Oxidized soluble guanylyl cyclase causes erectile dysfunction in alcoholic mice.

Background And Purpose: Alcohol abuse has been associated with erectile dysfunction (ED), but the implicated molecular mechanisms are unresolved. This study analyses the role of alterations in soluble guanylyl cyclase (sGC) in ED.

Experimental Approach: ED was analysed in adult male C57BL/6J mice subjected to the Chronic Intermittent Ethanol (CIE) paradigm.

Influx of kynurenine into the brain is involved in the reduction of ethanol consumption induced by Ro 61-8048 after chronic intermittent ethanol in mice.

Background And Purpose: The kynurenine pathway has been proposed as a target for modulating drug abuse. We previously demonstrated that inhibition of kynurenine 3-monooxygenase (KMO), using Ro 61-8048, reduces ethanol consumption in a binge drinking model. Here, we investigate the effect of the kynurenine pathway modulation in ethanol-dependent mice.

Decreased kynurenine pathway potentiate resilience to social defeat effect on cocaine reward.

The kynurenine (KYN) pathway of tryptophan (TRP) degradation is activated by stress and inflammatory factors. It is now well established that social stress induces the activation of the immune system, with central inflammation and KYN metabolism being two of the main factors linking stress with depression. The aim of the present study was to evaluate the long-lasting changes in the KYN pathway induced by social defeat (SD) associated with the resilience or susceptibility to an increase in the conditioned rewarding effects of cocaine.

Addiction and the kynurenine pathway: A new dancing couple?

Drug use poses a serious threat to health systems throughout the world and the number of consumers rises relentlessly every year. The kynurenine pathway, main pathway of tryptophan degradation, has drawn interest in this field due to its relationship with addictive behaviour. Recently it has been confirmed that modulation of kynurenine metabolism at certain stages of the pathway can reduce, prevent or abolish drug seeking-like behaviours in studies with several different drugs.

Plasma tryptophan and kynurenine pathway metabolites in abstinent patients with alcohol use disorder and high prevalence of psychiatric comorbidity.

Background: Alterations in tryptophan (TRP) metabolism has been linked to drug exposure and mental disorders. However, most of studies have been performed without considering the co-occurrence of both disorders in the context of addiction. This cross-sectional study examines TRP metabolism through the serotonin (5-HT) and kynurenine (KYN) pathways in subjects with alcohol use disorders (AUD) and high prevalence of psychiatric comorbidity.

Serotonin is the main tryptophan metabolite associated with psychiatric comorbidity in abstinent cocaine-addicted patients.

The lack of effective treatments and a high rate of relapse in cocaine addiction constitute a major health problem. The present study was conducted to examine the expression of tryptophan-derived metabolites in the context of cocaine addiction and psychiatric comorbidity, which is common in addicted subjects. Abstinent patients with cocaine use disorder (CUD) and control subjects were recruited for a cross-sectional study.

Changes in brain kynurenine levels gut microbiota and gut-barrier disruption induced by chronic ethanol exposure in mice.

Inflammatory processes have been shown to modify tryptophan (Trp) metabolism. Gut microbiota appears to play a significant role in the induction of peripheral and central inflammation. Ethanol (EtOH) exposure alters gut permeability, but its effects on Trp metabolism and the involvement of gut microbiota have not been studied.

Increasing kynurenine brain levels reduces ethanol consumption in mice by inhibiting dopamine release in nucleus accumbens.

Recent research suggests that ethanol (EtOH) consumption behaviour can be regulated by modifying the kynurenine (KYN) pathway, although the mechanisms involved have not yet been well elucidated. To further explore the implication of the kynurenine pathway in EtOH consumption we inhibited kynurenine 3-monooxygenase (KMO) activity with Ro 61-8048 (100 mg/kg, i.p.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) produces edema due to BBB disruption induced by MMP-9 activation in rat hippocampus.

The recreational drug of abuse, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier (BBB) integrity in rats through an early P2X receptor-mediated event which induces MMP-9 activity. Increased BBB permeability often causes plasma proteins and water to access cerebral tissue leading to vasogenic edema formation. The current study was performed to examine the effect of a single neurotoxic dose of MDMA (12.

Disruption of blood-brain barrier integrity in postmortem alcoholic brain: preclinical evidence of TLR4 involvement from a binge-like drinking model.

Inflammatory cytokines and reactive oxygen species are reported to be involved in blood-brain barrier (BBB) disruption. Because there is evidence that ethanol (EtOH) induces release of free radicals, cytokines and inflammatory mediators we examined BBB integrity and matrix metalloproteinase (MMP) activity in postmortem human alcoholic brain and investigated the role of TLR4 signaling in BBB permeability in TLR4-knockout mice under a binge-like EtOH drinking protocol. Immunohistochemical studies showed reduced immunoreactivity of the basal lamina protein, collagen-IV and of the tight junction protein, claudin-5 in dorsolateral prefrontal cortex of alcoholics.

Effects of repeated social defeat on adolescent mice on cocaine-induced CPP and self-administration in adulthood: integrity of the blood-brain barrier.

