title: Neural Substrates of Dopamine D2 Receptor Modulated Executive Functions in the Monkey Prefrontal Cortex.
abstract: Dopamine D2 receptors (D2R) play a major role in cognition, mood and motor movements. Their blockade by antipsychotic drugs reduces hallucinatory and delusional behaviors in schizophrenia, but often fails to alleviate affective and cognitive dysfunctions. The prefrontal cortex (PFC) expresses D2R and is altered in schizophrenia. We investigated how D2R modulate behavior and PFC function in monkeys. Two monkeys learned new and performed highly familiar visuomotor associations, where each cue was associated with a saccade to a right or left target. We recorded neural spikes and local field potentials from multiple electrodes while injecting the D2R antagonist eticlopride in the lateral PFC. Blocking prefrontal D2R impaired associative learning and cognitive flexibility, reduced motivation, but left the performance of familiar associations intact. Eticlopride reduced saccade-direction selectivity of prefrontal neurons, leading to a decrease in neural information about the associations, and an increase in alpha oscillations. These results, together with our recent study using a D1R antagonist, suggest that D1R and D2R in the primate lateral PFC cooperate to modulate several executive functions. Our findings help to gain insight into why antipsychotic drugs, with strong antagonistic actions on D2R, fail to ameliorate cognitive and emotional deficits in schizophrenia.
authors.affiliation: The Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Puig
authors.affiliation: The Picower Institute for Learning and Memory and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Earl K
authors.initials: EK
authors.lastname: Miller
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000513:Alpha Rhythm / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001245:Association Learning / Q000502:physiology; D001552:Benzazepines / Q000494:pharmacology; D003463:Cues; D015259:Dopamine Agents / Q000494:pharmacology; D056344:Executive Function / Q000502:physiology*; D005583:Fourier Analysis; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008568:Memory / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012457:Salicylamides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001552:Benzazepines; D015259:Dopamine Agents; D017448:Receptors, Dopamine D2; C534628:SCH 23390; D012457:Salicylamides; C045989:eticlopride
keywords: dopamine D2 receptors; learning and memory; neural oscillations; prefrontal cortex; schizophrenia