Nebulized vasopressin penetrates CSF and improves social cognition without inducing aggression in a rhesus monkey model of autism

Abstract

Low cerebrospinal (CSF) arginine vasopressin (AVP) concentration is a biomarker of social impairment in low-social monkeys and children with autism, suggesting that AVP administration may improve primate social functioning. However, AVP administration also increases aggression, at least in "neurotypical" animals with intact AVP signaling. Here, we tested the effects of a voluntary drug administration method in low-social male rhesus monkeys with high autistic-like trait burden. Monkeys received nebulized AVP or placebo, using a within-subjects design. Study 1 (N = 8) investigated the effects of AVP administration on social cognition in two tests comparing responses to social versus nonsocial stimuli. Test 1: Placebo-administered monkeys lacked face recognition memory, whereas face recognition memory was "rescued" following AVP administration. In contrast, object recognition memory was intact and did not differ between administration conditions. Test 2: Placebo-administered monkeys did not respond to conspecific social communication cues, whereas following AVP administration, they reciprocated affiliative communication cues with species-typical affiliative responses. Importantly, AVP administration did not increase aggressive responses to conspecific aggressive or affiliative overtures. Study 2 (N = 4) evaluated the pharmacokinetics of this administration method. Following AVP nebulization, we observed a linear increase in cisternal CSF AVP levels, and a quadratic rise and fall in blood AVP levels. These findings indicate that nebulized AVP likely penetrates the central nervous system, selectively promotes species-typical responses to social information, and does not induce aggression in low-social individuals. Nebulized AVP therefore may hold promise for managing similar social symptoms in people with autism, particularly in very young or lower functioning individuals.

Keywords: autism; primate model; rhesus monkey; social functioning; vasopressin.

Fig. 1.

Experimental overview. We tested N = 8 (Study 1) and N = 4 (Study 2) young adult male low-social rhesus monkeys. Prior to testing, all monkeys were trained to inhale doses through the nebulization apparatus pictured in the Top Left panel. The Top Right panel displays the experimental timelines for Studies 1 and 2. In both studies, monkeys received every dose of either 0 IU AVP (i.e., placebo), 25 IU AVP, or 50 IU AVP in a random order. In Study 1, we assessed the effects of AVP administration on social cognition (Bottom Left panel). In study 2, CSF and blood samples were collected at four timepoints (30-, 60-, 90-, and 120-min) postnebulization to assess AVP pharmacokinetics and to confirm central nervous system penetration of nebulized AVP. AVP concentrations were quantified using a previously validated ELISA (Bottom Right panel).

Fig. 2.

AVP administration selectively improves social recognition memory in low-social monkeys. Data are plotted as the LSM ± SE ratio of looks to novel versus familiar stimuli. Data were log transformed prior to analysis (to make the measure symmetric). The 25 IU AVP and 50 IU AVP doses did not significantly differ and therefore are plotted together. The dashed line indicates a 50:50 looking ratio (i.e., no preference). Treatment differentially impacted social versus nonsocial recognition memory (P = 0.0233). Thus, placebo-administered monkeys lacked face recognition memory, whereas face recognition memory ability was “rescued” following AVP administration. In contrast, object recognition memory in the same monkeys was intact and did not differ between treatment conditions.

Fig. 3.

AVP administration selectively improves species-typical responses to social communication cues. Data are plotted as the LSM ± SE ratio of responding to social versus nonsocial stimuli. Data were log transformed prior to analysis (to make the measure symmetric). The 25 IU AVP and 50 IU AVP doses did not significantly differ and therefore are plotted together. The dashed line indicates a 50:50 response ratio (i.e., no differential responding to social versus nonsocial stimuli). (A) Treatment differentially impacted subjects’ affiliative responses to conspecific affiliative versus aggressive overtures (P = 0.0154). Thus, placebo-administered monkeys did not respond affiliatively to conspecific aggressive or affiliative overtures, whereas following AVP administration, subjects selectively reciprocated affiliative communication cues with species-typical affiliative responses. (B) Treatment did not differentially impact subjects’ aggressive responses to conspecific affiliative versus aggressive overtures (P = 0.5348). Furthermore, AVP administration did not increase aggressive responses to conspecific social communication cues overall.

Fig. 4.

AVP administration increases measured AVP levels in serially collected CSF and plasma samples. Data are presented as the LSM ± SE ratio of AVP levels in CSF or plasma when monkeys were administered AVP versus placebo for each timepoint. Data were log transformed prior to analysis to preserve symmetry. (A) Cisternal CSF AVP levels changed significantly post-AVP administration relative to when the same monkeys were administered placebo (P = 0.0099), due to a progressive linear increase in CSF AVP concentration. This effect was consistently stronger when monkeys received the 50 IU AVP dose versus the 25 IU AVP dose (P = 0.0269). There was no significant dose-by-timepoint interaction. (B) Plasma AVP levels changed significantly post-AVP administration relative to when the same monkeys were administered placebo (P = 0.0194), due to a progressive rise and fall in blood AVP concentrations. This effect was consistently stronger when monkeys received the 50 IU AVP dose versus the 25 IU AVP dose (P = 0.0025). There was no significant dose-by-timepoint interaction.