Biomedical subjects

I Hanin

Publications and source records attributed to I Hanin.

At least 109 records · Page 6Linked to original sources

PubMed1985

AF64A produces long-term cognitive impairments following infusion into the lateral cerebral ventricles or the dorsal hippocampus: involvement of hippocampal cholinergic processes in learning and memory.

In summary, the data presented here suggest that depleting ACh in the HPC has long term consequences on cognitive behavior. It is suggested that HPC cholinergic processes are an important neurobiological substrate of cognitive behavior. Finally, AF64A seems a useful tool for elucidating the cholinergic mechanisms underlying the modulation of behavior.

Animals↗

PubMed1985

The pharmacological treatment of delusional depression.

The authors investigated the pharmacological treatment of delusional depression by assigning patients on a random double-blind basis to amitriptyline alone, perphenazine alone, or a combination of the two. Fourteen (78%) of the 18 patients assigned to amitriptyline plus perphenazine were responders, compared with seven (41%) of 17 patients treated with amitriptyline alone and three (19%) of the 16 patients treated with perphenazine alone. The combination of amitriptyline and perphenazine was clearly superior (p less than .01).

Adolescent↗

PubMed1985

Regional differences in ethylcholine mustard aziridinium ion (AF64A)-induced deficits in presynaptic cholinergic markers for the rat central nervous system.

Several highly selective biochemical markers were used to assess the persistent central cholinergic dysfunction which accompanies administration of the cholinergic neurotoxin ethylcholine mustard aziridinium ion (AF64A). Rats received a single bilateral intracerebroventricular injection of AF64A (3 nmol/3 microliter/side) or vehicle and measurements were carried out in the cerebral cortices, hippocampi and corpora striata at 7 and 21 days postinjection. The drug binding sites of muscarinic cholinergic receptors, as revealed by high-affinity binding of (-)-[3H]quinuclidinyl benzilate (a classical muscarinic antagonist), [3H]pirenzepine (a selective antagonist of the putative M1 muscarinic receptor subclass) and (+)-[3H]cis-methyldioxolane (a potent muscarinic agonist), were not significantly affected by AF64A treatment. As reported previously, activity of the cholinergic synthetic enzyme choline acetyltransferase was reduced markedly (60-65%) in the hippocampi of AF64A-treated rats. A similar reduction was noted in high-affinity binding of [3H]hemicholinium-3 (a putative radioligand for sodium-dependent high-affinity choline uptake sites on cholinergic nerve terminals) in hippocampal membranes (59-65%). However, in the cerebral cortex, these presynaptic cholinergic markers were differentially altered by AF64A pretreatment (choline acetyltransferase, unchanged; [3H]hemicholinium-3 binding, reduced by 59-65%). These results indicate that a single intracerebroventricular injection of AF64A promotes biochemical and possibly functional deficits in presynaptic cholinergic nerve terminals distal from the injection site while having minimal influences upon muscarinic cholinergic receptor populations.

Animals↗

PubMed1984

AF64A, a cholinergic neurotoxin, selectively depletes acetylcholine in hippocampus and cortex, and produces long-term passive avoidance and radial-arm maze deficits in the rat.

The behavioral and biochemical effects of AF64A, a presynaptic cholinergic neurotoxin, were investigated. Bilateral administration of this compound into the lateral cerebral ventricles produced transient and dose-related effects on sensorimotor function and long-term impairments of cognitive behavior. Male Fischer-F344 rats dosed with either 15 or 30 nmol of AF64A reacted 29-62% faster than CSF-injected controls in a hot-plate test 14 (but not 1, 7, 21 or 28) days following dosing. The group administered 15 nmol of AF64A was also significantly more active (41%) than controls 28 days following dosing. The activity level of this group was comparable to that of controls at other times and hyperactivity was never observed in the 30 nmol group. Retention of a step-through passive avoidance task, assessed 35 days after dosing, was impaired in both the 15 and the 30 nmol groups. Their step-through latencies were significantly shorter than the control latencies, and they exhibited more partial entries during the 24-h retention test. Radial-arm maze performance, measured 60-80 days following treatment, was markedly impaired in the treated groups. Animals treated with AF64A made fewer correct responses in their first 8 choices, required more total selections to complete the task, and had an altered pattern of spatial responding in the maze. The neurochemical changes produced by AF64A, determined 120 days after dosing, were specific to the cholinergic system and consisted of decreases of ACh in both the hippocampus (15 and 30 nmol groups) and the frontal cortex (30 nmol group). The concentrations of catecholamines, indoleamines, their metabolites and choline in various brain regions were not affected by AF64A. Furthermore, histological analysis revealed that the doses of AF64A used in the present study did not damage the hippocampus, the fimbria-fornix, the septum or the caudate nucleus. These data support the contention that cholinergic processes in the hippocampus and/or frontal cortex play an important role in learning and memory processes. Furthermore, based upon the behavioral and biochemical data presented, it is suggested that AF64A could be a useful pharmacological tool for examining the neurobiological substrates of putative cholinergic disorders such as senile dementia of the Alzheimer's type.

