit Drugs / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques
D002491:Central Nervous System Agents; C583261:Drd1 protein, mouse; C121673:Gprin1 protein, mouse; D013287:Illicit Drugs; D009419:Nerve Tissue Proteins; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D009270:Naloxone; D009020:Morphine; D003042:Cocaine; D004298:Dopamine
NMDA receptors; dopamine; drugs of abuse; operant conditioning; reinforcement