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International Journal of Molecular... Feb 2024Prolactin (PRL) is a pleiotropic hormone released from lactotrophic cells of the anterior pituitary gland that also originates from extrapituitary sources and plays an... (Review)
Review
Prolactin (PRL) is a pleiotropic hormone released from lactotrophic cells of the anterior pituitary gland that also originates from extrapituitary sources and plays an important role in regulating lactation in mammals, as well as other actions. Acting in an endocrine and paracrine/autocrine manner, PRL regulates the hypothalamic-pituitary-ovarian axis, thus influencing the maturation of ovarian follicles and ovulation. This review provides a detailed discussion of the current knowledge on the role of PRL in the context of ovulation and ovulatory disorders, particularly with regard to hyperprolactinemia, which is one of the most common causes of infertility in women. Much attention has been given to the PRL structure and the PRL receptor (PRLR), as well as the diverse functions of PRLR signaling under normal and pathological conditions. The hormonal regulation of the menstrual cycle in connection with folliculogenesis and ovulation, as well as the current classifications of ovulation disorders, are also described. Finally, the state of knowledge regarding the importance of TIDA (tuberoinfundibular dopamine), KNDγ (kisspeptin/neurokinin B/dynorphin), and GnRH (gonadotropin-releasing hormone) neurons in PRL- and kisspeptin (KP)-dependent regulation of the hypothalamic-pituitary-gonadal (HPG) axis in women is reviewed. Based on this review, a rationale for influencing PRL signaling pathways in therapeutic activities accompanying ovulation disorders is presented.
Topics: Animals; Female; Humans; Kisspeptins; Mammals; Ovulation; Pituitary Gland, Anterior; Prolactin; Receptors, Prolactin
PubMed: 38396659
DOI: 10.3390/ijms25041976 -
Addiction Biology Feb 2024Adolescent alcohol use is a strong predictor for the subsequent development of alcohol use disorders later in life. Additionally, adolescence is a critical period for...
Adolescent alcohol use is a strong predictor for the subsequent development of alcohol use disorders later in life. Additionally, adolescence is a critical period for the onset of affective disorders, which can contribute to problematic drinking behaviours and relapse, particularly in females. Previous studies from our laboratory have shown that exposure to adolescent intermittent ethanol (AIE) vapour alters glutamatergic transmission in the bed nucleus of the stria terminalis (BNST) and, when combined with adult stress, elicits sex-specific changes in glutamatergic plasticity and negative affect-like behaviours in mice. Building on these findings, the current work investigated whether BNST stimulation could substitute for stress exposure to increase the latency to consume a palatable food in a novel context (hyponeophagia) and promote social avoidance in adult mice with AIE history. Given the dense connections between the BNST and the parabrachial nucleus (PBN), a region involved in mediating threat assessment and feeding behaviours, we hypothesized that increased negative affect-like behaviours would be associated with PBN activation. Our results revealed that the chemogenetic stimulation of the dorsolateral BNST induced hyponeophagia in females with AIE history, but not in female controls or males of either group. Social interaction remained unaffected in both sexes. Notably, this behavioural phenotype was associated with higher activation of calcitonin gene-related peptide and dynorphin cells in the PBN. These findings provide new insights into the neurobiological mechanisms underlying the development of negative affect in females and highlight the potential involvement of the BNST-PBN circuitry in regulating emotional responses to alcohol-related stimuli.
Topics: Male; Mice; Female; Animals; Parabrachial Nucleus; Alcoholism; Septal Nuclei; Ethanol
PubMed: 38380710
DOI: 10.1111/adb.13366 -
BioRxiv : the Preprint Server For... Feb 2024The role of the dynorphin/kappa opioid receptor (KOR) system in dopamine (DA) regulation has been extensively investigated. KOR activation reduces extracellular DA...
