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, 102 (44), 16066-71

Prostaglandin E Receptor EP1 Controls Impulsive Behavior Under Stress

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Prostaglandin E Receptor EP1 Controls Impulsive Behavior Under Stress

Yoko Matsuoka et al. Proc Natl Acad Sci U S A.

Abstract

Animals under stress take adaptive actions that may lead to various types of behavioral disinhibition. Such behavioral disinhibition, when expressed excessively and impulsively, can result in harm in individuals and cause a problem in our society. We now show that, under social or environmental stress, mice deficient in prostaglandin E receptor subtype EP1 (Ptger1(-/-)) manifest behavioral disinhibition, including impulsive aggression with defective social interaction, impaired cliff avoidance, and an exaggerated acoustic startle response. This phenotype was reproduced in wild-type mice by administration of an EP1-selective antagonist, whereas administration of an EP1-selective agonist suppressed electric-shock-induced impulsive aggression. Dopamine turnover in the frontal cortex and striatum was increased in Ptger1(-/-) mice, and administration of dopaminergic antagonists corrected their behavioral phenotype. These results suggest that prostaglandin E(2) acts through EP1 to control impulsive behavior under stress, a finding potentially exploitable for development of drugs that attenuate impulsive behavior in humans.

Figures

Fig. 1.
Fig. 1.
Increased aggressiveness and reduced social interaction in EP1-deficient mice. (A) Effects of EP deficiency on social interaction. Sniffing time of wild-type mice in the resident–intruder test was compared with that of Ptger1-/- (n = 7 for each group), Ptger2-/- (n = 9 for each group), Ptger3-/- (n = 13 for each group), or Ptger4-/- (n = 8 for each group) mice. In the case of aggressive encounters, the sniffing time until the fighting episode was determined. ***, P < 0.001. (B) Cumulative incidence of fighting events between the subject and the juvenile intruder. Data are from wild-type (open circles, n = 15), Ptger1-/- (filled circles, n = 15), Ptger2-/- (blue inverted triangles, n = 8), Ptger3-/- (green triangles, n = 7), and Ptger4-/- (crosses, n = 8) mice. *, P < 0.05 vs. wild-type mice. (C) Effect of the EP1 antagonist ONO-8713 on social interaction. Wild-type mice were treated with either vehicle (n = 6) or ONO-8713 (10 mg/kg i.p.) (n = 6) 1 h before the resident–intruder test. ***, P < 0.001. (D) Effect of LPS on social interaction. Wild-type (BL6) or Ptger1-/- mice (n = 4 per group) were treated with either saline or LPS (0.1 mg/kg i.p.) 1 h before the resident–intruder test. *, P < 0.05. (E) Cumulative incidence of fighting events between LPS-treated mice and a juvenile intruder. Wild-type (open circles, n = 7) or Ptger1-/- (red circles, n = 7) mice were treated with LPS and tested 1 h later (see Movie 2). **, P < 0.01 vs. wild type.
Fig. 2.
Fig. 2.
Behavioral analyses of EP1-deficient mice (A) Electric-shock-induced fighting behavior. Age-matched pairs of male wild-type or Ptger1-/- mice (n = 8 pairs for each) were placed in a transparent container and exposed to electric shock for 3 min. The latency to the first fighting episode, the number of fighting events, and the total duration of fighting were counted. **, P < 0.001 vs. wild type. (B) Open-field test. Individual wild-type (n = 12) or Ptger1-/- (n = 11) mice were allowed to explore freely the open field for 5 min. Ambulation was measured with an automatic infrared beam counter, and the occurrence of each typical behavior (rearing, grooming, urination, defecation, jumping) was scored from a video recording. **, P < 0.01 vs. wild type. (C) Acoustic startle reflex. Wild-type or Ptger1-/- mice (n = 16 for each) were placed in a startle chamber, and the startle reflex to audible stimuli of the indicated frequencies was measured. Background noise (BG) is 70 dB. **, P < 0.01 vs. corresponding value for wild type. (D) Impaired cliff avoidance in Ptger1-/- mice. Wild-type or Ptger1-/- mice were placed on the base of an inverted glass beaker, and their behavior was recorded with a video camera (see Movie 3). (E) The cumulative frequency of jumping for Ptger1-/- (red circles), Ptger3-/- (blue inverted triangles), or wild-type (black triangles) mice (n = 7 for each) and for wild-type mice injected with ONO-8713 (10 mg/kg i.p.) 1 h before the test (green triangles, n = 6) was determined over 7 min in the cliff-avoidance test. **, P < 0.01, ***, P < 0.001 vs. nontreated wild-type mice.
Fig. 3.
Fig. 3.
Increased DA turnover in the frontal cortex and the striatum of EP1-deficient mice. Contents of DA and serotonin and of their metabolites in the frontal cortex and the striatum of wild-type and Ptger1-/- mice (n = 6–7) were determined (see Table 1). The ratios of the content of dihydroxyphenylacetic acid (DOPAC) to DA, homovanillic acid (HVA) to DA, (DOPAC plus HVA) to DA, and 5-hydroxyindole acetic acid (5-HIAA) to serotonin (5-HT) of Ptger1-/- mice (filled bars) were normalized, relative to the average of the corresponding measures of wild-type animals (open bars). **, P < 0.01; ***, P < 0.001 vs. the corresponding wild-type value.
Fig. 4.
Fig. 4.
Effects of dopaminergic antagonists on the behavioral abnormalities of EP1-deficient mice. Wild-type (open bars) or Ptger1-/- (filled bars) male mice were treated with SCH23390 (SCH) (12.5 μg/kg i.p.), haloperidol (hal) (0.3 mg/kg per os), or raclopride (rac) (0.3 or 0.6 mg/kg i.p.) and were subsequently examined for electric-shock-induced fighting (A), the acoustic startle reflex to a 110-dB stimulus (B), and spontaneous locomotor activity (C). All of the tests were run simultaneously with corresponding control groups with proper vehicle (veh) over multiple days. The numbers of mice for each group are shown below each column. *, P < 0.05; **, P < 0.01 compared with vehicle-treated mice of the same genotype.
Fig. 5.
Fig. 5.
Effect of an EP1-selective agonist on behaviors. (A) Effect of ONO-DI-004 on electric-shock-induced fighting. Age-matched pairs of wild-type male mice were exposed to electric shock 30 min after i.c.v. injection of ONO-DI-004 (2 or 10 nmol per animal, n = 9 pairs per dose) or vehicle (n = 10 pairs). The amplitude and duration of the electric shock and the size of the arena were adjusted to increase the rate of fighting in wild-type animals. The latency to the first fighting episode and the total number and duration of fighting episodes during 5 min were measured. **, P < 0.01. (B) Effect of ONO-DI-004 on the open-field test. Wild-type male mice were put into a round open field 10 min after i.c.v. injection of ONO-DI-004 (2 or 10 nmol per animal, n = 12 and 13 pairs, green triangles and blue squares, respectively) or vehicle (n = 12 pairs, filled circles). Ambulation, rearing, grooming, defecation, and urination were scored during three separate 5-min intervals during 10–15, 20–25, and 30–35 min after the injection. #, P < 0.05 for the comparison between the group injected with 2 nmol of ONO-DI-004 vs. the one injected with vehicle. *, P < 0.05 and **, P < 0.01 for the comparison between the group injected with 10 nmol of ONO-DI-004 vs. the one injected with vehicle.

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