A review of the in vitro and in vivo neurochemical characterization of the NMDA/PCP/glycine/ion channel receptor macrocomplex.
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Animals↗
Biomedical subjects
S Iyengar
Publications and source records attributed to S Iyengar.
Inhibition of climbing and mossy fiber, and basket and stellate cell inputs to mouse cerebellar Purkinje cells by novel anti-ischemic agents, ifenprodil and BMY-14802.
Cerebellar cyclic guanosine monophosphate (cGMP) levels reflect the ongoing neuronal activity mediated by the N-methyl-D-aspartate (NMDA) receptor complex. Due to the putative role of the NMDA receptor complex in the etiology of ischemic neuronal injury, the effects of two novel anti-ischemic agents, ifenprodil and BMY-14802, were examined on cGMP responses mediated by harmaline, methamphetamine (MA), and pentylenetetrazol (PTZ), agents which modulate the Purkinje cell activity by three distinct pharmacological mechanisms. Similar to the competitive NMDA antagonist, CPP [(+/-)-3-carboxypiperazin-4-yl)propyl-1-phosphonic acid], ifenprodil and BMY-14802 reversed the harmaline-, MA- and PTZ-induced cGMP levels. Unlike CPP, ifenprodil was nearly 3-times less potent at reversing the harmaline-induced increases in cGMP levels than at reversing MA-and PTZ-induced increases in cGMP levels. These results suggest a differential modulation of basket and stellate, and mossy fiber activity by ifenprodil.
Analysis of Variance↗
Sigma receptors modulate the hypothalamic-pituitary-adrenal (HPA) axis centrally: evidence for a functional interaction with NMDA receptors, in vivo.
The present report investigates the modulation of the hypothalamic-pituitary-adrenal (HPA) axis in the rat by sigma receptors, using a selective ligand, (+) pentazocine, and comparing the effects with (+) SKF 10, 047. Both compounds stimulate ACTH release potently after central and peripheral administration. These effects are centrally mediated, since they did not release ACTH from anterior pituitary primary cultures. The effects are not blocked by naloxone, but are blocked by the NMDA antagonist, CPP, indicating a centrally mediated functional interaction between NMDA and sigma receptors, in vivo.
Adrenocorticotropic Hormone↗
Neuropharmacological characterization of 1-aminocyclopropane-1-carboxylate and 1-aminocyclobutane-1-carboxylate, ligands of the N-methyl-D-aspartate-associated glycine receptor.
Following intravenous administration, 1-aminocyclobutane-1-carboxylate (ACBC, 100 mg/kg), a N-methyl-D-aspartate (NMDA)-associated glycine receptor antagonist, was eliminated with a T1/2 of 5 min in mouse brain and 4 min in rat cerebrospinal fluid (CSF). 1-Aminocyclopropane-1-carboxylate (ACC), a NMDA-associated glycine receptor agonist, was found to have a T1/2 of less than 5 min in mouse brain. ACC and ACBC did not alter basal cerebellar cGMP. Glycine and D-serine increased cGMP, and 1-hydroxy-3-aminopyrrolidone-2 (HA-966), a glycine antagonist, reversed the D-serine-induced increases in cGMP. In contrast, ACBC did not reverse the D-serine-induced increases in cGMP. These data suggest that despite their brain bioavailability and marked potency at the glycine receptor in vitro, ACC and ACBC are rapidly inactivated and thus have limited in vivo utility.
Amino Acids↗
In vivo antagonism of agonist actions at N-methyl-D-aspartate and N-methyl-D-aspartate-associated glycine receptors in mouse cerebellum: studies of 1-hydroxy-3-aminopyrrolidone-2.
