Molecular Changes in Glutamatergic Synapses Induced by Pb2+: Association with Deficits of LTP and Spatial Learning

Nihei, Michelle K.; Guilarte, Tomás R.

doi:10.1016/s0161-813x(01)00035-3

Cited by 65 publications

(33 citation statements)

References 76 publications

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“…Also, there is the issue of the potential role played by glutamate in lead-related changes in cocaine selfadministration. Apart from matters related to potential redefinition of drug reinforcer potency (Cornish et al, 1999;Trujillo and Akil, 1995;Wolf, 1998), glutamate is instrumental in learning and memory function (Nihei and Guilarte, 2001). Since developmental lead affects gene and protein expression of specific glutamate subunits in the morphologically immature brain (Guilarte, 1998;Guilarte and Miceli, 1992;, undefined alterations in associative conditioning mechanisms may have contributed to the acquisition patterns observed here.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Acquisition of Cocaine Self-Administration in Rats Developmentally Exposed to Lead

Rocha

Valles

Cardon

et al. 2005

Neuropsychopharmacol

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The rate of acquisition of drug self-administration may serve as a predictor of later drug-taking behavior, possibly influencing the vulnerability to use drugs. The present study examined the effects of perinatal (gestation/lactation) lead exposure on adult rates of acquisition of intravenous cocaine self-administration using an automated procedure that included both Pavlovian and operant components. For Experiment 1, female rats were gavaged daily with 0 or 16 mg lead for 30 days prior to breeding with nonexposed males. Metal administration continued through pregnancy and lactation and was discontinued at weaning (postnatal day (PND) 21). Animals born to control or lead-exposed dams subsequently were tested daily as adults in a preparation where sessions included an initial 3-h autoshaping period followed by a 3-h self-administration period where 0.20 mg/kg cocaine was delivered contingently. During autoshaping, intravenous cocaine infusions were paired with the extension and retraction of a lever, while infusions occurred during selfadministration only when a lever press was executed (FR-1). The criterion for acquisition was a 2-day period during which a mean of 50 infusions/session occurred during self-administration. Animals were given 35 days to reach criterion. In Experiment 1, accelerated rates of acquisition of cocaine self-administration were evident for lead-exposed animals relative to controls. Overall, the number of selfadministered cocaine infusions per session was significantly higher for lead-exposed rats as compared to control rats. Experiment 2 replicated Experiment 1 except that a higher dose of cocaine (0.80 mg/kg) was employed as the reinforcer, and 30 infusions/session was the set criterion. At the higher cocaine dose (Experiment 2), acquisition rates for control and lead-exposed animals were not markedly different, and significantly different infusion rates were not observed.

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Section: Discussionmentioning

confidence: 99%

Enhanced Acquisition of Cocaine Self-Administration in Rats Developmentally Exposed to Lead

Rocha

Valles

Cardon

et al. 2005

Neuropsychopharmacol

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“…However, although the interaction of Pb 2+ with different proteins involved in exocytosis has been demonstrated, the mechanism through which Pb 2+ exerts its action is still unresolved, because specific activators of PKC, but also of calmodulin and calcineurin, have failed to mimic the Pb 2+ effect (Westerink and Vijverberg, 2002). A recent work (Nihei et al, 2001) suggested that PKCγ gene and protein expression modulations by Pb 2+ are correlated with Pb 2+ -induced deficit in LTP maintenance (although not LTP induction) and spatial learning alterations; however the exposureinduced changes in spatial learning have not been reproduced in other laboratories so far. Finally, PKC modulation has been frequently correlated to altered Immediate Early Response Genes (IERG) and expression of other genes (reviewed in Bouton and Pevsner, 2000).…”

Section: Protein Kinase Cmentioning

confidence: 99%

“…Although compelling evidence exists that the NMDAR subunit proteins are key targets for Pb 2+ -induced neurotoxicity (Nihei and Guilarte, 2001), how all these effects are related and whether they bear any link to the Pb 2+ -caused impairment of higher mental functions is still a matter of debate.…”

Section: Models Of Synaptic Plasticitymentioning

confidence: 99%

“…Possible molecular targets for Pb 2+ in the brain are numerous, as described in a great variety of in vivo studies (Nihei and Guilarte, 2001) and this suggests that the neurotoxic action of Pb 2+ is not confined to a single specific protein, but involves several proteins and their proteomic unit. A proteomic structure has been identified in the glutamatergic synapse and has been named after its electron microscopy appearance "postsynaptic density" (PSD).…”

