Biomedical subjects

I Hanin

Publications and source records attributed to I Hanin.

At least 91 records · Page 5Linked to original sources

PubMed1986

Sex differences in muscarinic receptor binding after chronic ethanol administration in the rat.

Male and female rats were administered ethanol (5% v/v) in a liquid diet for 18 weeks. Pair-fed control animals were fed the same diet except that dextrose was substituted isocalorically for ethanol. Normal controls received a commercial laboratory chow for the same duration. Results showed that, in females, chronic ingestion of an ethanol liquid diet significantly increased the number of muscarinic receptor binding sites compared to both control groups. In contrast, for males, there was no significant difference in the mean number of binding sites among the treatment groups. Furthermore, the mean maximum number of binding sites for males and females varied across brain areas. Males had a significantly greater number of receptor binding sites than females in the striatum, while females had a greater number in the cortex. It was suggested that the geuder differences observed in the present study could be mediated by hormonal effects on central muscarinic functioning.

Alcoholism↗

PubMed1986

Path analysis of psychopharmacological data: catecholamine breakdown in man.

This article applies path analysis to the problem of characterizing metabolic alterations in catecholamine systems when only static or single measures of precursor and products are available. In this article, simulated data from kinetic models of norepinephrine metabolism were examined using path analysis. The method of path analysis, which is based on correlations between compartments and not actual flow, correctly identified operative and nonoperative metabolic pathways in simulated models. In addition, actual data from normal subjects as to the 24-hour urinary values for norepinephrine, normetanephrine, vanillylmandelic acid, and 3-methoxy-4-hydroxyphenylglycol were analyzed using path analysis. It was found that metabolic routes that are known to be incomplete did not fit these data, whereas the known metabolic pathways for norepinephrine were correctly identified using path analysis. These results suggest that path analysis may provide a useful tool in identifying normal and abnormal catecholamine metabolic pathways in experimental situations where only single values of precursor and products are available.

Humans↗

PubMed1986

Effects of intracerebroventricular AF64A administration on cholinergic, serotoninergic and catecholaminergic circuitry in rat dorsal hippocampus.

Five nmol ethylcholine mustard aziridinium ion, a potential cholinotoxin was administered bilaterally into the cerebral ventricles of male rats at coordinates A -1.5, L +/- 1.5 and V -4.0 mm. The dorsal hippocampi were processed for choline acetyltransferase, serotonin or tyrosine hydroxylase immunocytochemistry 7 days after the injection to determine the specificity of the effect of the drug. Intrinsic choline acetyltransferase positive cells were also found after treatment, while the overall staining of fibres decreased. No change was observed in staining for either serotonin or tyrosine hydroxylase. Using the electron microscope, degenerating nerve terminals, with recognizable synaptic specializations were encountered, most frequently in stratum oriens and occasionally, degenerated CA3 pyramidal cells were observed. These findings are consistent with the neurochemical data obtained in parallel experiments with the morphological study in which it was found that acetylcholine content of the hippocampus was reduced by 73.4% 7 days after ethylcholine mustard aziridinium ion treatment, while dopamine, noradrenaline and serotonin levels were unaffected. Furthermore, the morphological studies indicate that ethylcholine mustard aziridinium ion can exert selective effects on the cholinergic system of dorsal hippocampus without significantly altering its cytoarchitecture.

Animals↗

PubMed1986

Neurochemistry of aging. 1. Toxins for an animal model of Alzheimer's disease.

A chronic deficiency in central cholinergic function has been implicated in a number of neuropsychiatric diseases including Alzheimer's disease. Until recently, animal models that simulate the neurochemical conditions that appear to cause these diseases in humans, as a result of a direct manipulation of the central cholinergic system, were not available. Over the past few years, however, we have been successful in developing a cholinotoxin, 1-ethyl-1-(2-hydroxyethyl)aziridinium chloride (AF64A), which has the potential to serve as a novel compound in developing animal models of human brain disorders in which a cholinergic hypofunction has been implicated. In this paper are described the design, synthesis, and testing of several structural analogues of AF64A as potential cholinotoxins, by evaluating them for their ability to inhibit high-affinity choline transport and their affinity toward brain muscarinic receptors. One of the compounds, 1-cyclopropyl-1-(2-hydroxyethyl)aziridinium chloride (i.e. aziridine analogue of 13) was found to have a remarkably high affinity (about 40 times higher than AF64A) toward brain muscarinic receptors.

Alzheimer Disease↗

PubMed1986

Potential animal models for senile dementia of Alzheimer's type, with emphasis on AF64A-induced cholinotoxicity.

