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Disruption of Social Approach by MK-801, Amphetamine, and Fluoxetine in Adolescent C57BL/6J Mice

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Disruption of Social Approach by MK-801, Amphetamine, and Fluoxetine in Adolescent C57BL/6J Mice

Sheryl S Moy et al. Neurotoxicol Teratol.

Abstract

Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10 mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice.

Conflict of interest statement

Conflict of Interest Statement

No conflicts to disclose.

Figures

Figure 1
Figure 1. Effects of MK-801, amphetamine, and fluoxetine on sociability in adolescent mice
Data shown are means (+ SEM) for 9–10 mice per drug treatment group, and 29–40 mice per vehicle treatment group. Data for time spent in each side were lost for one mouse from the MK-801 group, and data for sniffing were lost from three mice (one in the MK-801 group and two in the fluoxetine group), due to equipment failure or experimenter error. #Vp<0.05, comparison with vehicle. *p<0.05, within-treatment comparison to opposite side.
Figure 2
Figure 2. Effects of MK-801, amphetamine, and fluoxetine on entries during the sociability (A, C, and E) and social novelty (B, D, and F) tests
The measure for entries served as an index for exploration and activity during the 3-chamber choice task. #Vp<0.05, comparison with vehicle.
Figure 3
Figure 3. Effects of MK-801, amphetamine, and fluoxetine on social novelty preference
MK-801 attenuated preference for the newly-introduced stranger 2 mouse, in comparison to the more-familiar stranger 1 mouse, at all doses. #Vp<0.05, comparison with vehicle. *p<0.05, within-treatment comparison to opposite side.
Figure 4
Figure 4. Selective disruption of social novelty preference, but not sociability, by fluoxetine (10.0 mg/kg)
Results are from a separate set of C57BL/6J male mice (age 5–6 weeks), tested to confirm initial findings on fluoxetine effects, shown in Figures 1E and 3E. N = 12 mice treated with vehicle, and 13 mice treated with fluoxetine. *p<0.05, within-treatment comparison to opposite side.
Figure 5
Figure 5. No disruption of sociability during withdrawal from chronic ethanol
Mice were tested 5–6 hours following withdrawal from a 12-day regimen of ethanol liquid diet, or after exposure to control liquid diet. N = 4 mice per treatment group. #p<0.05, comparison with group given control liquid diet. *p<0.05, within-group comparison to opposite side.
Figure 6
Figure 6. Dose-dependent attenuation of marble-burying by MK-801 and amphetamine
Data shown are means (+ SEM) from 7–11 mice per vehicle and drug dose, with two separate sets of mice tested for MK-801 (A and B). Mice given amphetamine received two tests: a first test (C) with two low drug doses (1.0 and 2.0 mg/kg), and a second test (D), one week later, with a mid-range dose (1.5 mg/kg). Groups in (D) were balanced across drug treatment in the first test. *p<0.05, comparison to vehicle group. Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice

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