Intraperitoneal injection of d-serine inhibits high-fat diet intake and preference in male mice

Abstract d -serine is a co-agonist of the N-methyl d -aspartate (NMDA) receptor, an important modulator of glutamatergic excitatory synaptic transmission. We previously reported that oral d -serine ingestion inhibited the intake of highly preferred food and promoted the intake of less preferred food in mice. Here, we analyzed the effects of intraperitoneal (IP) d -serine injections on feeding behavior in mice. We assessed the effects of d -serine during both the acquisition and maintenance of a preference for high-fat diets (HFDs). Aversiveness of IP d -serine was analyzed in the conditioned taste aversion paradigm. The effects on food intake were assessed by providing liquid meals with different fat contents. Finally, we measured brain d -serine and l -serine levels after d -serine administration. We found that IP-injected d -serine effectively inhibited the acquisition of a HFD preference, but failed to prevent expression of a previously learned HFD preference. IP-injected d -serine was not sufficient to condition taste aversion. The effect on HFD preference acquisition was associated with increases in d -serine levels in the cerebral cortex, hypothalamus, and cerebellum. IP-injected d -serine most effectively inhibited the intake of liquid meals with high fat content. This effect was dose-dependent, but the responses varied significantly among male C57BL/6J mice. The differential responses to d -serine were consistent among multiple trials in each mouse. In summary, IP-injected d -serine inhibited HFD intake and the acquisition of an HFD preference. Individual mice with the same genetic background showed different sensitivities to d -serine; thus, d -serine sensitivity may be associated with unidentified traits.