Neurotransmitter-receptor Interactions Research Articles

Exploring neurotransmitters and their receptors for breast cancer prevention and treatment.

While psychological factors have long been linked to breast cancer pathogenesis and outcomes, accumulating evidence is revealing how the nervous system contributes to breast cancer development, progression, and treatment resistance. Central to the psychological-neurological nexus are interactions between neurotransmitters and their receptors expressed on breast cancer cells and other types of cells in the tumor microenvironment, which activate various intracellular signaling pathways. Importantly, the manipulation of these interactions is emerging as a potential avenue for breast cancer prevention and treatment. However, an important caveat is that the same neurotransmitter can exert multiple and sometimes opposing effects. In addition, certain neurotransmitters can be produced and secreted by non-neuronal cells including breast cancer cells that similarly activate intracellular signaling upon binding to their receptors. In this review we dissect the evidence for the emerging paradigm linking neurotransmitters and their receptors with breast cancer. Foremost, we explore the intricacies of such neurotransmitter-receptor interactions, including those that impinge on other cellular components of the tumor microenvironment, such as endothelial cells and immune cells. Moreover, we discuss findings where clinical agents used to treat neurological and/or psychological disorders have exhibited preventive/therapeutic effects against breast cancer in either associative or pre-clinical studies. Further, we elaborate on the current progress to identify druggable components of the psychological-neurological nexus that can be exploited for the prevention and treatment of breast cancer as well as other tumor types. We also provide our perspectives regarding future challenges in this field where multidisciplinary cooperation is a paramount requirement.

Putative Role of Monoaminergic Systems in Antidepressant and Anxiolytic Effects of Naringin in Mice: An Interaction Study with Receptor Antagonists

Aim: Stress-related disorders like depression and anxiety represent one of the greatest therapeutic challenges globally. Although previous studies have revealed the antidepressant-like potentials of naringin, the neurotransmitter receptor interaction mechanisms of action have not been studied, hence, this study was carried out to evaluate the role of neurotransmitter-receptor antagonists in the antidepressant-like effects of naringin in mice.
 Method: Male Swiss mice were subjected to chronic unpredictable mild stress (CUMS) apart from mice in the control group. The mice were then pretreated with different neurotransmitter antagonists; metergoline (4 mg /kg i.p.), a 5-HT1 - and 5-HT2 -receptor antagonist; propranolol; (0.2 mg/kg i.p.), β1,2-noradrenoceptor antagonist or haloperidol (0.2 mg/kg i.p.), D 2 -dopaminergic receptor antagonists prior to the administration of naringin or vehicle (10 mL/kg). The antidepressant-like and anxiolytic effects of naringin were evaluated 30 min later using the tail suspension test (TST), open-field test (OFT), sucrose preference test (SPT) and elevated plus maze (EPM) tests paradigms.
 Results: Administration of naringin following CUMS significantly decrease immobility time and locomotion activity in TST and OFT respectively, relative to control while increasing preference to sucrose in SPT, open arm entries as well as time spent in open arm in EPM, relative to control suggesting antidepressant-like property. Pretreatment with metergoline, propranolol, and haloperidol following CUMS increased immobility time in TST, locomotor activity in OFT and IOAA in the EPM. Reduced preference for sucrose in SPT, open arm entry and duration in EPM relative to control (p < 0.05), however, these effects were attenuated by naringin.
 Conclusion: These findings suggest that the antidepressant-like activity exhibited by naringin might be mediated via interactions with 5-HTergic, noradrenergic, and dopaminergic receptors, while the anxiolytic effect might involve interaction with both 5-HTergic and noradrenergic receptors.

