title: Appetitive instrumental learning requires coincident activation of NMDA and dopamine D1 receptors within the medial prefrontal cortex.
abstract: Through its complex role in cognition, memory, and emotion, the mammalian prefrontal cortex is thought to contribute to the organization of adaptive behavioral actions. In the present studies we examined the role of dopaminergic D1 and glutamatergic NMDA receptors within the prefrontal cortex of the rat during the development of adaptive instrumental learning. Hungry rats with bilateral indwelling cannulas aimed at the medial prefrontal cortex were trained to lever-press for food. Infusion of the selective D1 antagonist SCH-23390 (0.15, 0.3, 3.0 nmol) dose-dependently impaired acquisition of this behavior. Higher doses also impaired expression of this task. Co-infusion of the lowest dose of SCH 23390 with a low dose of the NMDA antagonist AP-5 (0.5 nmol), each of which had no effect on learning when infused alone, potently reduced the ability to acquire the response. Inhibition of intracellular protein kinase A with the selective PKA inhibitor Rp-cAMPS also disrupted acquisition, suggesting that PKA is an intracellular substrate for a D1-NMDA receptor interaction. In control experiments, drug infusions that impaired learning did not affect food intake or locomotion, suggesting a specific effect on learning. We hypothesize that coincident detection of D1-NMDA receptor activation and its transcriptional consequences, within multiple sites of a distributed corticostriatal network, may represent a conserved molecular mechanism for instrumental learning.
authors.affiliation: Neuroscience Training Program and Department of Psychiatry, University of Wisconsin-Madison Medical School, Madison Wisconsin 53719-1176, USA.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Baldwin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Sadeghian
authors.forename: Ann E
authors.initials: AE
authors.lastname: Kelley
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000008:administration & dosage; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects / Q000502:physiology*; D001552:Benzazepines / Q000008:administration & dosage; D002404:Catheterization; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018492:Dopamine Antagonists / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008845:Microinjections; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013873:Thionucleotides / Q000008:administration & dosage
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D015763:2-Amino-5-phosphonovalerate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases