dizocilpine-maleate and Lead-Poisoning

This study sought to further evaluate potential mechanistic relationships between Pb-induced alterations in glutamate neurotransmission and behavioral toxicity. It examined correlations between Pb-induced changes in [3H]MK-801 and [3H]CGP-39653 binding sites in 4 different brain regions (frontal cortex, dentate gyrus, CA1 and striatum) and (1) changes in learning accuracy on a multiple repeated acquisition and performance schedule, and (2) sensitivity to the accuracy-impairing effects of MK-801 and NMDA on this learning baseline. All data were obtained from a single population of rats that had been chronically exposed from weaning to 0, 50 or 250 ppm Pb acetate in drinking water and demonstrated selective learning impairments and altered sensitivity to the effects of MK-801 and NMDA on learning accuracy. Pb exposure decreased MK-801 binding and possibly increased CGP-39653 binding, effects statistically significant in some brain regions, but generally exhibiting similar trends across regions. At 0 ppm, higher levels, particularly of MK-801 binding, were associated with higher accuracy levels in the learning paradigm and with greater decrements in learning accuracy following MK-801 or NMDA administration. These linear correlations were negated and in some cases even reversed by 50 and 250 ppm Pb, an effect that might be attributable to an alteration of NMDA receptor complex subunit composition and thus, ligand binding. Of the 4 brain regions examined, striatal MK-801 binding proved to be the best predictor of learning accuracy levels. These data provide additional support for an involvement of the NMDA receptor complex in Pb-induced learning impairments. The fact that these effects were noted most frequently in striatum also raises the possibility that dopamine-glutamatergic interactions contribute to Pb's effects.

Topics: 2-Amino-5-phosphonovalerate; Animals; Appetitive Behavior; Autoradiography; Brain; Brain Mapping; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Lead Poisoning; Male; Mental Recall; N-Methylaspartate; Organometallic Compounds; Rats; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission

Lead (Pb2+) is a potent inhibitor of the NMDA receptor complex. In the present study we have measured high and low affinity components of NMDA receptor inhibition by Pb2+ using [3H]-MI-801 binding as a biochemical indicator of NMDA receptor function. The inhibitory effects of Pb2+ were dependent on the age of the rat and the brain region analyzed. The number of [3H]-MK-801 binding sites associated with the high and low affinity sites of Pb2+ inhibition in the hippocampus increased as a function of age, peaking at postnatal day 28 and 21, respectively. In the cerebellum, a steady decrease in the number of both types of Pb(2+)-sensitive [3H]-MK-801 binding sites was measured from postnatal day 1 to adulthood. High and low affinity Pb(2+)-sensitive [3H]-MK-801 binding sites were measured in the cerebral cortex in early development, but the resolution of the two sites was not possible after postnatal day 14. The Pb2+ sensitivity of the NMDA receptor complex also appeared to be regulated developmentally.

Topics: Analysis of Variance; Animals; Brain; Cerebellum; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Lead Poisoning; Radioligand Assay; Rats; Receptors, N-Methyl-D-Aspartate

Postweaning Pb exposure has been associated with subsensitivity to the stimulus properties of the non-competitive NMDA receptor complex antagonist MK-801 (Cory-Slechta, 1995a). This study sought to determine whether Pb exposures occurring postnatally, i.e., during the primary period of development of many NMDA receptor subunits, would alter the nature of these glutamatergic system changes. Rat pups were exposed to Pb from 0-21 days of age via lactating dams consuming solutions of 0, 100 or 350 ppm Pb acetate. Beginning at 9 mos of age, rats were trained to discriminate 0.05 mg/kg MK-801 from saline using standard operant drug discrimination procedures. Following acquisition of the discrimination, various doses of MK-801, the non-competitive antagonist phencyclidine (PCP), the competitive antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP) and the agonist N-methyl-D-aspartate (NMDA) were substituted for 0.05 mg/kg MK-801 and percent MK-801 lever responding to each determined. Subsequently, a drug washout period was imposed, after which MK-801 dose-effect curves were re-established. Increasing doses of MK-801 and PCP produced dose-dependent increases in MK-801 lever responding resulting in full substitution, whereas CPP and NMDA evoked primarily saline-appropriate responding. Pb exposure was associated with enhanced MK-801 sensitivity during the pre-washout phase, but attenuated sensitivity following MK-801 washout. In both cases, however these effects were of relatively modest magnitude. No systematic Pb-related changes in response to PCP, CPP or NMDA were observed. These data raise the possibility, particularly when considered in relation to studies based on other Pb exposure protocols, that NMDA receptor changes may depend upon ongoing or extant Pb exposures, or that postnatal exposure effects on this system may be largely reversible. In addition, the differential nature of the effects seen with postnatal vs postweaning exposure (Cory-Slechta, 1995a) underscores the significance of the developmental period of exposure to Pb effects on the NMDA receptor complex.