The role of the dynorphin/kappa opioid receptor (KOR) system in dopamine (DA) regulation has been extensively investigated. KOR activation reduces extracellular DA concentrations and increases DA transporter (DAT) activity and trafficking to the membrane. To explore KOR influences on real-time DA fluctuations, we used the photosensor dLight1.2 with fiber photometry in the nucleus accumbens (NAc) core of freely moving male and female C57BL/6 mice. First, we established that the rise and fall of spontaneous DA signals were due to DA release and reuptake, respectively. Then mice were systemically administered the KOR agonist U50,488H (U50), with or without pretreatment with the KOR antagonist aticaprant (ATIC). U50 reduced both the amplitude and width of spontaneous signals in males, but only reduced width in females. Further, the slope of the correlation between amplitude and width was increased in both sexes, suggesting that DA uptake rates were increased. U50 also reduced the frequency of signals in both males and females. All effects of KOR activation were stronger in males. Overall, KORs exerted significant inhibitory control over spontaneous DA signaling, acting through at least three mechanisms - inhibiting DA release, promoting DAT-mediated uptake, and reducing the frequency of signals.
PubMed: 38370660
DOI: 10.1101/2024.02.05.578840 -
International Journal of Molecular... Jan 2024Tobacco smoking is the leading cause of preventable death and disease. Although there are some FAD-approved medicines for controlling smoking, the relapse rate remains... (Review)
Review
Tobacco smoking is the leading cause of preventable death and disease. Although there are some FAD-approved medicines for controlling smoking, the relapse rate remains very high. Among the factors that could induce nicotine relapse, stress might be the most important one. In the last decades, preclinical studies have generated many new findings that lead to a better understanding of stress-induced relapse of nicotine-seeking. Several molecules such as α3β4 nicotinic acetylcholine receptor, α2-adrenergic receptors, cannabinoid receptor 1, trace amine-associated receptor 1, and neuropeptide systems (corticotropin-releasing factor and its receptors, dynorphine and kappa opioid receptor) have been linked to stress-induced nicotine relapse. In this review, we discuss recent advances in the neurobiology, treatment targets, and potential therapeutics of stress-induced nicotine relapse. We also discuss some factors that may influence stress-induced nicotine relapse and that should be considered in future studies. In the final section, a perspective on some research directions is provided. Further investigation on the neurobiology of stress-induced nicotine relapse will shed light on the development of new medicines for controlling smoking and will help us understand the interactions between the stress and reward systems in the brain.
Topics: Humans; Nicotine; Tobacco Use Disorder; Reward; Corticotropin-Releasing Hormone; Recurrence; Receptors, Nicotinic
PubMed: 38338760
DOI: 10.3390/ijms25031482 -
Nature Communications Jan 2024The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for...
The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for episodic, spatial, and associative memory, and has been shown to be necessary for context- and cue-associated reward behaviors. The nucleus accumbens (NAc), a central structure in the mesolimbic reward pathway, integrates the salience of aversive and rewarding stimuli. Despite extensive research on dHPC→NAc direct projections, their sufficiency in driving reinforcement and reward-related behavior remains to be determined. Our study establishes that activating excitatory neurons in the dHPC is sufficient to induce reinforcing behaviors through its direct projections to the dorso-medial subregion of the NAc shell (dmNAcSh). Notably, dynorphin-containing neurons specifically contribute to dHPC-driven reinforcing behavior, even though both dmNAcSh dynorphin- and enkephalin-containing neurons are activated with dHPC stimulation. Our findings unveil a pathway governing reinforcement, advancing our understanding of the hippocampal circuity's role in reward-seeking behaviors.
Topics: Nucleus Accumbens; Dynorphins; Hippocampus; Reward; Neurons; Phospholipid Ethers
PubMed: 38286800
DOI: 10.1038/s41467-024-44836-9 -
BioRxiv : the Preprint Server For... Jan 2024Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing...
Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing fear-related behavioral states. Dynorphin (Dyn) has been implicated in mediating negative affect and mal-adaptive behaviors induced by severe threats and is expressed in limbic circuits, including the vmPFC. However, there is a critical knowledge gap in our understanding of how vmPFC Dyn-expressing neurons and Dyn transmission detect threats and regulate expression of defensive behaviors. Here, we demonstrate that Dyn cells are broadly activated by threats and release Dyn locally in the vmPFC to limit passive defensive behaviors. We further demonstrate that vmPFC Dyn-mediated signaling promotes a switch of vmPFC networks to a fear-related state. In conclusion, we reveal a previously unknown role of vmPFC Dyn neurons and Dyn neuropeptidergic transmission in suppressing defensive behaviors in response to threats via state-driven changes in vmPFC networks.
PubMed: 38283686
DOI: 10.1101/2024.01.08.574700 -
Frontiers in Neurology 2023A lack of treatment options for temporal lobe epilepsy (TLE) demands an urgent quest for new therapies to recover neuronal damage and reduce seizures, potentially... (Review)
Review
A lack of treatment options for temporal lobe epilepsy (TLE) demands an urgent quest for new therapies to recover neuronal damage and reduce seizures, potentially interrupting the neurotoxic cascades that fuel hyper-excitability. Endogenous opioids, along with their respective receptors, particularly dynorphin and kappa-opioid-receptor, present as attractive candidates for controlling neuronal excitability and therapeutics in epilepsy. We perform a critical review of the literature to evaluate the role of opioids in modulating microglial function and morphology in epilepsy. We find that, in accordance with anticonvulsant effects, acute opioid receptor activation has unique abilities to modulate microglial activation through toll-like 4 receptors, regulating downstream secretion of cytokines. Abnormal activation of microglia is a dominant feature of neuroinflammation, and inflammatory cytokines are found to aggravate TLE, inspiring the challenge to alter microglial activation by opioids to suppress seizures. We further evaluate how opioids can modulate microglial activation in epilepsy to enhance neuroprotection and reduce seizures. With controlled application, opioids may interrupt inflammatory cycles in epilepsy, to protect neuronal function and reduce seizures. Research on opioid-microglia interactions has important implications for epilepsy and healthcare approaches. However, preclinical research on opioid modulation of microglia supports a new therapeutic pathway for TLE.
PubMed: 38249734
DOI: 10.3389/fneur.2023.1298489 -
Journal of Molecular Neuroscience : MN Jan 2024Although the antidepressant-like effect of magnolol has been revealed in previous reports, the mechanism remains unclear. In this study, the antidepressant-like effect...
Although the antidepressant-like effect of magnolol has been revealed in previous reports, the mechanism remains unclear. In this study, the antidepressant-like effect of magnolol on corticosterone-induced (CORT-induced) mice was investigated in vivo. After 21 days of CORT induction, the mice showed marked depressive-like behaviors, with a decrease in sucrose preference score and an increase in immobility time in the tail suspension test (TST) and forced swimming test (FST). Pretreatment with either magnolol (50 mg/kg, i.p.) or the kappa opioid receptor (KOR) antagonist nor-BNI (10 mg/kg, i.p.) prevented CORT-induced depression-like behavior and reduced CORT-induced dynorphin (DYN A) elevation in the hippocampal ventral DG. However, no depression-like behavior was observed in mice with KOR downregulation in the ventral DG. We further found that upregulation of DYN A in the DG caused depression-like behavior, which was blocked by intraperitoneal injection of nor-BNI and modulated by magnolol. The present study demonstrated that magnolol could ameliorate CORT-induced depression-like behaviors, by modulating the DYN A/KOR system in the ventral DG of the hippocampus.
