Lance McCoy

Chronic antipsychotic treatment alters glycine-stimulated NMDA receptor binding in rat brain ☆

In this study the chronic effect of antipsychotic drugs (APDs) on N-methyl-D-aspartate (NMDA) receptor binding was evaluated. Rats were treated for 21 days with i.p. injections of haloperidol (0.5 mg/ kg), pimozide (0.5 mg/kg), clozapine (20 mg/kg), risperidone (1 mg/kg) or water vehicle (1 ml/kg). Brain tissue sections underwent different [3H]MK-801 assay conditions. Following a short preincubation wash, there were no effects of APDs on either unenhanced or agonist enhanced [3H]MK-801 binding. Following a prolonged preincubation wash, APDs resulted in a reduction in both unenhanced binding and glycine enhanced binding. The attenuation of glycine stimulation in the APD treated animals was selective as neither NMDA nor spermidine enhanced binding was significantly affected. The present data suggest specific actions at the glycine regulatory site on the NMDA receptor as part of the chronic effects of APDs.

Antipsychotic drug regulation of AMPA receptor affinity states and GluR1, GluR2 splice variant expression

We recently reported that chronic administration of antipsychotic drugs dramatically elevated [3H]AMPA binding, with minimal elevation of [3H]CNQX binding in rat brain. The aim of the current study was to examine the mechanism of this effect. Chronic haloperidol minimally increased the total number of binding sites (total Bmax) compared to saline‐injected animals. Specifically, haloperidol dramatically increased the proportion of high‐affinity‐site AMPA receptors (≈30% increase) without inducing a significant change in the low‐affinity constant. In situ hybridization for flip and flop isoforms of GluR1 and GluR2 (AMPA receptors) was not altered in a pattern or degree that compared to the changes seen in AMPA receptor binding. These findings suggest that the long‐term action of antipsychotic drugs may be to regulate AMPA receptor responsiveness to agonist stimulation via posttranscriptional means, and is unlikely to be related to GluR1 or GluR2 splice variant expression. This effect may have relevance to both the therapeutic effects and side effects of antipsychotic drugs in humans. Synapse 28:195–207, 1998.

Time Course and Regional Basis of Pb‐Induced Changes in MK‐801 Binding: Reversal by Chronic Treatment with the Dopamine Agonist Apomorphine but Not the D1 Agonist SKF‐82958

Abstract: In the present study we attempted to further define the time course and regional specificity of lead (Pb)‐induced changes in the NMDA receptor complex and the influence of dopaminergic system modulations on these changes. Autoradiographic measurements of alterations in MK‐801 binding, as evaluated under four different activation conditions (none, spermidine, glycine, or maximal activation), were performed in medial frontal cortex, dorsal striatum, and nucleus accumbens of male rats after 2 weeks or 8 months of chronic postweaning (from 21 days of age on) exposure to 0, 50, or 150 ppm Pb acetate in drinking water. The 8‐month groups also received chronic intermittent intraperitoneal injections of saline, or of the dopamine (DA) agonist apomorphine or the D1 agonist SKF‐82958 2–3 times per week beginning at 60 days of age. Two weeks of 50 ppm Pb exposure resulted in small but significant increases in MK‐801 binding under conditions of glycine or spermidine activation, whereas decreases were observed in response to 150 ppm under conditions of no or maximal activation in all regions. After 8 months of Pb, concentration‐dependent decreases in MK‐801 binding were observed across regions under all activation conditions. These effects were noted at blood Pb concentrations averaging as low as 16 µg/dl. Pb‐induced decreases in MK‐801 binding were either partially or fully reversed by chronic intermittent treatment with the DA agonist apomorphine but not by the D1 agonist SKF‐82958, implicating D2‐based mechanisms in this reversal. Combined findings from this and previous studies based on this exposure protocol indicate a Pb‐induced pattern of widespread hypoglutamatergic function accompanied by increased DA function in mesolimbic systems, a pattern of changes reminiscent of those proposed to underlie schizophrenia. Such findings suggest that Pb exposure, even at current environmental levels, could be a risk factor for behavioral and/or neurological disturbances arising from imbalances of glutamate/dopamine function in mesocorticolimbic systems.

Chronic treatment with typical and atypical antipsychotics increases the AMPA-preferring form of AMPA receptor in rat brain.

