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Biomedical subjects

E Richelson

Publications and source records attributed to E Richelson.

At least 109 records · Page 6Linked to original sources
PubMed1990

Antidepressants and brain neurochemistry.

Most antidepressant drugs prescribed today have been available for decades. Nonetheless, their mechanism of action in treating depression has remained elusive. On the basis of neurochemical studies in laboratory animals, hypotheses explaining their therapeutic effects have been formulated. The most attractive of these theories involves antidepressant-induced changes in the sensitivity of certain catecholamine and serotonergic receptors in the brain. Support for this hypothesis from clinical studies has been difficult to obtain. Pharmacologic studies of antidepressant drugs, however, indicate the involvement of blockade of neuronal uptake systems for norepinephrine and serotonin and blockade of many receptors for neurotransmitters. These properties of antidepressants can explain some of their adverse effects and certain interactions with other drugs.

Animals↗
PubMed1989

Neurotensin(8-13): comparison of novel analogs for stimulation of cyclic GMP formation in neuroblastoma clone N1E-115 and receptor binding to human brain and intact N1E-115 cells.

Neurotensin(8-13), the carboxyl-terminal portion of neurotensin, is 4-50 times more potent than native neurotensin in binding to intact neuroblastoma N1E-115 cells and human brain tissue and in stimulation of intracellular cyclic GMP production and inositol phospholipid hydrolysis in clone N1E-115 (Gilbert JA and Richelson E, Eur J Pharmacol 99: 245-246, 1984; Gilbert JA et al., Biochem Pharmacol 35: 391-397, 1986; Kanba KS et al., J Neurochem 46: 946-952, 1986; and Kanba KS and Richelson E, Biochem Pharmacol 36: 869-874, 1987). A series of novel analogs of neurotensin (8-13) was synthesized, and a structure-activity study was done comparing the abilities of these peptides to stimulate intracellular cyclic GMP production in intact neuroblastoma clone N1E-115 and to inhibit the binding of [3H]neurotensin to these cells and to membranal preparations from human brain. A direct correlation was found for each analog between its EC50 for biochemical activity and its KD for binding ability in studies with clone N1E-115. Furthermore, a strong correlation existed for each peptide between its KD for binding to neurotensin receptors on these cells and its KD for binding to neurotensin receptors in human brain tissue. In this study, the residues that were important to the biochemical and binding activities of neurotensin (8-13) proved to be identical to the amino acids that are necessary for the functional integrity of native neurotensin (Gilbert JA et al., Biochem Pharmacol 35: 391-397, 1986.

Brain↗
PubMed1988

Desensitization of neurotensin receptor-mediated cyclic GMP formation in neuroblastoma clone N1E-115.

Murine neuroblastoma clone N1E-115 possesses receptors that specifically bind the tridecapeptide neurotensin, mediate the formation of intracellular cyclic GMP, and stimulate inositol phospholipid hydrolysis. These cells also rapidly degrade neurotensin in a sequential fashion. We studied the effect of prolonged exposure of cells to neurotensin on subsequent neurotensin receptor-mediated intracellular cyclic GMP formation under conditions that prevented degradation of this peptide [J. A. Gilbert and E. Richelson, Soc. Neurosci. Abstr. 12, 762 (1986)]. Neurotensin receptor-mediated cyclic GMP formation in neuroblastoma clone N1E-115 was decreased following prolonged exposure of intact cells to nondegraded neurotensin. The time course of this desensitization was very rapid; the maximal effect on cyclic GMP production (reduction to 10-30% of control values) occurred within 5 min of exposure of intact cells to neurotensin. This desensitization was homologous, as cells desensitized by neurotensin demonstrated no decrease in their cyclic GMP response to angiotensin II (1 microM) or bradykinin (10 nM). Neurotensin preincubation with intact N1E-115 cells for increasing lengths of time caused time-dependent shifts to the right of the dose-response curve and reductions in the maximum cyclic GMP response. Desensitization was reversible, but resensitization was a slower process than desensitization: full recovery of cyclic GMP production required incubation of the desensitized cells for at least 10 min at 37 degrees. From binding studies with [3H]neurotensin, we found that both the apparent equilibrium dissociation constant, KD, and the maximum number of receptor sites, Bmax, for this radioligand were decreased significantly (P less than 0.05) for completely desensitized cells from those values for control cells. These data suggest that desensitization of the neurotensin receptor involved an uncoupling of the pathway of events connecting receptor activation to intracellular cyclic GMP formation; complete desensitization involved both the apparent loss of neurotensin receptors on the cellular surface and the increase in affinity of the remaining receptors for the agonist. This decrease in Bmax is more likely to be a result of intracellular sequestration of recyclable NT receptors than of true down-regulation due to the rapid resensitization seen for the NT-mediated biological response.