Intracerebellar injections of either NMDA or D-serine dramatically elevated levels of cGMP in the cerebellum of the mouse, in vivo. These actions were both antagonized by simultaneous injection of the NMDA-associated glycine receptor antagonist, HA-966. Intracerebellar injections of D-serine were also antagonized by peripheral (s.c.) injections of HA-966, demonstrating the bioavailability of this glycine receptor antagonist. Parenteral administration of HA-966 was also effective in antagonizing the actions of intravenously injected harmaline, an activator of the cerebellar climbing fiber pathway, on cGMP in the cerebellum. An evaluation of the parenteral dose-response curve for HA-966, revealed no effect on basal activity within the cerebellum. This contrasts sharply with the abilities of both competitive and non-competitive NMDA antagonists to decrease basal levels of cGMP in the cerebellum. In summary, these studies demonstrate that HA-966 is a bioavailable antagonist of the NMDA-associated glycine receptor and that this compound can limit excessive stimulation of the NMDA receptor by exogenous application of agonist, with minimal effects on basal activity. These data suggest that antagonists of the NMDA-associated glycine receptor may be optimal therapies in the treatment of stroke and epilepsy.
Animals↗
Neurochemical characterization of dopaminergic effects of opipramol, a potent sigma receptor ligand, in vivo.
Opipramol, a tricyclic antidepressant drug, potently interacted with sigma recognition sites labelled by [3H](+)-3-hydroxyphenyl)N-(1-propyl)piperidine [( 3H](+)-3-PPP) with a Ki value of 50 +/- 8 nM and with minimal affinity for phencyclidine receptors (Ki greater than 30,000 nM). Opipramol potently increased the metabolism of dopamine in the striatum, olfactory tubercle and pyriform cortex of the rat and increased the release of dopamine from the striatum of the mouse, as measured by increases in the levels of 3-methoxytyramine in vivo. Opipramol increased plasma prolactin in the rat, only at a dose as large as 50 mg/kg dose. Irreversible inactivation of dopamine receptors by EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) did not affect the opipramol-induced increases in levels of dihydroxyphenylacetic acid (DOPAC) in the striatum of the rat, indicating a predominant role of activation of sigma receptors in the dopaminergic effects of opipramol. However, pretreatment with the putative sigma ligand, rimcazole, markedly potentiated the ability of opipramol to increase the metabolism of release of DA in the striatum of the mouse in vivo. These results suggest that rimcazole and opipramol interact at two distinct receptors, the pharmacological significance of which is yet to be elucidated.
3,4-Dihydroxyphenylacetic Acid↗
Opipramol, a potent sigma ligand, is an anti-ischemic agent: neurochemical evidence for an interaction with the N-methyl-D-aspartate receptor complex in vivo by cerebellar cGMP measurements.
Opipramol, a potent sigma ligand and a tricyclic antidepressant compound, provided significant neuronal protection (P less than 0.0001) against ischemia-induced neuronal cell loss in the hippocampus in Mongolian gerbils, at a dose of 50 mg/kg (30 min pretreatment). However, opipramol did not offer protection when given 60 min after the ischemic insult. Opipramol decreased basal levels of cGMP in the cerebellum of the mouse and harmaline-induced increases in levels of cGMP, with approximate ED50 values of 4 and 27 mg/kg. Opipramol antagonized methamphetamine- and pentylenetetrazol-induced increases in levels of cGMP. Parenteral administration of opipramol also antagonized the increases in levels of cGMP in the cerebellum of the mouse after the local administration of D-serine, an agonist at the N-methyl-D-aspartate (NMDA)-associated, strychnine-insensitive glycine receptor. These results indicate that opipramol attenuates responses mediated through the NMDA receptor complex. These results further support the functional modulation of the NMDA receptor complex by sigma ligands and provide a neurochemical correlate for the observed anti-ischemic properties of opipramol.
Animals↗
6,7-Dinitroquinoxaline-2,3-dione and 6-nitro,7-cyanoquinoxaline-2,3-dione antagonize responses mediated by N-methyl-D-aspartate and NMDA-associated glycine recognition sites in vivo: measurements of cerebellar cyclic-GMP.
