D-Cycloserine Enhances Social Cognition in An Animal Model Relevant to Autism

Background: Social bonding in the highly affiliative, socially monogamous prairie vole is a complex cognitive process involving social motivation, integration of social information, and social learning and memory. We propose that an assay of social bonding may be an effective approach to identify novel pharmacotherapies for the treatment of the social deficits associated with neuropsychiatric disorders, such as autism. In the laboratory, social bonding is assessed by measuring partner preference. Previous studies in prairie voles have implicated an interaction between the oxytocin (OT), dopamine (DA) and glutamate (Glu) receptor systems in nucleus accumbens (NA) in the formation of partner preferences. In this study we directly examine the role of the Glu receptor system in social bonding using two clinically-relevant compounds that target ionotropic Glu receptors, D-cycloserine (DCS) and Ampakine CX614.  The Glu receptor system functions in the cellular encoding of learning and memory and has been utilized in the clinical setting to enhance cognitive processes.  We hypothesize that by enhancing Glu neurotransmission with these compounds, partner preference formation will be accelerated.
Objectives: To determine the effect of glutamate receptor enhancers on social cognition as measured through partner preference formation in prairie voles and to assess the usefulness of this model in identifying novel pharmacotherapies for the treatment of social deficits.
Methods: In Experiment 1, DCS and Ampakine CX614 were injected intraperitoneally (IP) in female prairie voles.  DCS was tested at doses of 0, 10, or 20 mg/kg and CX614 was tested at doses of 0, 1, 5 and 10 mg/kg.  After injection the females were paired with a male for six hours.  This cohabitation typically does not produce partner preferences in our colony. Following cohabitation, the females were tested for partner preference formation. Time spent in social proximity to either the partner or stranger was quantified in the partner preference apparatus
In Experiment 2, DCS was site-specifically infused into socially relevant or control brain regions of female prairie voles.   The animals were cannulated and injected with 10 μg per side of DCS directly into the NA, medial amygdala (MeA) and caudate-putamen. The animals were then paired with males for 6 hrs, and tested for partner preference

Results: Animals receiving 0, and 20 mg/kg doses of DCS IP failed to form a partner preference for their partner. In contrast, females that received 10 mg/kg IP did form a partner preference. CX614 did not promote partner preference formation. Microinjection of DCS into the NA and the MeA induced partner preference formation whereas a control injection did not.
Conclusions: DCS accelerated partner preference formation in female prairie voles, suggesting that this drug enhances social cognition. We hypothesize that by enhancing glutamatergic transmission in the nucleus accumbens, we are expediating the process of social learning, potentially through interactions with the oxytocin system.  Future studies will test the hypothesis that combined oxytocin and DCS will act synergistically to accelerate social bond formation in female prairie voles.  If this hypothesis is correct, we predict that a similar combined therapy may be useful in ameliorating the social cognitive deficits in autism.