Animals↗
PubMed1988

Organic causes of mania.

Manic syndromes have many neurologic, toxic, and metabolic causes. It is important for clinicians to be able to distinguish these organic disorders from primary idiopathic mania (bipolar disorder). The cardinal symptom of organic mania is an abnormally and persistently elevated or irritable mood. Organic mania usually develops in patients who are older than 35 years of age, whereas bipolar disorder generally has its onset between late adolescence and age 25 years. In patients with the first episode of mania, the clinician should thoroughly elicit information about current symptoms, recent infections, use of drugs, and past or family history of psychiatric disorders. In addition, a complete medical examination, computed tomography of the head, electroencephalography, and screening for drugs and toxins should be done. Treatment of organic mania includes correcting the underlying disorder when possible.

Adolescent↗
PubMed1988

[3H]neurotensin(8-13) binds in human brain to the same sites as does [3H]neurotensin but with higher affinity.

The binding of [3H]neurotensin(8-13) to membranes from human frontal cortex at 0 degree C was time dependent, specific, saturable, and reversible. Saturation isotherms provided an equilibrium dissociation constant (KD) of 0.52 nM, and the maximal number of binding sites (Bmax) was 3.5 pmol/g original wet weight of tissue. Scatchard analysis yielded a straight line, and the Hill coefficient was equal to 1, a result indicating that [3H]neurotensin(8-13) bound to single, noncoopertive sites. The KD values of several analogs of neurotensin determined in competition with [3H]neurotensin(8-13) were similar to those previously determined in competition with [3H]neurotensin. The regional distribution of binding sites for [3H]neurotensin(8-13) was also similar to that for [3H]neurotensin. These results suggest that [3H]neurotensin(8-13) binds to the same sites as [3H]neurotensin and that [3H]neurotensin(8-13) has a higher affinity than [3H]neurotensin for these sites in human brain.

Aged↗
PubMed1988

Neuroleptic binding to human brain receptors: relation to clinical effects.

Table 2 summarizes the potential clinical consequences of neurotransmitter receptor blockade by neuroleptics. These pharmacological effects of neuroleptics at receptors in brain and elsewhere in the body are likely responsible for therapeutic and certain adverse effects as well as some drug-drug interactions. Data presented here should allow the physician a rational basis for selecting neuroleptics to minimize these unwanted effects in patients.

Antipsychotic Agents↗
PubMed1988

Pseudo-noncompetitive antagonism of muscarinic receptor-mediated cyclic GMP formation and phosphoinositide hydrolysis by pirenzepine.

Pirenzepine selectively antagonized muscarinic receptor-mediated cyclic GMP formation in a noncompetitive fashion in mouse neuroblastoma cells (clone N1E-115). These effects of pirenzepine were time- and concentration-dependent and they were also reversible. Interestingly, whereas atropine elicited competitive antagonism of the cyclic GMP response at low concentrations, it also behaved like a noncompetitive antagonist at higher concentrations and its effects were partially reversible. Using additional approaches to study the mechanisms underlying this anomalous antagonistic profile of pirenzepine, we investigated whether this deviation from competition could be due to the short time of exposure to muscarinic agonists (30 sec) used in cyclic GMP measurements. Our data indicated that the mode of pirenzepine-induced antagonism of ligand binding to muscarinic receptors was different when assessed using nonequilibrium (30 sec) or equilibrium (1 hr) incubations. Thus, pirenzepine appeared to be noncompetitive and competitive under these two conditions, respectively. Furthermore, although pirenzepine blocked receptor-mediated phosphoinositide hydrolysis competitively when the response was measured at 20 min, it was clearly noncompetitive using 5-min incubations. Therefore, the noncompetitive antagonism by pirenzepine detected in cyclic GMP measurements might be only apparent and might be attributed, at least in part, to a lack of an equilibrium state under the specific conditions of these assays.

Animals↗
PubMed1988

Histamine-induced intracellular free Ca++, inositol phosphates and electrical changes in murine N1E-115 neuroblastoma cells.