In this review we have described and critiqued several commonly used proposed animal models for SDAT. In particular, we have focussed on the AF64A-treated animal. Major pertinent neurochemical and behavioral data obtained so far with AF64A have been presented, and these effects have been compared with neurochemical and behavioral changes in the SDAT patient. We have commented on the possible mechanism(s) of action of AF64A in vivo, and have also presented some observations and speculations concerning the selectivity of action of AF64A as a specific presynaptic cholinotoxin. Much work has yet to be done with all the available animal models, including the AF64A-treated animal, before one could definitively state which one is the ideal model for SDAT. Data obtained to date with the AF64A-treated animal are nevertheless most encouraging. Despite some caveats, AF64A is a valuable neurochemical tool with which one can induce a persistent cholinergic deficiency of presynaptic origin. As with all new tools, however, one must always exercise due care to use it properly, and interpret the results obtained following its administration with caution.

Aged↗

PubMed1986

Imipramine and amitriptyline plasma concentrations and clinical response in major depression.

Plasma drug concentrations and clinical response were measured in two groups of hospitalised depressed patients, who received amitriptyline or imipramine double-blind, in a dosage of 250 mg for four weeks. Virtually no significant linear or curvilinear relationships were found between any plasma measure and any measure of clinical response. Modest but significant direct relationships were found between age and concentration of parent drugs but not demethylated metabolites. Blood drug level measurement therefore appears to be of little value in monitoring drug treatment of depressed in-patients.

Age Factors↗

PubMed1986

Treating delusional depressives with amitriptyline.

Thirty-five delusional depressed patients were treated for either 28 or 35 days with amitriptyline. The 12 responders could not be differentiated from the nonresponders on a variety of demographic and clinical characteristics. Patients with amitriptyline+nortriptyline plasma levels above 250 ng/ml were significantly more likely to be responders than were patients with levels below that value (p less than .05). A review of the relevant literature revealed that, although some delusional depressives do respond to treatment with tricyclic antidepressants, the presence of delusions is a predictor of poor response to tricyclic antidepressants.

Adult↗

PubMed1986

The pharmacological treatment of delusional depression: Part II.

This study investigated the pharmacological treatment of delusional depressives by assigning patients on a random double-blind basis to amitriptyline (AT) alone, perphenazine (PER) alone, or AT + PER. As reported in an earlier paper, the combination of AT + PER was the superior treatment with a response rate of 78% compared with 41% for AT alone and 19% for PER alone. This difference is both clinically and statistically significant (p less than 0.01). In this second article, the authors report that the patients on AT + PER had higher plasma levels of AT and its pharmacologically active metabolite nortriptyline (NT) than the patients on AT alone. Although the response rate had a direct relationship to AT + NT plasma levels, an analysis of variance showed that the group of patients treated with AT + PER still had a significantly higher response rate, even after controlling for the plasma levels of AT + NT (p less than 0.05). There was also a correlation between PER plasma levels and clinical response.

Amitriptyline↗

PubMed1986

Psychobiology and psychopharmacology: issues in clinical research training.

Although the scope of basic studies in psychopharmacology and psychobiology has been expanding steadily for about 30 years, relatively few clinical psychiatrists, psychologists, and psychopharmacologists now choose to become researchers or teachers in these disciplines. Such training is crucial to the future vitality of both academic and private-practice psychiatry, and in view of increasing constraints on training funds, student researchers may well be an endangered species. With these concerns in mind, at its 1984 meeting, the American College of Neuropsychopharmacology's Education and Training Committee organized a symposium of investigators, administrators, and former trainees to explore aspects of effective clinical research training in psychobiology and psychopharmacology. Aspects discussed included mentoring, settings and content of training, depth versus breadth of curriculum, and the effect of a critical mass of colleagues at various stages of professional development. Following a brief overview, selected panelists addressed the issues from their individual perspectives.

National Institute of Mental Health (U.S.)↗

PubMed1985

Ethylcholine mustard aziridinium blocks the axoplasmic transport of acetylcholinesterase in cholinergic nerve fibres of the rat.

A cholinotoxin, ethylcholine mustard aziridinium ion, (AF64A) specifically and irreversibly blocks the intraaxonal transport of acetylcholinesterase in the rat. Impairment of the transport of this enzyme in the septo-hippocampal cholinergic fibres and in the sciatic nerve has been studied, using different doses of AF64A. It is demonstrated that the effect on the axonal transport is dose-dependent, but is not related to the mode of drug application. AF64A thus may exert its neurotoxic effects on cholinergic neurons at several target sites of action. In addition to the localized presynaptic mechanisms, it may also be compromising cholinergic function by inhibiting axonal transport in vivo.

Animals↗

PubMed1985

Lipid composition of different areas of murine brain: effects of lipid extraction procedures.

