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Transl Psychiatry. 2017 Apr 18;7(4):e1095. doi: 10.1038/tp.2017.64.

Adenosine A2A receptor and ERK-driven impulsivity potentiates hippocampal neuroblast proliferation.

Author information

1
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
2
Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA.
3
Neurobiology of Disease Program, Mayo Clinic College of Medicine, Rochester, MN, USA.
4
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
5
Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, USA.

Abstract

Dampened adenosine A2A receptor (A2AR) function has been implicated in addiction through enhancement of goal-directed behaviors. However, the contribution of the A2AR to the control of impulsive reward seeking remains unknown. Using mice that were exposed to differential reward of low rate (DRL) schedules during Pavlovian-conditioning, second-order schedule discrimination, and the 5-choice serial reaction time task (5-CSRTT), we demonstrate that deficits of A2AR function promote impulsive responses. Antagonism of the A2AR lowered ERK1 and ERK2 phosphorylation in the dorsal hippocampus (dHip) and potentiated impulsivity during Pavlovian-conditioning and the 5-CSRTT. Remarkably, inhibition of ERK1 and ERK2 phosphorylation by U0126 in the dHip prior to Pavlovian-conditioning exacerbated impulsive reward seeking. Moreover, we found decreased A2AR expression, and reduced ERK1 and ERK2 phosphorylation in the dHip of equilibrative nucleoside transporter type 1 (ENT1-/-) null mice, which displayed exacerbated impulsivity. To determine whether impulsive response behavior is associated with hippocampal neuroblast development, we investigated expression of BrdU+ and doublecortin (DCX+) following 5-CSRTT testing. These studies revealed that impulsive behavior driven by inhibition of the A2AR is accompanied by increased neuroblast proliferation in the hippocampus.

PMID:
28418405
PMCID:
PMC5416704
DOI:
10.1038/tp.2017.64
[Indexed for MEDLINE]
Free PMC Article

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