Investigating gender differences in the behavioural response to kappa opioid receptor antagonists in mice

: (Alternative Format Thesis)

Abstract

Depression is a neuropsychiatric disorder which affects around 280 million people globally. According to the World Health Organization (WHO), depression is the leading cause of disability globally because symptoms cause clinically significant impairment in social, occupational and other areas of functioning. Furthermore, more women are suffering from depression than men. While antidepressant treatments are available, they have limited efficacy, significant side effect profiles and delayed onset of therapeutic effects. With the aim of developing better antidepressants, numerous drug development approaches are being investigated including blockade of glutamatergic neurotransmission, hallucinogenic compounds and modulation of the opioid system, particularly the kappa opioid (KOP) receptor system. KOP receptor ligands have been investigated as KOP receptors play a role in mediating the response to stress and aversive behaviours. At the outset of this thesis, a few studies had shown evidence for sex differences in aversive behaviours thought to be modulated by the KOP receptors. Due to the presence of sex differences, greater incidence of depression in women, and with the goal of developing better antidepressants, the aim of this thesis was to test the hypothesis that stress-induced dynorphin release activates KOP receptor signalling differentially in male and female rodents to produce behaviours in a sex-dependent manner.

The ability of the KOP receptor agonist U50488 to produce sex-dependent effects was investigated in diuresis studies in rats, behaviourally in mice and by analysis of intracellular signalling in mice. U50488 elicited a diuretic response in both female and male Wistar rats at doses of 3mg/kg and 10mg/kg. The diuretic effects of U50488 at the 10mg/kg dose were significantly higher in water loaded males when compared to their respective female counterparts. Baseline behaviours in the elevated plus maze (EPM) showed sex differences in both adult CD1 and C57BL/6 strains, whereas there were no sex differences in behaviour in the forced swim test (FST). In CD1 mice, U50488 (5mg/kg) showed anxiolytic effects in the EPM in both males and females, anxiolytic effects in the novelty induced hypophagia (NIH) task in males only, and pro-depressant effects in the FST in both males and females. In CD1 mice, females may be more sensitive to U50488 at lower doses (1mg/kg) than males in the FST. In C57BL/6 mice, however there was evidence of both sex and strain differences in the response to U50488 (5mg/kg). In male mice in the EPM, U50488 was anxiolytic but there was no apparent effect in females. When data was segregated by phase of the oestrous cycle, the data indicated that U50488 may be anxiogenic during high oestrogen phases of the oestrous cycle (oestrous/proestrous). In the FST, C57BL/6 mice showed an antidepressant effect to U50488 (5mg/kg) in females only, although the same dose of U50488 (5mg/kg) increased the latency to first immobility in both male and female animals. In the CA1/DG of the dorsal hippocampus from female, but not male, C57BL/6 mice, U50488 (20mg/kg) administration enhanced the phosphorylation of mitogen activated protein kinases (MAPKs), P38 and extracellular regulated kinase 1 and 2 (ERK1/2), identified by semi-quantitative Western blotting. No sex difference was seen in other brain regions investigated which included the prelimbic cortex, nucleus accumbens and anteromedial section of bed nucleus of stria terminalis.

Administration of the short acting KOP receptor antagonist, BU10119, in C57BL/6 mice significantly reduced the duration of immobility in the FST in the female sex only. The male sex was not sensitive to the antidepressant-like effects of BU10119. Although numbers were small, phase of the oestrous cycle did not have an impact on the antidepressant-like effects of BU10119 in female C57BL/6 mice. Taken together these findings suggest that there are significant sex differences in the response to KOP receptor activation, and its blockade, that impact on the development of novel KOP receptor ligands aimed at targeting stress-responsiveness and aversive behaviours. Understanding the cellular mechanisms underlying such sex differences is important in the rational development of targeted antidepressants at the KOP receptor with improved efficacy for women and men.

Date of Award	22 Jun 2022
Original language	English
Awarding Institution	University of Bath
Supervisor	Sarah Bailey (Supervisor), Chris Bailey (Supervisor) & Stephen Husbands (Supervisor)