Abrahams, Abigail Bethany
(2021)
Deciphering the neural mechanisms of oxytocin’s prosocial and antipsychotic-like effects.
PhD thesis, University of Nottingham.
Abstract
Both clinical and preclinical research has indicated administration of the endogenous neuropeptide oxytocin (OXY) may help restore normal social functioning in patients with social deficits, such as those seen in schizophrenia. In addition, ‘antipsychotic-like’ effects of OXY have also been reported in rats, through the attenuation of phencyclidine (PCP)-induced hyperactivity. OXY has affinity at both the oxytocin (OXTR) and vasopressin 1a (V1aR) receptors, and evidence suggests both are involved in social behaviour. However, the neural mechanisms underpinning these behavioural effects of OXY remain poorly understood. The overall aims of this thesis are to gain an insight into the neural mechanisms that underlie the prosocial and antipsychotic-like effects of subcutaneous (s.c.) OXY in healthy rats, through the use of selective antagonists and intracranial micro-injections of the OXTR targeting toxin, OXY-saporin, into discrete brain nuclei.
First, we developed an in vitro calcium assay to determine whether a conjugation of OXY to a novel cell-penetrating peptide, GET, was biologically active and could be used to enhance intranasal OXY administration. This experiment demonstrated that conjugation of OXY to GET hinders biological activity at the OXTR, and therefore was unsuitable for intranasal administration. A low dose of s.c. OXY was subsequently selected for the behavioural experiments performed, due to the fact it can modulate brain OXY levels without having any profound concomitant peripheral effects, such as hypothermia or sedation.
Second, we demonstrated s.c. OXY can both enhance social interaction between two male rats and attenuate PCP-induced hyperactivity, indicative of an antipsychotic-like effect and consistent with previous work from this laboratory. Utilising selective V1aR and OXTR antagonists, SR 49059 and L-368,899 respectively, we demonstrated activity at the OXTR was responsible for OXY enhancement of social behaviour following systemic administration. In contrast, activity at both the OXTR and V1aR are involved in the ability of OXY to reverse PCP-induced hyperactivity, such that both antagonists reduced OXY-attenuation of PCP-hyperactivity.
Finally, using discrete micro-injections of the OXTR targeted toxin, OXY-saporin, we sought to determine the role of NAc and VTA OXTRs on OXYs prosocial and antipsychotic-like effects. OXY was no longer able to increase social interaction following microinjection of NAc OXY-saporin, however, removal of NAc OXTR expressing neurons had no effect on the ability of OXY to attenuate PCP-induced hyperactivity. In the same way, removal of OXTR expressing neurons in the VTA also prevented OXY enhancement of prosocial behaviours but had no effect on OXY’s attenuation of PCP-induced hyperactivity.
Overall, our results suggest that OXYs prosocial and antipsychotic-like effects are modulated by different neural mechanisms. Our findings strongly implicate mesolimbic dopamine in the prosocial effect of s.c. OXY and are consistent with work suggesting mesolimbic dopamine can enhance social reward and social interaction. The antipsychotic-like effects of s.c. OXY are likely modulated by an alternative neural mechanism, such as modulation of the nigrostriatal pathway. Overall, this work has significantly contributed to our understanding of OXYs neural mechanisms, providing robust evidence peripheral OXY can modulate behaviour through central activity. Although further work is required, the use of OXY to treat social deficits in psychiatric disorders remains promising.
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