LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism.

Oxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V1a and V2 vasopressin receptor subtypes (V1a-R and V2-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure-affinity and structure-efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration.

Microparticle-based delivery of oxytocin receptor antisense DNA in the medial amygdala blocks social recognition in female mice.

Social recognition constitutes the basis of social life. In male mice and rats, social recognition is known to be governed by the neuropeptide oxytocin (OT) through its action on OT receptors (OTRs) in the medial amygdala. In female rats and mice, which have sociosexual behaviors controlling substantial investment in reproduction, an important role for OT in sociosexual behaviors has also been shown. However, the site in the female brain for OT action on social recognition is still unknown. Here we used a customized, controlled release system of biodegradable polymeric microparticles to deliver, in the medial amygdala of female mice, "locked nucleic acid" antisense (AS) oligonucleotides with sequences specific for the mRNA of the OTR gene. We found that single bilateral intraamygdala injections of OTR AS locked nucleic acid oligonucleotides several days before behavioral testing reduced social recognition. Thus, we showed that gene expression for OTR specifically in the amygdala is required for normal social recognition in female mice. Importantly, during the same experiment, we performed a detailed ethological analysis of mouse behavior revealing that OTR AS-treated mice underwent an initial increase in ambivalent risk-assessment behavior. Other behaviors were not affected, thus revealing specific roles for amygdala OTR in female social recognition potentially mediated by anxiety in a social context. Understanding the functional genomics of OT and OTR in social recognition should help elucidate the neurobiological bases of human disorders of social behavior (e.g., autism).

Contribution of endogenous oxytocin to sodium excretion in anaesthetized, surgically operated rats.

In order to determine the possible role of endogenous oxytocin in controlling electrolyte and water excretion in animals whose renal function is being assessed by invasive techniques, rats were anaesthetized and subjected to micropuncture surgery. Clearance measurements were made in the presence and absence of the potent oxytocin receptor antagonist d(CH(2))(5)[Tyr(Me)(2), Thr(4), Orn(8), Tyr(NH(2))(9)]-vasotocin. In rats infused with vehicle alone, glomerular filtration rate (GFR), sodium excretion and urine flow rate remained stable. In contrast, in antagonist-treated rats GFR was modestly reduced (P<0.05), and there were large falls in both absolute and fractional sodium excretion (P<0.01 in each case) and absolute and fractional water excretion (P<0.05 in each case), indicating effects on both filtered load and fractional tubular reabsorption. The antinatriuresis was not accompanied by a change in the fractional excretion of lithium, suggesting that proximal tubular function is unaffected by oxytocin receptor antagonism; nor was it accompanied by a change in the fractional excretion of potassium, suggesting that the tubular effect is located beyond the potassium secretory site, i.e. downstream of the cortical collecting tubule. We conclude that circulating plasma concentrations of oxytocin during anaesthesia and moderate surgery are sufficient to enhance GFR and reduce fractional tubular sodium and water reabsorption. This has important implications for the interpretation of invasive studies such as micropuncture.