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Females are less sensitive than males to the motivational- and dopamine-suppressing effects of kappa opioid receptor activation.

ABSTRACT: The neuropeptide dynorphin (DYN) activates kappa opioid receptors (KORs) in the brain to produce depressive-like states and decrease motivation. KOR-mediated suppression of dopamine release in the nucleus accumbens (NAc) is considered one underlying mechanism. We previously showed that, regardless of estrous cycle stage, female rats are less sensitive than males to KOR agonist-mediated decreases in motivation to respond for brain stimulation reward, measured with intracranial self-stimulation (ICSS). However, the explicit roles of KORs, circulating gonadal hormones, and their interaction with dopamine signaling in motivated behavior are not known. As such, we measured the effects of the KOR agonist U50,488 on ICSS stimulation thresholds before and after gonadectomy (or sham surgery). We found that ovariectomized females remained less sensitive than sham or castrated males to KOR-mediated decreases in brain stimulation reward, indicating that circulating gonadal hormones do not play a role. We used qRT-PCR to examine whether sex differences in gene expression in limbic brain regions are associated with behavioral sex differences. We found no sex differences in Pdyn or Oprk1 mRNA in the NAc and ventral tegmental area (VTA), but tyrosine hydroxylase (Th) mRNA was significantly higher in female compared to male VTA. To further explore sex-differences in KOR-mediated suppression of dopamine, we used fast scan cyclic voltammetry (FSCV) and demonstrated that U50,488 was less effective in suppressing evoked NAc dopamine release in females compared to males. These data raise the possibility that females are protected from KOR-mediated decreases in motivation by an increased capacity to produce and release dopamine.

SUBMITTER: Conway SM

PROVIDER: S-EPMC6339824 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Females are less sensitive than males to the motivational- and dopamine-suppressing effects of kappa opioid receptor activation.

Conway Sineadh M SM Puttick Daniel D Russell Shayla S Potter David D Roitman Mitchell F MF Chartoff Elena H EH

Neuropharmacology 20181205

The neuropeptide dynorphin (DYN) activates kappa opioid receptors (KORs) in the brain to produce depressive-like states and decrease motivation. KOR-mediated suppression of dopamine release in the nucleus accumbens (NAc) is considered one underlying mechanism. We previously showed that, regardless of estrous cycle stage, female rats are less sensitive than males to KOR agonist-mediated decreases in motivation to respond for brain stimulation reward, measured with intracranial self-stimulation (I ...[more]

PMID: 30528327

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Project description:Kappa Opioid receptors（KORs） belong to family A of G-protein–coupled receptors (GPCRs), and the involvement of their ligands in analgesia and sedation has been extensively studied. KORs, which are expressed in the central and peripheral nervous systems are well known to exert potent anti-nociceptive effects by negatively modulating excitatory neurotransmission. The present study reveals that acute activation of KOR weaken SERT function via protein kinase B/Akt (Akt) and calcium calmodulin dependent kinase II (CaMKII) dependent signaling pathways. Therefore, studying phosphorylation will be helpful to elucidate the cellular mechanisms and downstream effector(s). Studies correlating the dysphoric effects of KOR agonists to the G-protein–independent activation of the p38 MAPK pathway suggest that identification of KOR agonists biased to G-protein–mediated signaling could lead to the development of therapeutics with reduced side effects. Therefore, to better understand the cellular mechanisms and downstream effector(s) by which KOR ligands produce these effects, we employed dimethyl labeling quantitative proteomic approach in this study. In this study, three monoclonal HEK293T cell lines with KOR over-expression were successfully constructed as our experimental models. Then, mass spectrometry-based quantitative approach, based on dimethyl labeling and TiO2 beads-coupled phosphopeptides enrichment, was utilized to analyze the KOR-mediated dynamic phosphorylation network in these three KOR-over-expressed monoclonal cell lines disturbed by LPK-26 or U50,488 treatments. Further Substrate-kinase prediction analysis of 212 up-regulated phosphosites indicated that 18 kinases, such as AKT1 and p70S6K, were involved in the up-regulation of KOR phosphorylation. The up-regulated phosphorylation of AKT1 and p70S6K were further confirmed by western blot, which was consistent with our mass spectrometry results. In summary, quantitative phosphoproteomic study of KOR-over-expressed cells upon agonist stimulation paves the way to systematical investigation of KOR-mediated phosphorylation network dynamics, which will be helpful to research about targeted therapy of KOR related diseases and mechanism study of analgesia addiction.

Project description:BackgroundFertility preservation is an important healthcare focus in the paediatric and adolescent population when gonadotoxic treatments are required. Ovarian stimulation (OS) resulting in oocyte cryopreservation is a well-established fertility preservation option in the adult population. It's utility, however, is little known in young patients. The purpose of this review was to synthesise the available literature on OS in patients ≤18 years old, to identify gaps in current research and provide suggestions for future research directions.MethodsUsing PRISMA guidelines, a systematic review of the literature was performed for all relevant full-text articles published in English in Medline, Embase, the Cochrane Library and Google Scholar databases. The search strategy used a combination of subject headings and generic terms related to the study topic and population. Two reviewers independently screened studies for eligibility, extracted data and assessed the risk of bias. Characteristics of the studies, objectives and key findings were extracted and summarised in a narrative synthesis.ResultsDatabase search and manual review identified 922 studies, 899 were eliminated based on defined exclusion criteria. Twenty-three studies were included and comprised 468 participants aged ≤18 years who underwent OS (median 15.2, range 7-18 years old). Only three patients were premenarchal, and four patients were on treatment to suppress puberty. Patients had OS for a broad range of indications including oncology treatment, transgender care and Turner syndrome. A total of 488 cycles of OS were completed, with all but 18 of these cycles (96.3%) successfully resulting in cryopreserved mature oocytes (median 10 oocytes, range 0-35). Fifty-three cycles (9.8%) were cancelled. Complications were rare (<1%). One pregnancy was reported from a female who had OS aged 17 years old.ConclusionThis systematic review demonstrates that OS and oocyte cryopreservation is achievable in young females however there are only a few cases in the literature describing OS in premenarcheal children or those who have suppressed puberty. There is little proof that OS can lead to pregnancy in adolescents, and no proof that this can be achieved in premenarchal girls. Therefore it should be regarded as an innovative procedure for adolescents and experimental for premenarcheal girls.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=265705, identifier CRD42021265705.

Dataset Information

Females are less sensitive than males to the motivational- and dopamine-suppressing effects of kappa opioid receptor activation.

Publications

Females are less sensitive than males to the motivational- and dopamine-suppressing effects of kappa opioid receptor activation.

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