Apparent intracellular free Ca++ concentration [(Ca++]i) was measured in differentiated N1E-115 neuroblastoma by microinjecting cells with aequorin (estimated intracellular concentration, 4 microM) and measuring light emission. Histamine produced a transient, dose-dependent increase in [Ca++]i. Pyrilamine blocked completely the response to histamine whereas cimetidine had no effect. Omitting Ca++ from the external medium reversibly blocked the response. As well as a rise in [Ca++]i, histamine caused a concomitant cell hyperpolarization that was not blocked by ouabain, low Cl-, tetraethylammonium chloride/tetradotoxin or metiamide but was blocked by apamin and pyrilamine. A secondary small depolarization caused by histamine was also blocked by apamin but not by ouabain, low Cl- or tetraethylammonium chloride/tetrodotoxin. Direct iontophoretic injection of Ca++ into cells caused only hyperpolarization. Injection of inositol 1,4,5-trisphosphate [IP3(1,4,5)] caused an increase in [Ca++]i and rapid hyperpolarization. Inositol 1,3,4-trisphosphate [IP3(1,3,4)] caused an increase in [Ca++]i, rapid hyperpolarization and a slower depolarization. Repeated injections of IP3(1,3,4) led to a diminished [Ca++]i response and decreased hyperpolarization but had no effect on depolarization. Inositol 1,3,4,5-tetrakisphosphate was without effect on [Ca++]i or on cellular membrane potential. The results suggest that histamine causes an H1 receptor-dependent increase in [Ca++]i, probably by the increased entry of extracellular Ca++, although there may be a contribution from intracellular Ca++ released by IP3(1,4,5). The increase in [Ca++]i activates K+ channels leading to cell hyperpolarization. IP3(1,3,4) formed from inositol 1,3,4,5-tetrakisphosphate, which is itself a product of IP3(1,4,5), causes a slower depolarization by a mechanism that does not involve Na+ channels or an increase in [Ca++]i.

Animals↗
PubMed1987

Antagonism by neuroleptics of serotonin 5-HT1A and 5-HT2 receptors of normal human brain in vitro.

Using radioligand binding techniques and human frontal cortex, we determined the equilibrium dissociation constants (KDs) of 17 neuroleptics at the serotonin 5-HT1A and serotonin 5-HT2 receptors with [3H]WB4101 and [3H]ketanserin, respectively. At the serotonin 5-HT1A receptor, the most and least potent neuroleptics were chlorprothixene (KD = 230 nM) and fluphenazine (KD = 40 microM), respectively. At the serotonin 5-HT2 receptor, the most and least potent neuroleptics were spiperone (KD = 0.38 nM) and molindone, (KD = 5 microM), respectively.

Antipsychotic Agents↗
PubMed1987

Comparison of the stimulation of inositol phospholipid hydrolysis and of cyclic GMP formation by neurotensin, some of its analogs, and neuromedin N in neuroblastoma clone N1E-115.

Neurotensin, some of its analogs, and neuromedin N were examined for comparison of their potencies at stimulating inositol phospholipid hydrolysis and cyclic GMP synthesis in intact murine neuroblastoma cells (clone N1E-115). Neurotensin(8-13) and acetylneurotensin(8-13) had the highest potencies for the stimulation of the hydrolysis of inositol phospholipid, which were about three times as potent as neurotensin (EC50 = 0.9 nM). On the other hand, fragments of the amino-terminal portion of neurotensin, such as neurotensin(1-6), neurotensin(1-8) and neurotensin(1-11), showed no ability to stimulate this hydrolysis. Neuromedin N, which is similar in structure to neurotensin(8-13) and which has been demonstrated to stimulate cyclic GMP formation [J.A. Gilbert and E. Richelson, Eur. J. Pharmac. 129, 379 (1986)], had EC50 values of 2.5 and 4.5 nM for release of [3H]inositol phosphates and stimulation of cyclic [3H]GMP respectively. A strong correlation was obtained between the EC50 values for neurotensin and several analogs in the stimulation of the release of inositol phosphates and the EC50 values for these peptides in the stimulation of cyclic GMP formation in neuroblastoma clone N1E-115 cells under similar experimental conditions. Thus, these two different biochemical effects of neurotensin and its analogs appear to be mediated by the same receptor site, which may also have been the site of action of neuromedin N in these cells.

Animals↗
PubMed1987

Antipsychotic drugs: prediction of side-effect profiles based on neuroreceptor data derived from human brain tissue.

The affinities of antipsychotic agents for neurotransmitter receptors are believed to be responsible for their antipsychotic activity and side-effect profiles. Data on neuroreceptor affinity can be used to predict side-effect profiles of antipsychotic drugs. In this report, we present data on receptor affinity that have been modified to help clinicians clearly see the potential for each drug to produce a specific side effect at any dosage.

Antipsychotic Agents↗
PubMed1987

Rapid degradation of neurotensin by intact murine neuroblastoma cells (clone N1E-115).