Direct intracerebellar administration of quisqualate resulted in marked increases in levels of cGMP in the cerebellum of the mouse, with a Hill number of 2.0. Quinoxalinediones, DNQX (6,7-dinitroquinoxaline-2,3-dione) and CNQX (6-nitro,7-cyanoquinoxaline-2,3-dione) attenuated the quisqualate-induced response. 6,7-Dinitroquinoxaline-2,3-dione also attenuated the D-serine-induced increases in levels of cGMP in a competitive manner. Intracerebellar injection of DNQX also antagonized the response to parenterally-administered harmaline. Similar results were also obtained with CNQX. These results indicate that these quinoxalinediones can attenuate the responses, mediated through the NMDA-associated glycine recognition sites, as well as the NMDA receptor complex. However, the glycine antagonist HA-966 (3-amino-1-hydroxypyrrolidone-2), at doses which completely reversed the increases induced by D-serine, failed to alter the response to quisqualate, indicating a lack of effect of glycine antagonists on quisqualate-mediated synaptic events. These results further support the interaction of the quinoxalinediones, DNQX and CNQX, with the NMDA receptor complex as established in receptor binding and electrophysiological studies.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Glycine, glycinamide and D-serine act as positive modulators of signal transduction at the N-methyl-D-aspartate (NMDA) receptor in vivo: differential effects on mouse cerebellar cyclic guanosine monophosphate levels.
Direct intracerebellar (icb) administration of glycine, glycinamide and D-serine produced time- and dose-dependent changes in mouse cerebellar cGMP levels, indicating a modulation of ongoing neuronal activity through the NMDA receptor complex. Intracerebroventricular administration of glycinamide also produced a time-dependent change in cGMP levels, indicating a central mechanism of action. The icb dose-response data indicated a unimolecular interaction for these compounds. D-serine-, glycine-, and glycinamide-mediated increases in cGMP levels were reversed by the competitive NMDA antagonist, CPP and the NMDA-associated glycine receptor antagonist, HA-966, indicating mediation via the NMDA receptor complex. Glycine and D-serine were less effective than glycinamide at increasing cerebellar cGMP levels. In contrast, L- and D-serinamide did not affect cGMP levels. These results indicate that glycine receptor is not saturated under physiological conditions and also suggest possible existence of multiple glycine pools.
Animals↗
Increased release of dopamine in vivo by BMY-14802: contrasting pattern to clozapine.
In preclinical studies, BMY-14802 [alpha-(fluorophenyl)-4-(5-fluoro-2-pyramidinyl)-l-piperazine-buta nol], a potent sigma ligand, exhibited a profile similar to clozapine, an atypical antipsychotic agent. Several atypical antipsychotics have previously been demonstrated to increase dopamine (DA) metabolism without altering DA release in vivo, suggesting a potential mechanism for their lack of extrapyramidal side effects. BMY-14802 increased DA metabolism and release while clozapine increased DA metabolism but decreased DA release in the mouse. This is the first demonstration of a sigma ligand mediated DA release in vivo. The lack of extrapyramidal side effects, despite the enhanced DA release in vivo after BMY-14802 suggests that the atypical profile of clozapine can not be explained by its depressant actions on DA release alone.
3,4-Dihydroxyphenylacetic Acid↗
Psychological functioning among mothers of children with insulin-dependent diabetes mellitus: a longitudinal study.
Mothers of children with newly diagnosed insulin-dependent diabetes mellitus (IDDM) were assessed repeatedly over a period of 6 years in order to determine the psychological correlates of managing this chronic illness. Both maternal depression and overall emotional distress after the 1st year of the IDDM increased slightly with illness duration and were also influenced by other factors. Mothers' adjustment shortly after their children were diagnosed with IDDM was a strong predictor of their long-term emotional symptomatology. However, mothers' symptoms over time were not related to medical aspects of IDDM (i.e., the extent of the children's metabolic control, number of rehospitalizations, or their compliance with the medical regimen) and were also unrelated to the levels of depression or anxiety reported by their children. Mothers generally found it easier to cope with the IDDM the longer their children had the illness. However, the degree to which mothers perceived the IDDM to be bothersome or difficult to manage at any given point in time was associated with their overall levels of emotional distress.
