Chronic and acute intranasal oxytocin produce divergent social effects in mice

Abstract

Intranasal administration of oxytocin (OXT) might be a promising new adjunctive therapy for mental disorders characterized by social behavioral alterations such as autism and schizophrenia. Despite promising initial studies in humans, it is not yet clear the specificity of the behavioral effects induced by chronic intranasal OXT and if chronic intranasal OXT could have different effects compared with single administration. This is critical for the aforementioned chronic mental disorders that might potentially involve life-long treatments. As a first step to address these issues, here we report that chronic intranasal OXT treatment in wild-type C57BL/6J adult mice produced a selective reduction of social behaviors concomitant to a reduction of the OXT receptors throughout the brain. Conversely, acute intranasal OXT treatment produced partial increases in social behaviors towards opposite-sex novel-stimulus female mice, while on the other hand, it decreased social exploration of same-sex novel stimulus male mice, without affecting social behavior towards familiar stimulus male mice. Finally, prolonged exposure to intranasal OXT treatments did not alter, in wild-type animals, parameters of general health such as body weight, locomotor activity, olfactory and auditory functions, nor parameters of memory and sensorimotor gating abilities. These results indicate that a prolonged over-stimulation of a 'healthy' oxytocinergic brain system, with no inherent deficits in social interaction and normal endogenous levels of OXT, results in specific detrimental effects in social behaviors.

Figure 1

Chronic intranasal OXT treatment decreased male–female social interaction. (a) Frequency of occurrence of various social behaviors such as head sniffing, body sniffing, angogenital sniffing and following. (b) Duration of events of above-mentioned social behaviors. (c) Frequency of occurrence of various nonsocial behaviors such as standing/walking alone, digging, grooming, rearing and wall rearing. (d) Duration of events of above-mentioned nonsocial behaviors. (e) Sum of the frequency of all events of social and nonsocial behaviors. (f) Sum of the duration of all events of social and nonsocial behaviors. Ns=14 VEH, 16 OXT 0.15 IU/5 μl, 16 OXT 0.3 IU/5 μl. (g) Mean number of USV calls per minute, and (h) mean duration of USVs in milliseconds emitted by VEH-, OXT 0.15- or OXT 0.3-treated mice. Ns=9 VEH, 16 OXT 0.15 IU/5 μl, 10 OXT 0.3 IU/5 μl. *p<0.05, **p<0.005, ***p<0.0005 vs VEH group. Values represent mean±SEM throughout all Figures.

Figure 2

Chronic intranasal OXT treatment decreased male–male social interaction. (a) Duration of occurrence of various social behaviors such as head sniffing, body sniffing, anogenital sniffing, going on top of another mouse (above) and following. (b) Duration of occurrence of various nonsocial behaviors such as walking alone and standing alone. Sum of the duration of all events of above-mentioned (c) social behaviors and (d) nonsocial behaviors. Note that in this experiment we used cagemates in order to avoid any possible aggressive behavior. Ns=6 VEH, 16 OXT 0.15 IU/5 μl, 4 OXT 0.3 IU/5 μl. *p<0.05, **p<0.005 vs VEH.

Figure 3

Chronic intranasal OXT treatment decreased OXT receptors in various brain areas. Representative autoradiographs showing the rostro-caudal ligand binding (a) of 20 pmol/l I¹²⁵-labeled OVTA, a potent and selective ligand for OXTR and (b) of 20 pmol/l I¹²⁵-labeled linear vasopressin antagonist (LVA), a potent and selective ligand for V1aR. Autoradiograms were obtained from coronal sections of 3-month-old brains of mice chronically treated with intranasal OXT 0.15 IU/5 μl (OXT 0.15), OXT 0.3 IU/5 μl (OXT 0.3) or vehicle (VEH). (c and d) Quantification of the autoradiographic I¹²⁵⁻receptors was obtained using NIH ImageJ- Software. Data is expressed as nCi/mg tissue equivalent. Amy, amygdala; AON, anterior olfactory nucleus; Hippo, hippocampus; LS, lateral septum; NAcc, nucleus accumbens; PIR, piriform cortex; VP, ventral pallidum. Ns=7 for each group; *p<0.05; **p<0.005; ***p<0.0005 vs VEH.

Figure 4

Acute intranasal OXT treatment increased male–female social interaction. (a) Frequency of occurrence of various social behaviors such as head sniffing, body sniffing, angogenital sniffing and following in male mice towards female stimulus mice after a single acute dose of saline (VEH), OXT 0.15 IU/5 μl or 0.3 IU/5 μl. (b) Duration of events of above-mentioned social behaviors. (c) Frequency of occurrence of various nonsocial behaviors such as standing/walking alone, digging, grooming, rearing and wall rearing. (d) Duration of events of above-mentioned nonsocial behaviors. (e) Frequency of all events of social and nonsocial behaviors. (f) Duration of all events of social and nonsocial behaviors. (g) Mean number of USV calls per minute, and (h) mean duration of USVs in milliseconds. Ns=6 acute VEH, 6 acute OXT 0.15 IU/5 μl, 6 acute OXT 0.3 IU/5 μl. *p<0.05, **p<0.005 vs VEH.

Figure 5

Acute intranasal OXT treatment did not alter social interaction between familiar males but reduced it between unfamiliar males. (a) Duration of occurrence of various social behaviors such as nose-to-body, nose-to-nose, nose-to-back sniffing, going on top of another mouse—‘above' and following in male mice towards male cagemates after a single acute dose of saline (VEH), OXT 0.15 IU/5 μl or 0.3 IU/5 μl. (b) Duration of occurrence of various nonsocial behaviors such as walking alone and standing alone. Sum of the duration of all events of the above-mentioned (c) social and (d) nonsocial behaviors. Ns=6 acute VEH, 6 acute OXT 0.3 IU/5 μl, 6 acute OXT 0.15 IU/5 μl. (e and f) Data depict the amount of time in seconds allocated to (e) investigation of the same unfamiliar male and (f) other nonsocial behaviors in the cage but not towards the stimulus mouse during each of three successive 1-min trials. A fourth ‘dishabituation' trial depicts the response of the subject males to the presentation of a new unfamiliar male in a 1-min pairing 3 min after the third trial. Ns=13 acute VEH, 14 acute OXT 0.15 IU/5 μl, 13 acute OXT 0.3 IU/5 μl. *p<0.05 vs trials 2 and 3.