Topics: Animals; Mice; Depression; Antidepressive Agents; Biphenyl Compounds; Corticosterone
PubMed: 38183534
DOI: 10.1007/s12031-023-02185-0 -
Endocrinology Dec 2023There is considerable evidence that synchronized activity within a reciprocally connected population of cells in the arcuate nucleus (ARC) coexpressing kisspeptin,... (Review)
Review
There is considerable evidence that synchronized activity within a reciprocally connected population of cells in the arcuate nucleus (ARC) coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy cells) is crucial for the generation of gonadotrophin-releasing hormone (GnRH) pulses in mammals. The initial "KNDy hypothesis" proposed that pulsatile GnRH secretion is elicited by episodic kisspeptin release from KNDy cells following synchronized activation and termination of the population by NKB and dynorphin, respectively. Since then, the role of KNDy cells as a critical component of the pulse generator has been further supported by studies at the single-cell level, demonstrating that the population is both necessary and sufficient for pulsatility. In addition, there have been considerable modifications and expansion of the original hypothesis, including work demonstrating the critical role of glutamate in synchronization of the KNDy cell network, functional interactions with other ARC subpopulations, and the existence of species differences in the role of dynorphin in pulse generation. Here we review these recent changes and discuss how the translation of these findings has led to the development of new therapies for disorders related to pulse generation. We also outline critical gaps in knowledge that are currently limiting the application of KNDy research in the clinic, particularly regarding the role of dynorphin in pulse generation in primates.
Topics: Animals; Gonadotropin-Releasing Hormone; Dynorphins; Kisspeptins; Hypothalamus; Arcuate Nucleus of Hypothalamus; Neurokinin B; Neurons; Mammals
PubMed: 38170643
DOI: 10.1210/endocr/bqad194 -
Free Radical Biology & Medicine Feb 2024Opioids regulate various physiological and pathophysiological functions, including cell proliferation, immune function, obesity, and neurodegenerative disorders. They...
Opioids regulate various physiological and pathophysiological functions, including cell proliferation, immune function, obesity, and neurodegenerative disorders. They have been used for centuries as a treatment for severe pain, binding to opioid receptors a specific G protein-coupled receptor. Common opioids, like β-endorphin, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), and dynorphins, have analgesic effects. The use of a potent antagonist, like naltrexone hydrochloride, to block the effects of mu Opioid Receptor (μOR) may result in the withdrawal of physiological effects and could potentially impact immune responses in many diseases including respiratory disease. Asthma is a respiratory disease characterized by airway hyperresponsiveness, inflammation, bronchoconstriction, chest tightness, stress generation and release of various cytokines. Airway inflammation leads recruitment and activation of immune cells releasing mediators, including opioids, which may modulate inflammatory response by binding to their respective receptors. The study aims to explore the role of μOR antagonist (naltrexone) in regulating asthma pathophysiology, as the regulation of immune and inflammatory responses in asthma remains unclear. Balb/c mice were sensitized intranasally by 1% TDI and challenged with 2.5% TDI. Naltrexone hydrochloride (1 mg/kg body weight) was administered through intraperitoneal route 1 h before TDI induction. Blocking μOR by naltrexone exacerbates airway inflammation by recruiting inflammatory cells (lymphocytes and neutrophils), enhancing intracellular Reactive oxygen species in bronchoalveolar lavage fluid (BALF), and inflammatory mediator (histamine, Eosinophil peroxidase and neutrophil elastase) in lungs. Naltrexone administration modulated inflammatory cytokines (TNF-α, IL-4, IL-5, IL-6, IL-10, and IL-17A), and enhanced IgE and CRP levels. Naltrexone administration also increased the expression of NF-κB, and phosphorylated p-P38, p-Erk, p-JNK and NF-κB by inhibiting the μOR. Docking study revealed good binding affinity of naltrexone with μOR compared to δ and κ receptors. In future it might elucidate potential therapeutic against many respiratory pathological disorders. In conclusion, μOR blocking by naltrexone regulates and implicates inflammation, bronchoconstriction, and lung physiology.
Topics: Animals; Mice; Naltrexone; NF-kappa B; Receptors, Opioid, mu; Disease Models, Animal; Asthma; Inflammation; Lung; Cytokines; Oxidative Stress; Mice, Inbred BALB C; Ovalbumin
PubMed: 38142953
DOI: 10.1016/j.freeradbiomed.2023.12.023