We assessed the effects of chronic (21 day) administration of antipsychotic drugs on the density of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in rat brain. We used two typical antipsychotic drugs, haloperidol and pimozide, and two atypical antipsychotic drugs, risperidone and clozapine. Antipsychotic drugs as a group significantly elevated the density of the AMPA receptor measured with an AMPA receptor agonist ([3H]AMPA), but not with an AMPA receptor antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione ([3H]CNQX). In all regions studied, the magnitude of the increase seen with chronic typical antipsychotic drugs was significantly greater than that seen with chronic atypical antipsychotic drugs. In frontal cortex and striatum, typical antipsychotics but not atypical antipsychotics elevated AMPA receptor binding over control. These findings suggest that antipsychotic drugs alter the agonist affinity of the AMPA receptor without altering the number of AMPA receptors. Typical antipsychotic drugs may be more potent in this effect than atypical antipsychotic drugs, especially in critical corticostriatal circuits.

Regional Decreases in α‐[3H]Amino‐3‐Hydroxy‐5‐Methylisoxazole‐4‐Propionic Acid ([3H]AMPA) and 6‐[3H]Cyano‐7‐Nitroquinoxaline‐2,3‐dione ([3H]CNQX) Binding in Response to Chronic Low‐Level Lead Exposure: Reversal Versus Potentiation by Chronic Dopamine Agonist Treatment

Abstract: This study evaluated the hypotheses that in vivo lead (Pb) exposure would alter α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptor binding and, based on known glutamate‐dopamine interactions and Pb‐induced changes in dopamine (DA) systems, that AMPA binding might be differentially influenced by DA agonist treatment under conditions of Pb exposure. Alterations in high‐affinity ([3H]AMPA) versus total AMPA [6‐[3H]cyano‐7‐nitroquinoxaline‐2,3‐dione ([3H]CNQX)] receptor binding were determined in medial frontal cortex, dorsal striatum, and nucleus accumbens of rats exposed to 0, 50, or 150 ppm of Pb acetate for 2 weeks or 8 months. Additional 8‐month groups received chronic intermittent treatment with saline, the D1 agonist SKF82958, or the general DA agonist apomorphine. Two‐week exposures increased AMPA receptor densities, whereas robust decreases occurred after 8 months of Pb; at the latter time point changes were more pronounced for high‐affinity than total AMPA receptor binding, with high‐affinity effects expressed preferentially in dorsal striatum and nucleus accumbens. DA agonist treatments almost fully reversed Pb‐related declines in [3H]AMPA binding but either had no effect (apomorphine) or even further potentiated (SKF82958) the decreases in [3H]CNQX binding. One possible basis for the long‐term (8‐month) decrease in AMPA binding is a postsynaptic glutamatergic stimulation of non‐NMDA receptors.

Washable endogenous substances and regional heterogeneity in agonist enhanced [3H]MK-801 binding in rat brain

NMDA receptor/ion channel function is modulated through a number of distinct sites that regulate channel opening. Published studies report widely varying results in modulatory site agonist effects due to assay conditions and technique. Also, NMDA receptor regulation at these sites by endogenous substances remains poorly characterized. The objectives of the present study in Sprague-Dawley rat forebrain sections were: (i) determine the contribution of various prewash variables on agonist stimulation of the NMDA receptor, (ii) compare regional differences in functional glycine, spermidine and NMDA binding sites under optimized prewash conditions, and (iii) define the influence of endogenous substances at each modulatory site by analyzing changes in binding at different prewash durations. We demonstrate that prewash conditions have a critical influence on [3H]MK-801 binding in rat tissue sections and that this effect was differentially expressed across brain regions. An extended prewash duration caused a regionally specific decrease in unenhanced [3H]MK-801 binding, while a short prewash caused a regionally specific biphasic effect on enhanced [3H]MK-801 binding. After prolonged prewash, binding was restored to previous (unwashed) binding levels with exogenously added glycine, NMDA, or spermidine alone or combinations of agonists. These data suggest that washable endogenous substances contribute to the full functionality of the NMDA receptor and the regional heterogeneity in [3H]MK-801 binding is dependent on the interaction of receptor protein subtypes and the presence of one or more endogenous substances.

Effects of perinatal hypoxia on brain and behavior: Relevance to schizophrenia

mcnts. Video analysis revealed hypoxic animals were involved in rapid (almost one per second) sequences of a range of behaviors that was double control values (p <.01). This model of hypoxia induced a developmental lag in a vertical motor movement, gross motor over expression and subsequently a subtle reduction in ability to sustain ongoing behavior of all types. Results suggest alterations in behavior patterns secondary to perinatal hypoxic damage to striatal circuitry.