Lucyna Pomierny-Chamioło

The involvement of serotonergic system in the antidepressant effect of zinc in the forced swim test.

Recent preclinical data indicated the antidepressant-like activity of zinc in different tests and models of depression. The present study investigates the involvement of the serotonergic system in zinc activity in the forced swim test (FST) in mice and rats. The combined treatment of sub-effective doses of zinc (hydroaspartate, 2.5 mg Zn/kg) and citalopram (15 mg/kg), fluoxetine (5 mg/kg) but not with reboxetine (2.5 mg/kg) significantly reduces the immobility time in the FST in mice. These treatments had no influence on the spontaneous locomotor activity. Moreover, while the antidepressant-like effect of zinc (5 mg/kg) in the FST was significantly blocked by pretreatment with inhibitor of serotonin synthesis, p-chlorophenylalanine (pCPA, 3x200 mg/kg), 5HT-2(A/C) receptor antagonist, ritanserin (4 mg/kg) or 5HT-1A receptor antagonist, WAY 1006335 (0.1 mg/kg), the zinc-induced reduction in the locomotor activity was not affected by these serotonin modulator agents. These results indicate the specific involvement of the serotonergic system in antidepressant but not the motion behavior of zinc in mice. Also, an increase in the swimming but not climbing parameter of the rat FST observed following zinc administration (2.5 and 5 mg Zn/kg) indicates the serotonin pathway participation. This present data indicates that the antidepressant-like activity of zinc observed in the FST involves interaction with the serotonergic system.

Oxidative Stress Biomarkers in Some Rat Brain Structures and Peripheral Organs Underwent Cocaine

Oxidative stress (OS) generates or intensifies cocaine-evoked toxicity in the brain and peripheral organs. The aim of this study was to examine superoxide dismutase (SOD) activity and lipid peroxidation [measured by malondialdehyde (MDA) levels] in rats during maintenance of cocaine self-administration and after withdrawal by a yoked-triad procedure. Our results indicate that repeated cocaine self-administration provoked an elevation of SOD activity in the hippocampus, frontal cortex, dorsal striatum, and liver. MDA levels were reduced in the brain, increased in the liver, kidney, and heart during maintenance of self-administration, and increased in the kidney in cocaine-yoked rats. In addition, following extinction training, we found enhanced MDA levels and SOD activity in the rat hippocampus, while changes in the activity of OS biomarkers in other brain structures and peripheral tissues were reminiscent of the changes seen during cocaine self-administration. These findings highlight the association between OS biomarkers in motivational processes related to voluntary cocaine intake in rats. OS participates in memory and learning impairments that could be involved in drug toxicity and addiction mechanisms. Therefore, further studies are necessary to address protective mechanisms against cocaine-induced brain and peripheral tissue damage.

Zinc-induced adaptive changes in NMDA/glutamatergic and serotonergic receptors

Preclinical data indicate the involvement of glutamatergic and serotonergic pathways in the antidepressant activity of zinc. The present study investigated alterations in N-methyl-D-aspartate (NMDA)/glutamatergic and serotonergic receptors (using radioligand binding) induced by chronic treatment (14-day) with zinc hydroaspartate (65 mg/kg). Moreover, the mRNA and protein levels of brain-derived neurotrophic factor (BDNF) were also assessed. Chronic zinc administration reduced the affinity of glycine to glycine/NMDA receptors in the rat frontal cortex and increased the density of 5-HT(1A) and 5-HT(2A) serotonin receptors in the hippocampus and frontal cortex, respectively. These receptor alterations may be in part due to increased BDNF mRNA and protein levels in the rat frontal cortex. These results indicate that chronic zinc treatment alters glutamatergic and serotonergic systems, which is a hallmark of clinically effective antidepressants.

NMDA but not AMPA glutamatergic receptors are involved in the antidepressant-like activity of MTEP during the forced swim test in mice

Several lines of evidence suggest an antidepressant-like activity for 3-[(methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP), a highly selective, non-competitive antagonist of metabotropic glutamate receptors subtype 5 (mGluR(5)). This effect has been observed following both acute and chronic MTEP treatments in behavioral tests and experimental models of depression, such as the forced swim test (FST), the tail suspension test, and the olfactory bulbectomy model of depression. However, the mechanism of action for mGluR(5) antagonists remains unclear. The aim of this study was to investigate whether the antidepressant-like action of MTEPis dependent on ionotropic glutamatergic receptors. Male Albino Swiss mice were used, and antidepressant-like activity was evaluated using the FST. The antidepressant-like effect of MTEP (0.3 mg/kg) was significantly antagonized by pre-treatment with the NMDA receptor agonist N-methyl-D-aspartic acid (NMDA, 75 mg/kg, i.p.). The AMPA receptor antagonist NBQX (10 mg/kg, i.p.) did not affect the MTEP activity. Our results indicate that the antidepressant-like activity of MTEP in the FST involves NMDA but not AMPA receptors and suggest that the interaction between mGluR(5) and NMDA receptors plays an important role in the underlying antidepressant mechanism(s).

Neurotensin: A role in substance use disorder?