Evaluation of the role of monoaminergic and nonmonoaminergic systems in the psychotropic effects of morin in mice: an interaction study with receptor blockers

Treatment-resistance depression and memory impairment disease, burdened with high levels of serious adverse effects of currently existing antidepressants and memory enhancers, have necessitated the search for alternative agents. Although previous preclinical studies have revealed the antidepressant-like and memory-enhancing potentials of morin, a compound isolated from Morus alba, the neurotransmitter receptor interaction mechanisms of action remain unknown. Hence, the role of monoaminergic and nonmonoaminergic neurotransmitter receptors in the antidepressant-like and memory-enhancing effects in naive mice were evaluated in this study. Male Swiss mice were pretreated intraperitoneally with D2-dopaminergic receptor antagonists (haloperidol), 5-HT1- and 5-HT2-receptor antagonist (metergoline), 5-HT synthesis inhibitor (para-chlorophenylalanine), α1-noradrenoceptor antagonist (prazosin), α2-noradrenoceptor antagonist (yohimbine), or cholinergic receptor antagonist (atropine) prior to the administration of morin (100 mg/kg, i.p.) or vehicle (10 mL/kg, i.p.). The memory-enhancing and antidepressant-like effects were then evaluated 30 min later using the open-field test (OFT), Y-maze test (YMT), and forced swim test (FST). Morin reduced locomotor activity however, it was reversed by metergoline, pCPA, prazosin, yohimbine, haloperidol, and atropine independent of their actions. Morin exhibited antidepressant property in the FST when compared with control (p < 0.05). Metergoline, para-chlorophenylalanine, prazosin, and haloperidol decreased the antidepressant-like activity of morin. Morin showed memory-enhancing effect in the YMT relative to control. Pretreatment with metergoline, para-chlorophenylalanine, or atropine, however, decreased the memory-promoting effect of morin. These findings suggest that the antidepressant-like activity exhibited by morin might be mediated via interactions with 5-HTergic, noradrenergic, and dopaminergic receptors, while the memory-enhancing effect might involve interaction with both 5-HTergic and cholinergic receptors.

Possible Mechanism of the Effects of the Pulsed Electromagnetic Field on Analgesia

With the development of technology, it has become possible for various measuring devices to measure the size of electromagnetic fields nowadays. Therefore, it has been realized that biological creatures are under the influence of electromagnetic fields with increasing intensity. This mini-review aims to state that exposure to a very-low-frequency electromagnetic field affects living beings by using the systems we know and to draw the attention of researchers to this point. While very low frequency Electromagnetic Fields (ELF-EMF) affect living things thermally, researches that living things are made by strengthening or accelerating neurotransmitter-receptor interaction have increased in recent years.

Metabolic Syndrome in Bipolar Disorder: Review and Management

The increased prevalence of metabolic syndrome in bipolar disorder is multifactorial in etiology and has far-reaching implications on illness course, treatment adherence, functioning, and premature mortality. Treatment with mood-stabilizing and antipsychotic medications may contribute to the development of metabolic syndrome in this population. Among mood stabilizers, both lithium and valproate have been associated with weight gain, whereas lamotrigine and carbamazepine are considered weight neutral. Antipsychotic medications afford variable risks, with olanzapine and clozapine ranking highest and newer agents carrying less risk, including aripiprazole, ziprasidone, lurasidone, and cariprazine. Mechanisms underlying the metabolic risks of these medications are similarly variable and for antipsychotics may include neurotransmitter-receptor interactions, actions at receptors associated with hypothalamic control of food intake, and individual genetic risk factors. Management includes close monitoring and behavioral/lifestyle interventions, followed by pharmacologic interventions including switching medications or adding a medication to mitigate weight gain, among which metformin has been most extensively studied. [ Psychiatr Ann . 2020;50(8):334–339.]

Butyrylcholinesterase as a Diagnostic and Therapeutic Target for Alzheimer's Disease.

The serine hydrolase butyrylcholinesterase (BChE), like the related enzyme acetylcholinesterase (AChE), co-regulates metabolism of the neurotransmitter acetylcholine. In the human brain BChE is mainly expressed in white matter and glia and in distinct populations of neurons in regions that are important in cognition and behavior, functions compromised in Alzheimer's disease (AD). AD is a neurodegenerative disorder causing dementia with no cure nor means for definitive diagnosis during life. In AD, BChE is found in association with pathology, such as β-amyloid (Aβ) plaques, particularly in the cerebral cortex where BChE is not normally found in quantity. Up to 30% of cognitively normal older adults have abundant Aβ deposition in the brain. We have designed an imaging agent that can detect, through autoradiography, BChE-associated Aβ plaques in the cerebral cortex of AD brains, but does not visualize Aβ plaques in brains of cognitively normal individuals. Furthermore, in an AD mouse model with BChE gene knocked out, there are up to 70% fewer fibrillar Aβ brain plaques, suggesting diminished BChE activity could prove beneficial as a curative approach to AD. To that end, we have examined numerous N-10-carbonyl phenothiazines that are specific inhibitors of human BChE, revealing important details of the enzyme's active site gorge. These phenothiazines can be designed without potential side effects caused by neurotransmitter receptor interactions. In conclusion, BChE is potentially an important target for diagnosis and treatment of AD.

