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Kohli, Shivali (2018) The impact of oxytocin and GlyT1 inhibitors on social behaviour. PhD thesis, University of Nottingham.

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Abstract

Schizophrenia is a complex mental disorder characterised by various symptoms which fall into three categories of positive, negative and cognitive. In particular, negative symptoms are poorly treated by current medications although several adjunctive therapies are under investigation including Glycine Transporter (GlyT1) inhibitors and neuropeptides such as oxytocin. Despite accumulating preclinical and clinical evidence that such compounds can influence social behaviour and improve negative symptoms in patients, there is little information as to the precise mechanisms by which they work. Therefore, the aims of this thesis were to ultimately determine some of the key regions and potential signalling pathways activated following administration of these compounds in Lister-hooded rats.

Firstly, a functional map of GlyT1 inhibitor RO4993850, an analogue to Bitopertin, identified the selective activation of neurons within the rostral and caudal prefrontal cortex (PFC), suggesting potential NMDA receptor activation in brain areas involved in motivation and goal-directed behaviour. This was further assessed in a novel ‘dual-hit’ neonatal-PCP isolation-rearing rodent model for schizophrenia which was shown herein to induce locomotor hyperactivity and social deficits including reduced social interaction (an index for negative symptoms) and increased communication (as assessed by ultrasonic vocalisations (USVs)). Interestingly neonatal-PCP isolation-reared rats emitted more pro-social 50 kHz USVs which were also longer in duration and had a greater change in call bandwidth compared to controls. Neonatal-PCP isolation-rearing was also shown to selectively decrease parvalbumin expression (a calcium binding protein present in GABAergic interneurons) in the hippocampus but not in the rostral PFC sub-regions assessed, producing similar changes to other rodent models. Microdialysis studies however revealed no change to basal PFC and striatal dopamine levels in these rats. Chronic treatment with the GlyT1 inhibitor RO4993850 improved social deficits in the social interaction test and altered both USV emissions and call characteristics but showed no effect on locomotor hyperactivity, parvalbumin expression in either the PFC or hippocampus, nor dopamine overflow in the PFC or striatum. Finally, an established dose of the neuropeptide oxytocin which did not influence core body temperature, was shown to attenuate PCP-induced hyperactivity, increase pro-social behaviour and selectively enhance dopamine release in the nucleus accumbens (NAc) in group-housed Lister-hooded rats. Thereby providing supporting evidence for regionally-specific oxytocin-dopaminergic interactions within the mesocorticolimbic circuits responsible for regulating associative and rewarding behaviour.

There are therefore several potential mechanisms by which both GlyT1 inhibitors and oxytocin can influence social behaviour, most likely via activation of key brain loci involved in motivation. Although further work is required, results herein indicate the potential of GlyT1 inhibitors and oxytocin as adjunctive therapies to treat predominant negative symptoms in schizophrenia.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Fone, Kevin C.F. King, Madeleine V.
Keywords:	schizophrenia, oxytocin, GlyT1 inhibitors
Subjects:	Q Science > QP Physiology > QP501 Animal biochemistry R Medicine > RC Internal medicine > RC 321 Neuroscience. Biological psychiatry. Neuropsychiatry
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID:	51066
Depositing User:	Kohli, Shivali
Date Deposited:	12 Jul 2018 04:41
Last Modified:	08 May 2020 08:46
URI:	https://eprints.nottingham.ac.uk/id/eprint/51066

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