Section: Proteomic Synaptic Machinerymentioning

confidence: 99%

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Molecular targets of lead in brain neurotoxicity

Marchetti

2003

neurotox res

151

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The detrimental effects of lead poisoning have been well known since ancient times, but some of the most severe consequences of exposure to this metal have only been described recently. Lead [Pb(II)] affects the higher functions of the central nervous system and undermines brain growth, preventing the correct development of cognitive and behavioral functions. As an established neurotoxin, Pb(II) crosses the blood-brain barrier rapidly and concentrates in the brain. The mechanisms of lead neurotoxicity are complex and still not fully understood, but recent findings recognized that both Ca(II) dependent proteins and neurotransmitters receptors represent significant targets for Pb(II). In particular, acute and chronic exposure to lead would predominantly affect two specific protein complexes: protein kinase C and the N-methyl-D-aspartate subtype of glutamate receptor. These protein complexes are deeply involved in learning and cognitive functions and are also thought to interact significantly with each other to mediate these functions. This review outlines the most recent hypotheses and evidences that link lead poisoning to impairment of these protein functions, as well as the in vitro experimental approaches that are most likely to provide information on basic mechanicistic processes.

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“…Therefore, infants and children may develop toxic CNS symptoms, such as cognitive disorders, at doses lower than the ones that induce effects in adults (Finkelstein et al 1998;Goyer and Clarkson 2001). Although the mechanisms of Pb neurotoxicity are still poorly understood, it has been suggested that a number of neurotoxic effects of inorganic Pb may be due to its interference with neurotransmitter systems, cellular calcium homeostasis, and/or enzymes (Guilarte 1997;Finkelstein et al 1998;Savolainen et al 1998Savolainen et al a, 1998Bressler et al 1999;Goyer and Clarkson 2001;Nihei and Guilarte 2001;Gilbert and Lasley 2002).…”

Section: Introductionmentioning

confidence: 99%

Glutamate increases toxicity of inorganic lead in GT1-7 neurons: partial protection induced by flunarizine

Loikkanen

Naarala

Vähäkangas

et al. 2003

Archives of Toxicology

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Recent studies point to an interaction between the glutamatergic neurotransmitter system and inorganic lead (Pb) neurotoxicity. Pb (1-100 microM) evoked cytotoxicity over the period of 72 h in mouse hypothalamic GT1-7 neurons. Glutamate (0.1 or 1 mM) on its own did not have any effect on cell viability. However, 1 mM glutamate clearly increased Pb-induced cell death at 48 and 72 h. Although flunarizine (0.1-10 microM), an antagonist of L- and T-type voltage-sensitive calcium channels (VSCCs), partially protected from the cytotoxicity induced by co-exposure to Pb (10 or 100 micro M) and glutamate (1 mM), it had no protective effect on cytotoxicity induced by Pb alone. The flunarizine-induced protection was dependent on time and observed only at 48 h. Neither verapamil, an antagonist of L-type VSCCs, nor DIDS, an inhibitor of anion exchange, at non-toxic concentrations (0.1-10 microM) had any effect on cytotoxicity induced by Pb alone or together with glutamate at any studied time point. Co-exposure to Pb and glutamate also resulted in more prominent production of reactive oxygen species (ROS) than either of the compounds alone. Interestingly, we observed an increase in intracellular glutathione (GSH) levels in cells exposed to micromolar concentrations of Pb. Glutamate decreased the levels of intracellular GSH and also partially reduced the Pb-induced increase in GSH levels. These results suggest that the interaction of glutamate and Pb results in increased neuronal cell death via mechanisms that involve an increase in ROS production, a decrease in intracellular GSH defense against oxidative stress and probably T-type VSCCs.

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Molecular Changes in Glutamatergic Synapses Induced by Pb2+: Association with Deficits of LTP and Spatial Learning

Cited by 65 publications

References 76 publications

Enhanced Acquisition of Cocaine Self-Administration in Rats Developmentally Exposed to Lead

Enhanced Acquisition of Cocaine Self-Administration in Rats Developmentally Exposed to Lead

Molecular targets of lead in brain neurotoxicity

Glutamate increases toxicity of inorganic lead in GT1-7 neurons: partial protection induced by flunarizine

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