The effects of various chemical extraction procedures on the determination of lipid composition of rat and mouse brain have been investigated. Tissue extractions with formic acid/acetone or perchloric acid both resulted in significant losses of total phospholipids and cholesterol. Perchloric acid extraction also degraded, almost quantitatively, ethanolamine plasmalogens to lysophosphatidylethanolamine. Our findings have thus demonstrated that conventional procedures used for extraction of brain tissue for analysis of choline and acetylcholine content cannot also be used for concurrent/simultaneous extraction of phospholipids and cholesterol from the same tissue.

Animals↗

PubMed1985

Intracerebroventricular administration of ethylcholine mustard aziridinium ion (AF64A) reduces release of acetylcholine from rat hippocampal slices.

Ethylcholine mustard aziridinium ion (AF64A), or vehicle, was infused bilaterally (3 nmol/3 microliter per side) into the lateral ventricles of rats. The effect of such treatment on various cholinergic responses was measured in the hippocampus, cortex and striatum. Potassium-stimulated release of acetylcholine from superfused slices of hippocampus was reduced, 7 and 21 days after treatment with AF64A, to 24 and 35% of control, respectively. The activity of choline acetyltransferase in the hippocampus also decreased, to 42% of control, both 7 and 21 days after treatment with AF64A. Similarly, the activity of acetylcholinesterase and the high affinity transport of choline in the hippocampus were reduced, to 40 and 30% of control; and to 33 and 48% of control, respectively, 7 and 21 days after treatment with AF64A. Synthesis of acetylcholine in slices of hippocampus was also decreased after treatment with AF64A (71 and 51% of control, 7 and 21 days post-AF64A respectively). Only the binding of [3H]QNB in the hippocampus was unchanged at 7 days after treatment with AF64A, although a small reduction (11%) was noted 21 days after treatment with AF64A. The activity of choline acetyltransferase and acetylcholinesterase, the high-affinity transport of choline and the binding of [3H]QNB in cortex and striatum were unaffected by treatment with AF64A under the same experimental conditions. Using a substantially smaller dose than that earlier reported in mice, the earlier finding was thus confirmed, and extended, in rats, of a highly selective effect of AF64A on several components of the cholinergic system. Under the conditions of this study, these effects appeared to be confined to the hippocampus.

Acetylcholine↗

PubMed1985

Cerebrospinal fluid levels of amitriptyline, nortriptyline, imipramine and desmethylimipramine. Relationship to plasma levels and treatment outcome.

Fifty-five (55) depressed patients were treated with amitriptyline (AMI) or imipramine (IMI). Concentrations of AMI, IMI, and their metabolites, nortriptyline (NT) and desmethylimipramine (DMI), were measured in cerebrospinal fluid (CSF) and plasma at steady state by gas chromatography mass spectrometry (GC/MS). Highly significant correlations between CSF and plasma levels of AMI, NT, IMI, and DMI were found (r greater than 0.75; P less than 0.0001 in all cases). There were no significant sex, diagnostic subgroup, or geographic difference in any of the drug parameters measured. An evaluation of the relationship between CSF levels of drug variables and clinical response showed essentially no significant correlations between these various parameters. The results obtained do not support the concept of a 'therapeutic window' for levels of plasma NT in AMI-treated patients. Furthermore, the highly significant correlations between CSF and plasma compartments in terms of drug and metabolite levels would argue against the need to measure CSF levels of these parameters in clinical practice. Plasma level measurements should be equally informative, and simpler to obtain.

Amitriptyline↗

PubMed1985

Effects of amitriptyline and imipramine on brain amine neurotransmitter metabolites in cerebrospinal fluid.

The effects of amitriptyline (AMI) or imipramine (IMI) on levels of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) (the major brain metabolites of the neurotransmitters norepinephrine [NE], serotonin [5-HT], and dopamine [DA]) in cerebrospinal fluid were determined in 66 subjects with unipolar and bipolar depression. There were significant reductions in MHPG and 5-HIAA levels for the depressed group taken as a whole, but levels of HVA did not change significantly. The changes were similar when subjects were grouped as treated with AMI and IMI and with unipolar and bipolar depression. Reductions in MHPG and 5-HIAA levels were greater in women than in men. In all subjects with depression and in those treated with AMI and IMI, amine metabolite changes did not differ significantly between those who had a positive clinical response to drug therapy and those who did not. Responders with bipolar depression had smaller reductions in MHPG levels than did responders with unipolar depression. The similar effects of AMI and IMI on MHPG and 5-HIAA differ from the dissimilar effects of the two drugs on NE and 5-HT amine uptake systems reported in animal and in in vitro studies. Results provide conclusive evidence of the effects of AMI and IMI on noradrenergic and serotonergic (but not dopaminergic) systems in patients with depression.