Adaptation, Psychological↗
Psychological functioning of children with insulin-dependent diabetes mellitus: a longitudinal study.
Assessed school-age youth repeatedly over the first 6 years of their insulin-dependent diabetes mellitus (IDDM) to determine self-perceived psychological adjustment. After the first year of IDDM, Ss exhibited a mild increase in depressive symptoms. Anxiety decreased for boys but increased for girls over the duration of IDDM. In contrast, self-esteem remained stable regardless of rehospitalizations or degree of metabolic control. Ss' adjustment shortly after IDDM onset, as reflected by levels of depression, anxiety, and self-esteem, were predictors of later adjustment. In general, Ss found the implications of IDDM more upsetting and the regimen more difficult with time, and girls were more upset by their illness than boys. The degree to which children were upset by the implications and management of IDDM varied as a function of their anxiety and depression.
Adaptation, Psychological↗
Inhibition of nitric oxide synthase blocks N-methyl-D-aspartate-, quisqualate-, kainate-, harmaline-, and pentylenetetrazole-dependent increases in cerebellar cyclic GMP in vivo.
The synthesis of nitric oxide by brain slices has been demonstrated in several laboratories. In addition, in vitro studies have demonstrated stimulation of nitric oxide synthesis by excitatory amino acid receptor agonists. These data have led to the hypothesis that this readily diffusible "intercellular messenger molecule" acts to generate a cascade effect by activating guanylate cyclase in several cell types and thereby augment levels of the second messenger cyclic GMP (cGMP). Therefore, we evaluated this hypothesis in vivo, by testing the actions of the nitric oxide synthase inhibitor N-mono-methyl-L-arginine (NMMA) on elevations in level of mouse cerebellar cGMP generated by excitatory amino acid receptor agonists. The stimulatory effects of D-serine, quisqualate, and kainate were all found to be antagonized by this enzyme inhibitor. In addition, NMMA antagonized the increases in cerebellar cGMP level elicited by harmaline and pentylenetetrazole, pharmacological agents that augment endogenous excitatory amino acid transmission. Our data are, therefore, the first in vivo demonstration that nitric oxide is an important "messenger molecule" in the cerebellum, mediating the actions of kainate, quisqualate, and N-methyl-D-aspartate receptor agonists on guanylate cyclase. These data are consistent with previous in vitro findings with kainate and N-methyl-D-aspartate.
Alkaloids↗
Is locked seclusion necessary for children under the age of 14?
A retrospective study of the effect of the implementation of an unlocked seclusion policy was conducted on three child psychiatric inpatient units in a state hospital in Pennsylvania. Unlocked seclusion was associated with 1) increased use of tranquilizing medications administered as needed on all three units, 2) increased clustering of medications, administered as needed, in the units that used seclusion most, 3) diverse changes in the three units regarding frequency and clustering of unlocked seclusion, and 4) increased correlations between medications administered as needed and seclusion, particularly in the more behaviorally disturbed children. These findings suggest that locked seclusion may be a necessary therapeutic intervention, particularly with severely disturbed children with serious conduct and impulsive disorders.
Adolescent↗
BMY-14802 antagonizes harmaline- and D-serine-induced increases in mouse cerebellar cyclic GMP: neurochemical evidence for a sigma receptor-mediated functional modulation of responses mediated by the N-methyl-D-aspartate receptor complex in vivo.
BMY-14802 [alpha-(4-flurophenyl)-4-(5-fluoro-pyramidinyl)-1-piperazine butanol], a potent sigma ligand with poor affinity for dopamine and phencyclidine receptors in vitro, attenuated parenteral harmaline- and direct intracerebellar D-serine-induced increases in mouse cerebellar cGMP. Intracerebroventricularly injected BMY-14802 also antagonized the effects of intracerebellar D-serine, indicating a central mechanism. However, direct co-injection of BMY-14802 into the cerebellum failed to antagonize the D-serine-induced increases in cGMP, indicating a locus of action outside the cerebellum. In contrast, quisqualate-induced cGMP increases were not attenuated by BMY-14802. These results indicate a functional modulation of the N-methyl-D-aspartate/glycine/phencyclidine/ion channel complex-mediated events by BMY-14802, possibly through a transsynaptic mechanism, thus representing the first in vivo demonstration of a sigma ligand modulation of a response mediated through the N-methyl-D-aspartate receptor complex.
