The Effects of N-Acetylcysteine on the Rat Mesocorticolimbic Pathway: Role of mGluR5 Receptors and Interaction with Ethanol

N-acetylcysteine (NAC) is a prodrug that is marketed as a mucolytic agent and used for the treatment of acetaminophen overdose. Over the last few decades, evidence has been gathered that suggests the potential use of NAC as a new pharmacotherapy for alcohol use disorder (AUD), although its mechanism of action is already being debated. In this paper, we set out to assess both the potential involvement of the glutamate metabotropic receptors (mGluR) in the possible dual effect of NAC administered at two different doses and NAC’s effect on ethanol-induced activation. To this aim, 30 or 120 mg/kg of NAC was intraperitoneally administered to rats with the presence or absence of the negative allosteric modulator of mGluR5 (MTEP 0.1 mg/kg). Thereafter, the cFOS IR-cell expression was analyzed. Secondly, we explored the effect of 120 mg/kg of NAC on the neurochemical and behavioral activation induced by intra-VTA ethanol administration (150 nmol). Our results showed that the high NAC dose stimulated cFOS expression in the NAcc, and that this effect was suppressed in the presence of MTEP, thus suggesting the implication of mGluR5. Additionally, high doses could attenuate the ethanol-induced increase in cFOS-expression in the NAcc, probably due to a phenomenon based on the long-term depression of the MSNs. Additional experiments are required to corroborate our hypothesis.

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Psychedelics and potential benefits in “healthy normals”: A review of the literature

Journal of Psychedelic Studies ◽

10.1556/2054.2019.029 ◽

2019 ◽

Vol 3 (3) ◽

pp. 280-287 ◽

Cited By ~ 1

Author(s):

Sam Gandy

Keyword(s):

Psychological Functioning ◽

Well Being ◽

Future Research ◽

Life Meaning ◽

Potential Development ◽

Potential Benefits ◽

High Doses ◽

And Behavior

We are in the midst of a psychedelic research renaissance. With research examining the efficacy of psychedelics as a treatment for a range of mental health indications still in its early stages, there is an increasing body of research to show that careful use of psychedelics can yield a variety of beneﬁts in “healthy normals” and so lead to “the betterment of well people.” Psychedelics have been found to modulate neuroplasticity, and usage in a supportive setting can result in enduring increases in traits such as well-being, life satisfaction, life meaning, mindfulness, and a variety of measures associated with prosocial behaviors and healthy psychological functioning. The effect of psychedelic experience on measures of personality trait openness and is potential implications is examined, and the potential role of awe as a mediator of the beneﬁts of the psychedelic experience is discussed. Special attention is given to the capacity of psychedelics to increase measures of nature relatedness in an enduring sense, which is being correlated with a broad range of measures of psychological well-being as well as a key predictor of pro-environmental awareness and behavior. The effects of particular classical psychedelic compounds on healthy people are discussed, with special attention given to the mystical-type experiences occasioned by high doses of psychedelics, which appear to be an important mediator of long-term beneﬁts and psychotherapeutic gains. Research looking at the potential beneﬁts of psychedelic microdosing is discussed. Potential future research avenues are explored, focusing on the potential development of psychedelics as agents of ecotherapy.

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Current evidence and the emerging role of eltrombopag in severe aplastic anemia

Therapeutic Advances in Hematology ◽

10.1177/2040620721998126 ◽

2021 ◽

Vol 12 ◽

pp. 204062072199812

Author(s):

Beatrice Drexler ◽

Jakob Passweg

Keyword(s):

Aplastic Anemia ◽

Clonal Evolution ◽

Single Agent ◽

High Rate ◽

Current Evidence ◽

Long Term Effects ◽

Hematopoietic Stem ◽

High Doses

Acquired aplastic anemia (AA) is characterized by a reduced stem cell reserve. Several preclinical studies have confirmed the beneficial effect of thrombopoietin (TPO) on the expansion and maintenance of hematopoietic stem cells (HSCs). Thus, TPO receptor agonists seem to be an ideal therapeutic agent for AA to augment marrow function. First studies with eltrombopag as a single agent at 150 mg/day showed an overall response rate of 40–50% in patients with refractory severe AA (rSAA). Subsequent studies examined the first-line use of eltrombopag together with horse antithymocyte globulin and cyclosporine, reaching response rates up to 94%. Although used at high doses, known adverse events in the form of skin, gastrointestinal, or hepatic impairment are feasible in AA, however first data show a relatively high rate of clonal evolution in the form of karyotypic aberrations in patients with rAA. Nonetheless, there is a strong rationale that eltrombopag can contribute to restoring hematopoiesis in SAA by stimulating HSCs. Further studies are needed to decide if eltrombopag is clearly superior to current established treatments and to determine optimal treatment duration, dosage, and long-term effects.

