Table 2.

Relevance of animal models for oxytocin-based drug discovery.

Treatment strategy	Description	Potential predictive model
		Genotype based models				Phenotype based models
		OT-KO	OTR-KO	CD38-KO	Monogenic ASD models	Inbred mice	Microtine rodents
		Intranasal OT	Peripheral route of administration with hypothesized preferential access across the BBB.	+	−*	+	+*	+	+
		Non-peptide agonists	Small molecule agonists for the OT receptor that cross the BBB.	+	−*	+	+*	+	+
OT releasers	Agonists for receptors on OT neurons or intracellular signaling molecules that promote OT release.	−	−*	+	+*	+	+
P-LAP inhibitors	Inhibits the enzymatic activity of placental leucine aminopeptidase, to prevent the degradation of OT	−	−*	−	+*	+	+

The potential efficacy of OT based therapeutics can be best evaluated using different animal models of social cognition (+ indicates validity of testing that form of OT-based therapy in that specific model, − indicates lack of validity of testing that form of OT-based therapy in that specific model). OTKO and CD38KO mice are best utilized to test the effects of OT and OT receptor agonists, as the effect of OT in the social recognition test in these models is well characterized. Phenotype based models can be used to test all classes of OT-based therapies, though the best characterized behavioral endpoint uses the partner preference in female prairie voles. The use of OTR-KO mice has the most construct validity for the small subpopulation of ASD patients altered OTR expression, though the mechanism of action of OT-based drugs would be less clear in this model (−* indicates the model couldn’t be used to identifying therapeutics that act at OT receptors, but the model could be useful in understanding signaling through alternative pathways). Mouse models of monogenic forms of autism also have the potential to test the efficacy of OT based therapies, however the effect of central OT on social phenotypes must first be better defined (+*).