Selectivity of phenothiazine cholinesterase inhibitors for neurotransmitter systems

Synthetic derivatives of phenothiazine have been used for over a century as well-tolerated drugs against a variety of human ailments from psychosis to cancer. This implies a considerable diversity in the mechanisms of action produced by structural changes to the phenothiazine scaffold. For example, chlorpromazine treatment of psychosis is related to its interaction with dopaminergic receptors. On the other hand, antagonistic action of such drugs on cholinergic receptor systems would be counter-productive for treatment of Alzheimer’s disease. In a search for phenothiazines that are inhibitors of cholinesterases, especially butyrylcholinesterase, with potential to treat Alzheimer’s disease, we wished to ascertain that such molecules could be devoid of neurotransmitter receptor interactions. To that end, a number of our synthetic N-10-carbonyl phenothiazine derivatives, with cholinesterase inhibitory activity, were tested for interaction with a variety of neurotransmitter receptor systems. We demonstrate that phenothiazines can be prepared without significant neurotransmitter receptor interactions while retaining high potency as cholinesterase ligands for treatment of Alzheimer’s disease.

NMR Spectroscopy of the Ligand-Binding Core of Ionotropic Glutamate Receptor 2 Bound to 5-Substituted Willardiine Partial Agonists

Glutamate receptors mediate neuronal intercommunication in the central nervous system by coupling extracellular neurotransmitter–receptor interactions to ion channel conductivity. To gain insight into structural and dynamical factors that underlie this coupling, solution NMR experiments were performed on the bilobed ligand-binding core of glutamate receptor 2 in complexes with a set of willardiine partial agonists. These agonists are valuable for studying structure–function relationships because their 5-position substituent size is correlated with ligand efficacy and extent of receptor desensitization, whereas the substituent electronegativity is correlated with ligand potency. NMR results show that the protein backbone amide chemical shift deviations correlate mainly with efficacy and extent of desensitization. Pronounced deviations occur at specific residues in the ligand-binding site and in the two helical segments that join the lobes by a disulfide bond. Experiments detecting conformational exchange show that micro- to millisecond timescale motions also occur near the disulfide bond and vary largely with efficacy and extent of desensitization. These results thus identify regions displaying structural and dynamical dissimilarity arising from differences in ligand–protein interactions and lobe closure that may play a critical role in receptor response. Furthermore, measures of line broadening and conformational exchange for a portion of the ligand-binding site correlate with ligand EC 50 data. These results do not have any correlate in the currently available crystal structures and thus provide a novel view of ligand-binding events that may be associated with agonist potency differences.

Synthesis and Photophysical Characterization of a New, Highly Hydrophilic Caging Group

o-Nitrobenzyl-protected bioactive compounds are useful tools in biophysics, allowing controlled photorelease of biologically active compounds with high temporal and spatial precision. Thus, it is possible to study biological processes, such as neurotransmitter-receptor interaction, and many other processes, in much more detail than before. In this respect, these caged compounds have become established as extremely useful tools. In some cases, however, their biological properties (the caged compound should not interact with the biological system), their photochemical properties (quantum yield and kinetics of the photorelease), and their physical properties (high hydrophilicity) are not satisfactory. In order to address the last problem, we examined means to increase the hydrophilicity of caged compounds based on the o-nitrobenzyl moiety. Here, we report the synthesis and the photochemical and biological characterization of a new caged D-aspartate derivative with vastly improved hydrophilicity, compared to derivatives reported previously, and satisfactory photophysical properties. Caged compounds with this improved o-nitrobenzyl group may thus represent a valuable new tool for different kinds of biophysical investigations. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Psychobiology and psychopharmacotherapy of unipolar major depression: A review

Psychopharmacology has continually informed the biological perspective of major depression. Antidepressants affect a variety of neurotransmitters by a wide range of pharmacological actions. The complexity of these neurotransmitter receptor interactions likely underlies the discrepancies observed in biochemical and physiological responses among apparently clinically homogenous depressive subgroups. This report provides an integrated review of the neuroendocrine and neurochemical perspectives of unipolar depression and how these advances influence the psychopharmacotherapy of unipolar major depression.