Neurotensin is a tridecapeptide originally identified in extracts of bovine hypothalamus. This peptide has a close anatomical and functional relationship with the mesocorticolimbic and nigrostriatal dopamine system. Neural circuits containing neurotensin were originally proposed to play a role in the mechanism of action of antipsychotic agents. Additionally, neurotensin-containing pathways were demonstrated to mediate some of the rewarding and/or sensitizing properties of drugs of abuse. This review attempts to contribute to the understanding of the role of neurotensin and its receptors in drug abuse. In particular, we will summarize the potential relevance of neurotensin, its related compounds and neurotensin receptors in substance use disorders, with a focus on the preclinical research.

Ethylene Glycol Ethers Induce Oxidative Stress in the Rat Brain

Ethylene glycol ethers (EGEs) are components of many industrial and household products. Their hemolytic and gonadotoxic effects are relatively well known while their potential adverse effects on the central nervous system have not yet been clearly demonstrated. The aim of the present study was to examine the effects of 4-week administration of 2-buthoxyethanol (BE), 2-phenoxyethanol (PHE) and 2-ethoxyethanol (EE) on the total antioxidant capacity, activity of some antioxidant enzymes, such as the superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX) and glutathione reductase and lipid peroxidation in the frontal cortex and hippocampus in the rat. These studies showed that BE and PHE decreased the total antioxidant activity, SOD and GPX activity, while increased lipid peroxidation in the frontal cortex. Like in the frontal cortex, also in the hippocampus BE and PHE attenuated the total antioxidant activity, however, lipid peroxidation was increased only in animals which received BE while reduction in GPX activity was present in rats administered PHE. The obtained data indicated that 4-week administration of BE and PHE, but not EE, reduced the total antioxidant activity and enhanced lipid peroxidation in the brain. In the frontal cortex, adverse effects of PHE and BE on lipid peroxidation probably depended on reduction in SOD and GPX activity, however, in the hippocampus the changes in the total antioxidant activity and lipid peroxidation were not connected with reduction of the investigated antioxidant enzyme activity.

Potential neurotoxic effect of ethylene glycol ethers mixtures

BACKGROUND Ethylene glycol ethers (EGEs) are widely used as mixtures in various industrial processes and in many household products. 2-Methoxyethanol and 2-ethoxyethanol primarily exert gonadotoxic effect, while 2-butoxyethanol and 2-isopropoxyethanol have potent hemolytic activity. EGEs can cross the blood-brain barrier, but their potential neurodegenerative action in vivo has not been investigated, yet. In the present work, we examined potential adverse effects of EGEs on some selected brain structures. METHODS A mixture of two compounds: one with stronger hydrophilic properties (2-methoxyethanol or 2-ethoxyethanol) and the second more lipophilic (2-butoxyethanol or 2-isopropoxyethanol) were administered sc for 4 weeks. Total antioxidant capacity, lipid peroxidation and caspase-3 activity were determined in the frontal cortex and hippocampus. RESULTS It has been found that 4-week administration of a mixture of two EGEs, with various intensity, decreased total antioxidant capacity, enhanced lipid peroxidation and increased caspase-3 activity in the frontal cortex and hippocampus of Wistar rat. CONCLUSION The obtained results suggested that EGEs exerted adverse effects on the CNS cells and may contribute in pathogenesis of neurodegenerative disorders.

Ceftriaxone- and N-acetylcysteine-induced brain tolerance to ischemia: Influence on glutamate levels in focal cerebral ischemia

One of the major players in the pathophysiology of cerebral ischemia is disrupted homeostasis of glutamatergic neurotransmission, resulting in elevated extracellular glutamate (Glu) concentrations and excitotoxicity-related cell death. In the brain, Glu concentrations are regulated by Glu transporters, including Glu transporter-1 (GLT-1) and cystine/Glu antiporter (system xc-). Modulation of these transporters by administration of ceftriaxone (CEF, 200 mg/kg, i.p.) or N-acetylcysteine (NAC, 150 mg/kg, i.p.) for 5 days before focal cerebral ischemia may induce brain tolerance to ischemia by significantly limiting stroke-related damage and normalizing Glu concentrations. In the present study, focal cerebral ischemia was induced by 90-minute middle cerebral artery occlusion (MCAO). We compared the effects of CEF and NAC pretreatment on Glu concentrations in extracellular fluid and cellular-specific expression of GLT-1 and xCT with the effects of two reference preconditioning methods, namely, ischemic preconditioning and chemical preconditioning in rats. Both CEF and NAC significantly reduced Glu levels in the frontal cortex and hippocampus during focal cerebral ischemia, and this decrease was comparable with the Glu level achieved with the reference preconditioning strategies. The results of immunofluorescence staining of GLT-1 and xCT on astrocytes, neurons and microglia accounted for the observed changes in extracellular Glu levels to a certain extent. Briefly, after MCAO, the expression of GLT-1 on astrocytes decreased, but pretreatment with CEF seemed to prevent this downregulation. In addition, every intervention used in this study seemed to reduce xCT expression on astrocytes and neurons. The results of this study indicate that modulation of Glu transporter expression may restore Glu homeostasis. Moreover, our results suggest that CEF and NAC may induce brain tolerance to ischemia by influencing GLT-1 and system xc- expression levels. These transporters are presumably good targets for the development of novel therapies for brain ischemia.