Adult↗

PubMed1985

A pharmacokinetic approach to the study of cell membrane lithium transport in vivo.

Although many previous investigations have focused on in vitro studies of lithium transport by erythrocytes (RBCs) of psychiatric patients, the extent to which such studies actually reflect the transport of this drug by other types of cells in vivo is unknown. To study lithium transport in vivo, pharmacokinetic analysis of plasma lithium concentration data was performed in four subjects who were given single oral doses of lithium carbonate (600 mg). The data were analyzed according to a two-compartment model, consisting of a central compartment (extracellular, including plasma) and a peripheral (intracellular) compartment. Rate constants for the transfer of lithium into (ki) and out of (ko) the intracellular compartment were calculated. In RBCs from the same subjects, lithium transport in vitro was also directly measured. Rate constants were determined for phloretin-sensitive transport (ks), which corresponds to Na+-Li+ countertransport activity, and residual passive "leak" diffusion (kr). In RBCs, these two pathways account for major components of lithium efflux and influx, respectively. To compare the in vivo and in vitro rate constant data, the ratios ko/ki and ks/kr were also calculated. There was a significant correlation between these two rate-constant ratios (r = 0.96, p less than 0.05), although the values observed in vitro were higher than those found in vivo. Because the in vivo rate constants reflect lithium transport by many types of cells in the peripheral compartment, this finding supports the idea that the RBC may provide a useful model for studying lithium transport processes that are also operative in other types of cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Membrane Permeability↗

PubMed1985

AF64A: an active site directed irreversible inhibitor of choline acetyltransferase.

Ethylcholine mustard aziridinium ion (AF64A, MEChMAz) has been proposed as a cholinergic neuron-specific neurotoxin. We report that in further studies on its mechanism of action incubation of the cholinergic neuroblastoma X glioma cell line, NG-108-15, with 100 microM AF64A resulted in a rapid decrease in cellular choline acetyltransferase (ChAT) activity which preceded cytotoxicity. Thus, a 60-85% decrease in ChAT activity was measured within 5 h of AF64A exposure, whereas cell lysis (measured as the release of the cytosolic enzyme lactate dehydrogenase into the medium) did not become apparent until 18 h of AF64A exposure. This led us to examine the effects of AF64A on partially purified ChAT. We report a concentration- and time-dependent inhibition of partially purified ChAT by AF64A that could not be reversed by dialysis but could be prevented by coincubation of the enzyme and AF64A with choline but not with acetyl-coenzyme A. We present kinetic evidence that choline and AF64A compete for the same site on the enzyme. In addition, thiosulfate, which inactivates the aziridinium ion, eliminated AF64A's capacity to inhibit the enzyme. AF64A also irreversibly inhibited partially purified choline kinase and acetylcholinesterase but not lactate dehydrogenase, alcohol dehydrogenase, carboxypeptidase A, or chymotrypsinogen, enzymes that do not use choline as a substrate or product. Thus, the data suggest that AF64A acts as an irreversible active site directed inhibitor of ChAT and possibly other enzymes recognizing choline.

Animals↗

PubMed1985

Red blood cell abnormalities in Alzheimer disease.

In a prospective, double-blind study of 84 unselected persons in a dementia clinic, the red blood cell/plasma choline ratios were found to be significantly higher in 47 subjects with clinically defined Alzheimer disease (DAT) than in 37 non-DAT, nondepressed subjects (3.54 +/- 0.48 versus 2.04 +/- 0.34, p less than 0.02). The latter group included intellectually intact subjects as well as patients with other dementias who were comparable to the Alzheimer patients in age, sex, and degree of cognitive impairment. The elevated mean ratio reflected the greater proportion of Alzheimer patients with high red blood cell plasma choline ratios. These elevated ratios appeared to be related to both increases in red cell content and decreases in plasma choline. The authors conclude that the results confirm and extend those previously reported in short series of patients and agree with other evidence that Alzheimer disease has systemic manifestations in nonneural cells, which may be useful in further investigations of the disease's cellular pathophysiology.

Aged↗

PubMed1985

Blood choline and response to clonazepam and haloperidol in Tourette's syndrome.

This paper reports the results of a single blind clinical study of drug treatment response of 20 patients with Tourette's syndrome to haloperidol and clonazepam. Because patients with Tourette's syndrome have been reported to have increased red blood cell choline levels, choline levels were examined in relation to treatment response. Differential drug treatment response was found among patients with high versus low red blood cell-to-plasma choline ratios. Patients with high red blood cell-to-plasma choline ratios responded better to clonazepam than to haloperidol. This suggests that there may be two distinct subtypes of patients with Tourette's syndrome.

Adolescent↗