Dopamine D2 receptor upregulation in rat neostriatum following in vivo infusion of forskolin.

Intracerebroventricular (i.c.v.) forskolin infusion for 5 days resulted in a concentration-dependent increase in rat striatal dopamine (DA) D2 receptors measured with [3H]raclopride. In animals given 50 nmol/h forskolin, the highest concentration used, raclopride-mediated suppression of spontaneous locomotor activity was attenuated, and (+/-)-7-hydroxy-dipropyl-aminotetralin HBr (7-OH-DPAT)-mediated inhibition of striatal DA synthesis, as estimated by the accumulation of DOPA following inhibition of cerebral decarboxylase, was enhanced. These data suggest that the DA D2 receptor increase comprises receptors localized both post- and presynaptically. The density of striatal DA D1 receptors was also changed with the forskolin treatment, in a concentration-dependent fashion, but in the opposite direction to DA D2 receptors. These findings suggest that striatal DA receptor sensitivity can be changed by manipulation at the second messenger level (e.g. independent of direct neurotransmitter-receptor interactions) in vivo.

Clinical applications of neurotransmitter-receptor studies in geriatric neuropharmacology.

The use of ligand-binding methods to study neurotransmitter-receptor sites has made its impact on almost all aspects of biological pursuits including research on aging and neurodegenerative diseases. In the past, most of the research in biochemical gerontology has largely centered around changes in various neurotransmitters and enzymatic activities. The molecular basis of aging and neurodegeneration at the level of neurotransmitter-receptor interactions has been highly appreciated in the last two decades as a result of receptor binding studies. It is now possible to obtain information about the regional distribution of neurotransmitter receptors in the brain, the pharmacological and biochemical characteristics of these sites, and the functional interrelationships between different neuronal systems in normal and pathological conditions. The passage of time after maturity is accompanied by measurable physiologic decline in virtually all systems. It is the aim of this work to discuss the practical aspects of neurotransmitter and/or drug (ligand)-receptor binding studies, highlighting some examples of their applications to geriatric neuropharmacology research, with special consideration to learning impairment and memory loss in normal and in pathological aging processes.

Neurotransmitter receptor interactions with G-proteins: A critical link in receptor response mechanisms

The interaction of membrane bound receptors with guanine nucleotide binding regulatory proteins is necessary for the transduction of many extracellular signals across the cell membrane. Age-related impairments of this interaction illustrate that the efficiency of receptor effector coupling is complex, and is an additional factor for consideration in the future study of receptor mediated functions.

Sorption and transport of acetylcholine in reconstituted biomembrane structures

In this work, neurotransmitter transport was studied in structures similar to those found at the neuromuscular junction. Transport and sorption of acetylcholine in a collagenous model of the fibrous matrix of the synaptic cleft were investigated. Sorption level depended upon the degree of swelling of collagen. From diffusion experiments, mobile species concentrations were estimated and found to be roughly independent of the degree of swelling. In contrast, immobile concentrations were proportional to it. These phenomena are explained by two different penetrant binding affinity levels: one, a lower affinity for the mobile species which controls diffusion, and the other a higher affinity for the immobile species. In the range of low acetylcholine concentration, substantial accumulation of acetylcholine in collagen membranes was demonstrated and the effect was strongly amplified in reconstituted acetylcholine receptor-rich membrane vesicles from torpedo fish. Distribution coefficients ranged from 10 (collagen) to 10 3 (receptor vesicles). It is thought that accumulated ligand binding can play an important role in the observed transport of penetrant across biological membranes generally, and in the strength of the neurotransmitter-receptor interaction, in particular.

Reciprocal modulation of agonist and antagonist binding to muscarinic cholinergic receptor by guanine nucleotide.