Social stress in adulthood enhances cocaine self-administration, an effect that has been related with an increase in extracellular signal-regulated kinase and p38α mitogen-activated protein kinase phosphorylation. A detrimental effect of cocaine on blood-brain barrier (BBB) integrity has also been reported. This study evaluates the effects of repeated social defeat (RSD) during adolescence on the reinforcing and motivational effects of cocaine in adult mice and the changes induced by RSD on BBB permeability.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier integrity through a mechanism involving P2X7 receptors.

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') produces a neuro-inflammatory response in rats characterized by an increase in microglial activation and IL-1β levels. The integrity of the blood-brain barrier (BBB) is important in preserving the homeostasis of the brain and has been shown to be affected by neuro-inflammatory processes. We aimed to study the effect of a single dose of MDMA on the activity of metalloproteinases (MMPs), expression of extracellular matrix proteins, BBB leakage and the role of the ionotropic purinergic receptor P2X7 (P2X7R) in the changes induced by the drug.

The JNK inhibitor, SP600125, potentiates the glial response and cell death induced by methamphetamine in the mouse striatum.

This study investigates the effect of the selective Jun NH2-terminal kinase 1/2 (JNK1/2) inhibitor, (SP600125) on the striatal dopamine nerve terminal loss and on the increased interleukin-15 (IL-15) expression and glial response induced by methamphetamine (METH). Mice were given repeated low doses of METH (4 mg/kg, i.p.

A study on the effect of JNK inhibitor, SP600125, on the disruption of blood-brain barrier induced by methamphetamine.

Methamphetamine (METH) is a widely consumed drug with high abuse potential. Studies in animals have shown that the drug produces dopaminergic neurotoxicity following both single high-dose and repeated low-dose administration. In addition, METH produces an increase in matrix metalloproteinase expression and loss of BBB integrity.

Sex-dependent maternal deprivation effects on brain monoamine content in adolescent rats.

Rats subjected to a single prolonged episode of maternal deprivation (MD) [24h, postnatal days 9-10] show, later in life, behavioural alterations that resemble specific signs of schizophrenia and other neuropsychiatric signs including increased levels of impulsivity and an apparent difficulty to cope with stressful situations. Some of these behavioural modifications are observable in the periadolescent period. However there is no previous information regarding the possible underlying neurochemical correlates at this critical developmental period.

Evidence that MDMA ('ecstasy') increases cannabinoid CB2 receptor expression in microglial cells: role in the neuroinflammatory response in rat brain.

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') produces selective long-lasting serotonergic neurotoxicity in rats. The drug also produces acute hyperthermia which modulates the severity of the neurotoxic response. In addition, MDMA produces signs of neuroinflammation reflected as microglial activation and an increase in the release of interleukin-1beta, the latter of which appears to be a consequence of the hyperthermic response and to be implicated in the neurotoxicity induced by the drug.

Administration of neurotoxic doses of MDMA reduces sensitivity to ethanol and increases GAT-1 immunoreactivity in mice striatum.

Rationale: Mice with reduced dopamine activity following neurotoxic doses of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') consume more ethanol (EtOH) and show greater preference for EtOH. In keeping with human studies and other animal models where alcohol consumption and preference are also high, MDMA treatment will reduce sensitivity to certain physiological effects of EtOH.

Objective: We have examined the sensitivity to the acute effects of EtOH in MDMA-lesioned mice and the effects of EtOH on striatal gamma-aminobutyric acid (GABA) accumulation and expression of GABA subtype-1 transporter (GAT-1).

Administration of MDMA to ethanol-deprived rats increases ethanol operant self-administration and dopamine release during reinstatement.

Recreational use of (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often associated with other drugs, among which ethanol (EtOH) is one of the most common. However, little is known about how neurochemical sensitization produced by MDMA can modulate EtOH abuse. In this study we used EtOH operant self-administration tasks to investigate the effect of several low doses (0.

MDMA-induced neurotoxicity: long-term effects on 5-HT biosynthesis and the influence of ambient temperature.

1. 3,4-Methylenedioxymethamphetamine (MDMA or 'ecstasy') decreases the 5-HT concentration, [3H]-paroxetine binding and tryptophan hydroxylase activity in rat forebrain, which has been interpreted as indicating 5-HT neurodegeneration. This has been questioned, particularly the 5-HT loss, as MDMA can also inhibit tryptophan hydroxylase.

A comparative study on the acute and long-term effects of MDMA and 3,4-dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in mice.

1. This study investigated whether the immediate and long-term effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in mouse brain are due to the parent compound and the possible contribution of a major reactive metabolite, 3,4-dihydroxymethamphetamine (HHMA), to these changes. The acute effect of each compound on rectal temperature was also determined.

Neonatal guanethidine sympathectomy suppresses autotomy and prevents changes in spinal and supraspinal monoamine levels induced by peripheral deafferentation in rats.

In the rat, sciatic and saphenous nerve section resulted in self-mutilation of the ipsilateral limb. Fifteen and 60 days after surgery, monoamine levels were altered not only in the spinal cord but also in supraspinal structures. Thus, in the ipsi- and contralateral sides of the spinal lumbar region, an increase in the levels of 5-hydroxyindoleacetic acid (5-HIAA) was observed 15 days after surgery and in the levels of serotonin (5-HT) and noradrenaline 60 days later.