City Research Online

Abstract

Autism spectrum disorder (ASD) is characterised by impairment in the social domain and is often comorbid with depression and social anxiety. Several neuronal systems have been implicated in the neuropathology of ASD, yet the underlining neurobiology remains unclear, with no effective treatment being identified. Therefore, we utilised a well-validated mouse neurobiological candidate systems and we detected dysregulation of opioid, oxytocin, vasopressin, glutamate and dopamine in this model. Current ASD pharmacotherapy is only symptomatic and does not target core symptomatology. Intranasal oxytocin is a promising target for the treatment of ASD with known acute effects on related ASD-like symptomatology, but little currently is known about the effect of chronic exposure to the drug. Therefore, we performed a battery of behavioural experiments to assess the efficacy and neurobiological consequences of chronic oxytocin administration in the Fmr1 KO and wild-type mice. We observed restoration of sociability but not stereotypy upon acute and chronic oxytocin treatment in the mutants and prevention of comorbid anxiety following chronic oxytocin administration. Opposingly, detrimental effects in sociability, stereotypy and emotionality following chronic oxytocin treatment were detected in wild-type mice. Differential regulation of several transcripts was detected in Fmr1 KO and wild-type mice. Lastly, we investigated the effect of chronic exposure to social-defeat stress (CSS), a common psychopathology characterised by impairment in sociability and depression on central nicotinic acetylcholine receptor (nAchR) subtype and D2 dopamine receptor density. While CSS did not affect α7* and α4β2* nAChR binding, it downregulated D2. These findings offer better understanding of the neurobiology underpinning psychopathologies characterised by social deficit and highlight chronic OXT as an effective pharmacotherapy for their treatment. Nonetheless, our findings reveal potential safety concerns of its chronic use in healthy subjects with intact oxytocinergic system.

Publication Type:	Thesis (Doctoral)
Subjects:	R Medicine > R Medicine (General) R Medicine > RB Pathology R Medicine > RM Therapeutics. Pharmacology
Departments:	School of Health & Medical Sciences > Institute of Medical, Biomedical and Allied Health Education School of Health & Medical Sciences > School of Health & Medical Sciences Doctoral Theses Doctoral Theses

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