Alkaloids↗
Ifenprodil and SL 82.0715 antagonize N-methyl-D-aspartate (NMDA)-coupled glycine receptor responses in vivo.
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Adrenergic alpha-Antagonists↗
A controlled family history study of prepubertal major depressive disorder.
First-degree (N = 195) and second-degree (N = 785) adult relatives of prepubertal children with major depression (N = 48), children with nonaffective psychiatric disorders (N = 20), and normal children (N = 27) were assessed by the Family History-Research Diagnostic Criteria method (FH-RDC), except for the adult informant (usually the mother), who was directly interviewed. Compared with normal controls, prepubertal children with major depressive disorder (MDD) had significantly higher familial rates of psychiatric disorders in both first- and second-degree relatives, especially MDD, alcoholism, and "other" (mostly anxiety) diagnoses. Relatives of children in the nonaffective psychiatric control (PC) group had low rates of alcoholism, high rates of other (anxiety) disorder diagnoses, and intermediate rates of MDD (accounted for by those children with separation anxiety). This suggests that prepubertal onset of major depression may be especially likely in families with a high aggregation of affective disorders when these families also have a high prevalence of alcoholism, and that a proportion of children without affective disorder but with separation anxiety disorder in this study were at high risk for the development of affective illness later in life. These results support the validity of prepubertal-onset depressive illness as a diagnostic category, and are consistent with high familial rates of MDD and other psychiatric disorders found in family studies of adolescent and early-onset adult probands with major affective disorders, and with studies of the offspring of parents with major affective disorders. Within the child MDD group substantial heterogeneity was found. Low familial rates of MDD were associated with suicidality and comorbid conduct disorder in the child probands. The highest familial rates of MDD, approximately threefold those in the normal controls, and all the bipolar relatives, were found in the families of prepubertal probands with MDD who never had a concrete suicidal plan or act and who were without comorbid conduct disorder. A useful nosological continuum in which to classify prepubertal MDD may be to place at one end those patients with comorbid conduct disorder and at the other end those patients with manifestations related to bipolarity, including hypomania, mania, and psychotic subtype.
Adult↗
On the role of vitamin D binding globulin in glucose homeostasis: results from the San Luis Valley Diabetes Study.
Several studies have reported association between noninsulin-dependent diabetes mellitus and GC, the vitamin D binding protein of human plasma, with the GC 1 allele in significant excess among diabetics. Additionally, there is a considerable body of animal data suggesting that vitamin D has a significant impact on insulin secretion. Examination of the insulin levels in Dogrib Indians showed that the lowest levels of fasting insulin were associated with the GC IF-IF genotype. The present study examined levels of glucose, C-peptide, and insulin at fasting and 1 hr and 2 hr following a 75 g oral glucose challenge, in a population of Hispanic-Americans and Anglos in the San Luis Valley of southern Colorado. The sample comprised a total of 468 individuals with normal glucose tolerance. Of these, 289 were Anglos and 179 were Hispanic-Americans. An analysis of covariance was performed to determine the effect of the GC genotypes on mean levels of the primary variables--glucose, C-peptide, and insulin--and a secondary variable--insulinogenic index adjusting for the covariates age, body mass index (BMI), gender, and ethnicity. The analyses revealed that there is a significant difference in mean levels of glucose at fasting (F value = 2.46; P = 0.033) among the GC genotypes in the sample. Additionally, the differences in mean levels of 1 hr postprandial glucose among the GC genotypes although not significant at a 5% level, were significant at the 10% level. No other significant phenotypic effects were observed. These analyses are not in concordance with the results of an earlier study, where lower fasting insulin was associated with the GC 1F-1F genotype.
Blood Glucose↗