Topics: Analysis of Variance; Animals; Animals, Suckling; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Lead Poisoning; Male; N-Methylaspartate; Neuroprotective Agents; Phencyclidine; Piperazines; Rats; Receptors, N-Methyl-D-Aspartate

Reductions in membrane Ca2+ channel currents and depolarization-evoked neurotransmitter release have been repeatedly observed as a result of acute exposure to Pb2+. This study was performed to determine whether hippocampal glutamate and GABA release are impaired in intact animals chronically exposed to lead (Pb). As paired-pulse facilitation in the hippocampus is primarily mediated by an enhancement of glutamate release, this neurophysiological measure was also assessed in the dentate gyrus of Pb-exposed animals. Pregnant dams received 0.2% Pb acetate in the drinking water at parturition, and male offspring were weaned to the same solution as that given their dams. Control animals were maintained on distilled water. As adults, animals had intracerebral dialysis probes inserted through guide cannulae implanted 2-4 days previously and the hippocampal CAI-dentate area was perfused with modified Ringer's solution. Transmitter release was induced by perfusion with 150 mM K+ with half the animals in each group tested with Ca2+ present in the perfusate (total release) and the other half with Ca2+ absent (Ca(2+)-independent release). K(+)-stimulated total glutamate release was reduced in Pb-exposed animals relative to controls. No group differences were observed under Ca(2+)-free conditions, indicating that Ca(2+)-dependent glutamate release was decreased in exposed rats. In contrast no group differences in K(+)-stimulated total GABA release were evident, whereas an augmentation in GABA release under Ca(2+)-free conditions was revealed in Pb-exposed animals. The effects of exposure on the Ca(2+)-dependent components of release are consistent with in vitro evidence indicating an inhibitory action of Pb2+ at voltage-sensitive Ca2+ channels. A separate group of animals was prepared under urethane anesthesia with stimulating and recording electrodes placed in the perforant path and dentate gyrus, respectively. Pairs of stimulus pulses were delivered at interpulse intervals (IPI) of 10-250 ms. Pb exposure induced an increase in paired-pulse depression at the 20 ms 1PI and reduced paired-pulse facilitation at the 30 ms IPI. Decreases in paired-pulse facilitation could not be attributed to the reported effects of Pb2+ on N-methyl-D-aspartate (NMDA) receptors as MK-801 (1.0 mg/kg, s.c.) administration produced an opposing pattern of effects on paired-pulse measures. The Pb-induced suppression of paired-pulse facilitation is consistent with exposure-related decreases in t

Topics: Animals; Animals, Newborn; Animals, Suckling; Calcium; Dentate Gyrus; Dizocilpine Maleate; Electric Stimulation; Female; gamma-Aminobutyric Acid; Glutamic Acid; Lead; Lead Poisoning; Male; Microdialysis; Organometallic Compounds; Potassium; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Receptors, N-Methyl-D-Aspartate

Exposure to lead (Pb) has been reported to inhibit MK-801 binding and to alter other NMDA receptor complex-associated functions. These reported changes are provocative since both NMDA receptor antagonism and Pb exposure are know to impair learning processes. Whether the Pb-induced changes in NMDA function relate to the learning impairments associated with Pb exposure, however, has not been explored. The contention of this study was that if changes in NMDA function produced by Pb serve as the basis of Pb-associated learning impairments, then such changes should be of sufficient biological magnitude and clinical relevance to induce alterations in sensitivity at the level of the whole animal, i.e., changes in behavioral sensitivity to glutamatergic compounds. Thus, in this study, dose-effect curves of control and Pb-treated rats working on a multiple schedule of repeated learning (repeated acquisition, RA) and performance (P) were compared following acute administration of MK-801, the non-competitive NMDA antagonist. Based on the nature of the reported effects of Pb on NMDA systems, it was expected that the curves of Pb-exposed rats would be right-shifted relative to controls, if differential behavioral sensitivity was evident. Rats were chronically exposed to 0, 50 or 250 ppm Pb acetate in drinking water from weaning and trained on the multiple RA and P schedule beginning at 55 days old. The RA component required the rat to learn a new 3-member sequence of responses during each experimental session (center right left, RLC, CLR, RCL, or LRC), while the correct sequence of responses for the P component was constant across sessions (LCR), requiring performance of an already learned response. Acute administration of MK-801 (0.05-0.3 mg/k, i.p.) resulted in decrements in accuracy in both the RA and P components of the schedule, indicative of non-specific effects on behavior rather than selective effects on learning. The declines in accuracy during the RA component of the schedule were primarily the result of increased perseverative responding, i.e., repetitive responding on a single lever. Both the decline in RA accuracy and the increases in perseverative responding produced by MK-801 were attenuated by Pb exposure. Moreover, dose-effect curves relating MK-801 dose to changes in rates of responding were significantly shifted to the right in Pb-exposed rats relative to controls. Taken together, these data demonstrate a subsensitivity of Pb-exposed rats to both th

Topics: Animals; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Lead; Lead Poisoning; Male; Psychomotor Performance; Rats; Reinforcement Schedule

Lead (Pb2+) is a more potent inhibitor of [3H]MK-801 binding to rat neuronal membranes than Zn2+ and Mg2+. The inhibitory effects of Pb2+ appeared to be age-dependent since the IC50 was significantly lower in cortical membranes prepared from neonatal than from adult rats. The results also indicate that the hippocampus is more sensitive than the cerebral cortex since the Pb2+ IC50 was significantly lower in the hippocampus. These findings suggest developmental and regional brain heterogeneity to the inhibitory action of lead on [3H]MK-801 binding. Chronic in vivo exposure to Pb2+ resulted in the loss of [3H]MK-801 binding sites in the cerebral cortex of neonatal but not of adult rats. These lead-induced changes may influence developmental processes requiring NMDA receptor activation.

Topics: Aging; Animals; Animals, Newborn; Brain; Cell Membrane; Dizocilpine Maleate; Female; Kinetics; Lead; Lead Poisoning; Magnesium; Neurons; Radioligand Assay; Rats; Receptors, N-Methyl-D-Aspartate; Reference Values; Tritium; Zinc