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DUAL REGULATORY ROLE OF THE THYMUS IN THE MATURATION OF IMMUNE RESPONSE IN THE RABBIT

Journal of Experimental Medicine ◽

10.1084/jem.139.1.108 ◽

1974 ◽

Vol 139 (1) ◽

pp. 108-127 ◽

Cited By ~ 25

Author(s):

Masaru Taniguchi ◽

Tomio Tada

Keyword(s):

Immune Response ◽

T Cells ◽

Antibody Response ◽

Early Stage ◽

Early Adulthood ◽

Antibody Affinity ◽

Specific Antibody Response ◽

Different Doses

Rabbits thymectomized in early adulthood produced more antihapten antibody than sham-thymectomized controls after hyperimmunization with 2,4-dinitrophenyl bovine gamma globulin (DNP-BGG). The average associated constant of anti-DNP antibody produced by thymectomized animals was more than 10 times higher than that of the controls. Similar effects were obtained by extensive treatment of rabbits with antithymocyte serum (ATS) before and during the immunization with DNP-BGG. The results indicated that relative diminution of thymus-derived lymphocytes (T cells) resulted in a stimulation of antibody-forming cells with a higher affinity. On the other hand, preimmunization of rabbits with different doses of BGG caused either enhancement or suppression of the hapten-specific antibody response, depending on the priming dose of BGG. The suppressed antibody response was always associated with a marked decrease in the antibody affinity. If rabbits were partially tolerized with a large dose of soluble BGG, some of the animals produced little antibody against hapten (DNP) coupled to this carrier, and the affinity of produced antibody was low. However, other rabbits tolerized with BGG produced large amounts of anti-DNP antibody upon hyperimmunization with DNP-BGG, whose affinity was only slightly lower than that of the control. These results can be harmonized if it is assumed that the thymus plays an important role in the maturation of the immune response. It is postulated that T cells, in numbers ordinarily available, would first assist in the proliferation of antihapten antibody-forming cell precursors already selected by antigen, thus accounting for the rapid increase of antibody affinity in the early stage of immunization. However, after a larger number of carrier-specific T cells are made in response to continued immunization, these would suppress antibody-forming cells. The suppression would be greater for cells with higher affinity for antigen, resulting in a decrease in antibody affinity. This postulate explains preferential stimulation and suppression of cells having higher affinity receptors under circumstances in which T cell are relatively depleted or overstimulated, and further permits an explanation for the decrease of antibody affinity after long-term immunization.

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The Role of Histamine in Doxorubicin and Teniposide-Induced Cardiotoxicity in Dog and Mouse

Tumori Journal ◽

10.1177/030089168707300312 ◽

1987 ◽

Vol 73 (3) ◽

pp. 279-287 ◽

Cited By ~ 6

Author(s):

Nicola Gebbia ◽

Carla Flandina ◽

Gaetano Leto ◽

Francesca Maria Tumminello ◽

Rosario Sanguedolce ◽

...

Keyword(s):