Murine neuroblastoma clone N1E-115, which possesses receptors for neurotensin mediating the formation of intracellular cyclic GMP and the stimulation of inositol phospholipid hydrolysis, exhibited only partial desensitization to neurotensin. This result led to the observation that neurotensin was very rapidly degraded by intact N1E-115 cells. In experiments measuring the time course of [3H]neurotensin degradation, a minimum of six major tritiated products were found, with the breakdown peptides formed and the degree of proteolysis of [3H]neurotensin being dependent upon the length of incubation and the concentration of cells. Clone N1E-115 degraded [3H]neurotensin in an apparently sequential fashion; the primary initial cleavage of intact neurotensin was at the peptide bond between residues Arg8 and Arg9. Initial degradation peptides from the active carboxyl-terminal portion of neurotensin were more rapidly degraded, after formation, than were the peptides from the inactive amino-terminal half of neurotensin. The final two degradation products found were tyrosine, from the carboxyl-terminal portion of neurotensin, and an as yet unidentified peptide from the amino-terminal half of neurotensin. [3H]Neurotensin(8-13) was more rapidly hydrolyzed under identical conditions than was [3H]neurotensin itself. A combination of the protease inhibitors 1,10-phenanthroline and Z-Pro-Prolinal was able to inhibit almost completely the degradation of neurotensin by clone N1E-115.

Animals↗
PubMed1987

Pharmacology of antidepressants.

Choice of an antidepressant medication is, in part, based on the side effects produced by a drug and the desire to avoid certain reactions in a particular patient. The clinician needs a reliable method of predicting which medications are most likely to produce specific untoward effects. Understanding the synaptic pharmacology of the most commonly used agents could serve as a tool for predicting possible side effects and drug-drug interactions. Antidepressant drugs alter neurotransmitter effects at nerve synapses, probably by blocking norepinephrine and serotonin reuptake, and blockade of neurotransmitter receptor sites - primarily the histamine H1 receptor, the muscarinic receptor, and the alpha-1-adrenoceptor. Possible clinical side effects related to some of these interactions include tachycardia, tremor, and (possibly) male sexual dysfunction (associated with norepinephrine reuptake blockade); sedation (associated with histamine H1 blockade); orthostatic hypotension, dizziness, and reflex tachycardia (associated with alpha-1-adrenoceptor blockade), and blurred vision, dry mouth, and memory dysfunction (associated with muscarinic receptor blockade). Pharmacologic data that demonstrate the potencies and selectivities of the antidepressant drugs for reuptake blockade and receptor site antagonism might allow the clinician to make an informed, rational choice of antidepressant therapy. This paper presents data on drug potencies and selectivities, and attempts to relate these data to anticipated side effects and drug-drug interactions.

Antidepressive Agents↗
PubMed1987

Sodium-lithium countertransport in ambulatory hypertensive and normotensive patients.

Numerous studies have reported the mean value for Na+-Li+ countertransport to be increased in red blood cells from patients with essential hypertension. Although concomitant variables including age, body size, national origin, geographic location, gender, and family history of hypertension may affect Na+-Li+ countertransport values, most case-control studies have failed to assess the contribution of these factors to the differences in Na+-Li+ countertransport between hypertensive and normotensive groups. The present study was undertaken to provide estimates of Na+-Li+ countertransport in hypertensive and normotensive subjects after taking into account these potentially confounding sources of variation. In 187 subjects undergoing medical evaluation at the Mayo Clinic, Rochester, MN, the combined effects of variation in age, height, and weight accounted for 20.6% of the interindividual variability in Na+-Li+ countertransport. After adjustment to remove variability due to these concomitants, differences in national origin, region of birth, and place of current residence made no additional contribution to variability in this trait. There was no significant difference in mean adjusted Na+-Li+ countertransport between men and women (0.41 +/- 0.17 vs 0.40 +/- 0.12 [SD] mmol Li efflux/L red blood cells/hr; n = 107). The mean value for adjusted Na+-Li+ countertransport was significantly greater (p less than or equal to 0.001) in subjects with essential hypertension (0.44 +/- 0.15 mmol/L red blood cell/hr; n = 104) compared with normotensive subjects (0.31 +/- 0.07 mmol/L red blood cells/hr; n = 39) or subjects with borderline blood pressure elevation (0.35 +/- 0.11 mmol/L red blood cells/hr; n = 21). Subjects with a family history of hypertension in at least one parent or full sibling had significantly higher (p less than 0.02) Na+-Li+ countertransport values (0.42 +/- 0.16 mmol/L red blood cells/hr; n = 111) than those with no family history of hypertension (0.37 +/- 0.13 mmol/L red blood cells/hr; n = 76). These results suggest that increased mean Na+-Li+ countertransport in hypertensive subjects in this sample cannot be attributed to confounding effects of variation in age, body size, gender, national origin, birthplace, or residence. Forty-eight percent of subjects with essential hypertension had adjusted Na+-Li+ countertransport values above the range observed in normotensive controls.

Age Factors↗