The ability of guanine nucleotide to decrease the binding affinity of agonists but not antagonists has been documented in a number of hormone and neurotransmitter receptor systems. By contrast, recent reports indicate that both agonist and antagonist binding to the muscarinic cholinergic receptors appear to be regulated in a reciprocal fashion by guanine nucleotide. We document two forms of the muscarinic cholinergic receptor in frog heart, which are present in approximately equal proportions and which display high-agonist/low antagonist and low-agonist/high-antagonist affinities, respectively. Guanine nucleotide appears to convert the former type of site into the latter type. These observations can be interpreted in terms of a model for two interconvertible forms of the muscarinic cholinergic receptor reciprocally favored by agonists and antagonists. This model has implications both for the understanding of neurotransmitter-receptor interactions generally and for the nature of the biological effects of receptor antagonists.

Effects of L-prolyl-L-leucyl-glycinamide (MIF-I) on some neurotransmitter-receptor interactions

Some neurotransmitter-receptor interactions have been studied in an attempt to determine how L-prolyl-L-leucyl-glycinamide (MIF-I) exerts its antiparkinson effect. MIF-I affected neither the contractile responses of isolated mouse vas deferens and guinea pig ileum to noradrenaline, acetylcholine, substance P and histamine, nor the inhibitory effects of dopamine and GABA on the rat vas deferens and guinea pig ileum. MIF-I, as well as L-leucine and Pro-Leu, antagonized the contractile response of the ileum to 5-hydroxytryptamine (5-HT). Behavioural tests were used to examine the action of MIF-I on CNS transmitter-receptor interactions. MIF-I did not modify the circling produced by either dopamine agonists in nigro-striatal lesioned rats of 5-HT agonists in rats with a lesion of the medial raphe nucleus. MIF-I affected neither 5-hydroxytryptophan-induced head twitches in mice, which is a measure of 5-HT receptor stimulation, nor striatally-evoked head turning in the rat, which is a model for brain GABA function. It is concluded that MIF-I, at the doses used, does not directly modify the function of any of the CNS transmitter examined. Other possibilities to explain its antiparkinson action are discussed.

Increased cyclic GMP levels associated with contraction in muscle fibres of the giant barnacle

CYCLIC GMP has been implicated as an intracellular second messenger in a variety of systems. In particular, a number of hormones and neurotransmitters have been shown to raise cellular cyclic GMP levels in vitro1–9. In many of these systems, however, Ca2+ entry seems to be responsible both for the physiological effect of the hormone and for the hormone-stimulated increase in cyclic GMP (refs 4–9). We have investigated the relationship between calcium and cyclic GMP levels in muscles of the giant barnacle Balanus nubilus. This preparation has a number of advantages. Within fairly narrow limits intracellular free calcium levels in the resting muscle are known10. The depolarisation-induced increase in free calcium, and the resulting activation of contraction, have also been extensively documented10,11. In addition, the depolarisation-induced changes in intracellular free calcium can be easily manipulated because the extracellular fluid is the apparent source of the calcium which couples excitation to contraction12. We report here that either KC1 depolarisation or nerve stimulation increases the cyclic GMP content of barnacle muscle. This increase seems to be associated with Ca2+ entry rather than with a neurotransmitter–receptor interaction per se. This is the first report of an increase in cyclic GMP associated with contractile activity in cross-striated muscle.

The role of adaptive regulation in the pathophysiology of psychiatric disease

Publisher Summary This chapter discusses the role of adaptive regulation in the pathophysiology of psychiatric disease. When central biogenic amine synapses are impairedby drugs and normal neurotransmitter–receptor interaction is decreased, the receptor function appears capable of compensatory alterations in sensitivity. By maintaining the integrity of the nerve ending fraction during tissue homogenization, one is able to study the rate of conversion of substrate to transmitter as a function of the physical state of the enzyme. Some drugs induce prompt alterations in enzyme activity in nerve ending regions. Morphine inhibits intrasynaptosomal tryptophanhydroxylase activity without altering the rate of substrate uptake. However, a number of other drugs and treatments do alter tryptophan uptake into nerve endings. Changes induced in transmitter dynamics at the nerve ending somehow affect the rate of enzyme synthesis in the cell bodies, and those changes in amount of enzyme can be seen several days later at the nerve ending. Furthermore, the adaptive mechanisms within the brain are the major impediment to any continuing role in mental disorder for an aberrant metabolite, unless they fail.