Histamine Release ◽

Term Treatment ◽

Natural Resistance ◽

Cardiac Damage ◽

Cardiac Effects ◽

Cardiac Morphology ◽

Long Term Treatment ◽

High Doses

In previous studies we reported that teniposide (VM26) induced acute cardiac effects in dogs seem to be related to a release of histamine and that a prior treatment with chlorpheniramine, an H, histamine blocker, prevents the onset of this phenomenon. Since histamine and other vasoactive substances also seem to be involved in doxorubicin (DXR)-induced acute cardiac effects, experiments were undertaken in the aim to prevent, as in the case of VM26, the onset of this phenomenon by administering chlorpheniramine. Since DXR-induced chronic cardiomyopathy also seems to be related to the same mechanisms involved in the onset of acute cardiac effects induced by this drug, additional studies were carried out to investigate whether a long-term treatment with VM26 could induce in mouse alterations of cardiac morphology similar to those of DXR. In addition, because the mouse is known to be extremely insensitive to histamine, further studies were performed to investigate whether DXR or VM26 administration could induce in this animal model a massive histamine release and whether a long-term treatment with high doses of histamine could elicit, similarly to DXR, alterations in cardiac morphology. The results of our experiments demonstrated that DXR (1.5 mg/kg i.v.) caused in the dog a massive histamine release and a marked impairment of cardiac inotropism. As previously described for VM26, prior treatments with chlorpheniramine completely prevented this phenomenon. Furthermore, DXR administration, at a dose level able to induce cardiac damage in the mouse (2.5 mg/kg i.v.), or that of VM26 (2 mg/kg i.v.) failed to induce a massive histamine release. In addition, long-term treatment with VM26 (2 mg/kg i.v.) or high doses of histamine (100 mg/kg i.v.), unlike DXR, did not elicit in this animal alterations of cardiac morphology. Finally, chlorpheniramine (0.15 or 0.45 mg/kg i.v.) did not prevent the onset of chronic cardiomyopathy induced by DXR in mouse. In conclusion, our results show that the role of histamine in the onset of DXR-induced chronic cardiomyopathy, at least in mouse, remains questionable and suggest that this animal, because of its high natural resistance to histamine, is not a suitable experimental model to investigate the cardiovascular pharmacology of drug-induced histamine release.

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Neuromodulators and Long-Term Synaptic Plasticity in Learning and Memory: A Steered-Glutamatergic Perspective

Brain Sciences ◽

10.3390/brainsci9110300 ◽

2019 ◽

Vol 9 (11) ◽

pp. 300 ◽

Cited By ~ 8

Author(s):

Amjad Bazzari ◽

H. Parri

Keyword(s):

Synaptic Plasticity ◽

Learning And Memory ◽

Current Evidence ◽

Metabotropic Receptors ◽

Neuronal Connections ◽

Molecular Substrates ◽

Neuronal Encoding ◽

Review Current

The molecular pathways underlying the induction and maintenance of long-term synaptic plasticity have been extensively investigated revealing various mechanisms by which neurons control their synaptic strength. The dynamic nature of neuronal connections combined with plasticity-mediated long-lasting structural and functional alterations provide valuable insights into neuronal encoding processes as molecular substrates of not only learning and memory but potentially other sensory, motor and behavioural functions that reflect previous experience. However, one key element receiving little attention in the study of synaptic plasticity is the role of neuromodulators, which are known to orchestrate neuronal activity on brain-wide, network and synaptic scales. We aim to review current evidence on the mechanisms by which certain modulators, namely dopamine, acetylcholine, noradrenaline and serotonin, control synaptic plasticity induction through corresponding metabotropic receptors in a pathway-specific manner. Lastly, we propose that neuromodulators control plasticity outcomes through steering glutamatergic transmission, thereby gating its induction and maintenance.

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Effect Long-Term Exposure to Different Doses of Lipopolysaccharides on the Intestinal Mucosal Immune Barrier

10.20944/preprints201910.0335.v1 ◽

2019 ◽

Author(s):

Chao Li ◽

Baoyu Zhao ◽

Chenchen Wu

Keyword(s):

Layer Thickness ◽

Goblet Cells ◽

The Body ◽

Low Grade ◽

Low Doses ◽

Mucus Layer ◽

High Doses ◽

Low Grade Inflammation ◽

Different Doses

The small intestinal villus is covered with a thick layer of mucus that is secreted by goblet cells and functions primarily to first barrier from damage by toxic substance. Recent studies showed that goblet cells and mucins involved in complex immune function. Lipopolysaccharide (LPS) is widespread in the housing of livestock, which can induce bacterial infection symptoms and immunological stress within a short of time. Therefore, we aimed to study the effects of long-term exposure to different doses of LPS on intestinal mucus layer and immune barrier. The result showed that mucus layer thickness and goblet cell functions were significantly increased after low doses of LPS. The intestinal mucosal barrier can block the bacteria of the lumen, but LPS can penetrate this barrier into the blood, putting the body in a state of chronic low-grade inflammation and reducing the body’s immune function. However, after long-term exposure to high doses of LPS, a large number of lysosomes in goblet cells caused loss of function, and mucus layer thickness was significantly decreased. A large amount of LPS stuck to the mucus, leading to normal LPS and inflammatory cytokines level of plasma. The intestinal tissue morphology was damaged, and a number of immune cells were necrosis in the intestine. Collectively, long-term exposure to low doses of LPS lead to chronic low-grade inflammation in the body. Long-term exposure to high doses of LPS can be directly linked to the severity of the immunosuppression in the body.

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