Vasopressin as Possible Treatment Option in Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is rather common, presenting with prevalent early problems in social communication and accompanied by repetitive behavior. As vasopressin was implicated not only in salt-water homeostasis and stress-axis regulation, but also in social behavior, its role in the development of ASD might be suggested. In this review, we summarized a wide range of problems associated with ASD to which vasopressin might contribute, from social skills to communication, motor function problems, autonomous nervous system alterations as well as sleep disturbances, and altered sensory information processing. Beside functional connections between vasopressin and ASD, we draw attention to the anatomical background, highlighting several brain areas, including the paraventricular nucleus of the hypothalamus, medial preoptic area, lateral septum, bed nucleus of stria terminalis, amygdala, hippocampus, olfactory bulb and even the cerebellum, either producing vasopressin or containing vasopressinergic receptors (presumably V_1a). Sex differences in the vasopressinergic system might underline the male prevalence of ASD. Moreover, vasopressin might contribute to the effectiveness of available off-label therapies as well as serve as a possible target for intervention. In this sense, vasopressin, but paradoxically also V_1a receptor antagonist, were found to be effective in some clinical trials. We concluded that although vasopressin might be an effective candidate for ASD treatment, we might assume that only a subgroup (e.g., with stress-axis disturbances), a certain sex (most probably males) and a certain brain area (targeting by means of virus vectors) would benefit from this therapy.

Keywords: amygdala; autism spectrum disorder; lateral septum; medial preoptic area; social behavior; stereotype behavior; vasopressin.

Figure 1

The three-hit theory of autism spectrum disorder. Vasopressin may contribute to the development of symptoms at all levels. Abbreviations: ASD: autism spectrum disorder; VP: vasopressin; KO: knockout; VPA: valproate.

Figure 2

Comparison of core human symptoms with animal tests modeling them. Impaired social interaction can be modeled via the three-chamber sociability test or anxiogenic social interaction in a new cage. Communication can be measured using ultrasound vocalization, while enhanced allo-grooming in rodents—observable in an open-field—is a sign of stereotyped, repetitive behavior together with the increased number of buried marbles during the marble burying test.

Figure 3

Comparison of autism spectrum disorder (ASD) and schizophrenia (SCZ). Despite core similarities in social and cognitive domains, several unique features can be observed making the differential diagnosis easier.

Figure 4

Alterations in autism spectrum disorders with possible contribution of vasopressin. The observations were mainly in animals. Both social problems and repetitive behaviors—depicted in the middle—are core features of autism spectrum disorders and VP is obviously implicated in them. Peripheral VP functions (blue) might be only indirectly linked to autism, while other central VP effects (orange) might have a more important, although not yet fully clarified role. Abbreviations: ANS: autonomous nervous system; HPA: hypothalamic pituitary adrenocortical axis, VP: vasopressin.

Figure 5

According to the hypothesis of Newman, these brain areas form an integrated social behavior circuit, a subcortical limbic network (social behavior neural network (SBNN)) that subserves the entire spectrum of social behaviors. All these areas have been identified as an important place of activation or regulation of more than one social behavior and each is reciprocally interconnected with all others. Vasopressin (VP) and its V_1a receptor can be found on many parts of this network. Abbreviations: AH: anterior hypothalamus; BNST: bed nucleus of stria terminalis; LS: lateral septum; MeA: medial part of the amygdala; MPOA: medial preoptic area; VH: ventromedial hypothalamus.

Figure 6

Brain areas containing vasopressin producing neurons or vasopressin receptors with possible involvement in autistic behavior. Major role of the nucleus is given. Abbreviations: BNST: bed nucleus of stria terminalis; HC: hippocampus; LS: lateral septum; MeA: medial amygdala; MPOA: medial preoptic area; PAG: periaqueductal grey; PVN: paraventricular nucleus of the hypothalamus; SCN: suprachiasmatic nucleus; V_1a: vasopressin receptor; V_1b: vasopressin receptor; VP: vasopressin producing cells (based upon a mouse brain in https://scalablebrainatlas.incf.org/composer/index.php, accessed on 1 August 2023).

Figure 7

Treatment options in autism with contribution of vasopressin. VP might contribute to the effectiveness of presently available therapies (blue). However, VP alone (yellow) or its antagonists (orange) can be used for therapy. Most of the treatments aim to improve social skills; however, sometimes the results are questionable (+/−). Abbreviations: ASD: autism spectrum disorder; SSRI: selective serotonin reuptake inhibitor; V_1a: vasopressin 1a receptor; VP: vasopressin.