Acetylcholine↗

PubMed1984

Possible mechanisms involved in the presynaptic cholinotoxicity due to ethylcholine aziridinium (AF64A) in vivo.

AF64A is a toxin which can diminish irreversibly cholinergic transmission in vivo (1, 2). Disruption of neurotransmitter function in vivo is specific to the cholinergic system when AF64A is administered in nanomolar quantities (3, 4). The mechanisms involved appear to be mediated presynaptically (g). The neurochemical and behavioral consequences of AF64A administration are reminiscent of similar measures in patients with Alzheimer's disease (5, 6). Consequently, we have suggested tentatively that the AF64A treated animal may be explored as a potential animal model of this debilitating disease state (7). In this report we provide a brief overview of our recent findings using this compound in vivo, attempt to correlate these findings with those of others with similar aziridinium agnts in vitro, and propose a possible mechanism of action of AF64A in vivo, based on recent observations made in our laboratories.

Acetylcholine↗

PubMed1984

Selective cholinergic neurotoxin: AF64A's effects in rat striatum.

The selective neurotoxic effects of the aziridinium ion of ethylcholine (AF64A) have been examined after stereotaxic injection into the rat striatum. In a dose-response study (2-26 nmol), 8 nmol caused a 46% decrease in striatal choline acetyltransferase (CAT) activity with minimal effects on the activities of glutamate decarboxylase (GAD) and tyrosine hydroxylase (TH) at 7 days. Maximal CAT reductions of 78-82% occurred with doses of 16-26 nmol which also caused dose-related decreases in GAD and TH activities that paralleled the progressive decrements in CAT. A time course study with 8 nmol indicated a rapid 20% reduction of CAT activity by 12 h and an additional gradual fall of 20% over the next week; TH and GAD activities were not significantly reduced. The selective inhibition of CAT activity persisted for at least 3 months. Histological examination of Nissl stained sections revealed an area of nonspecific damage at the injection site with an abrupt border surrounded by apparently normal striatal neuropil; however; neuronal perikarya staining intensely for acetylcholinesterase were not reduced. These preliminary findings strongly suggest that AF64A has selective neurotoxic effects against striatal cholinergic neurons while relatively sparing striatal GABAergic intrinsic neurons or dopaminergic afferents.

Animals↗

PubMed1984

Effects of the cholinotoxin, AF64A, on neuronal trace-metal distribution in the rat hippocampus and neocortex.

Ethylcholine mustard aziridinium ion (AF64A) is a neurotoxin which is specific for cholinergic nerve terminals. Besides its effects on elements of the acetylcholine system, we observed that, after 2 and 8 days, a single 20-nmol intracerebroventricular dose altered the Timm's staining of certain regions of the central nervous system and reduced the tissue levels of trace metals. In the hippocampal formation, there was a considerable decrease in the staining of the neuropil of the stratum radiatum and stratum oriens, which contain cholinergic nerve terminals. A reduction in staining was also demonstrated in the perikarya of cortical pyramidal cells. The diminished trace-metal level in both regions was confirmed by quantitative measurements of zinc and copper levels. A similar reduction was not observed at a lower dose (8 nmol) of the cholinotoxin. The results led to the conclusion that AF64A may cause the decrease of the trace-metal content of the postsynaptic neurons through an indirect mechanism.

Animals↗

PubMed1984

Erythrocyte choline transport in drug-free and lithium-treated individuals.

The choline (Ch) content of erythrocytes (RBCs) has been reported to be elevated in several psychiatric and neurologic disorders. The present investigation was conducted in order to examine the relationship between in vivo RBC Ch content and Ch flux across the RBC membrane (measured in vitro). To perform the in vitro studies, we measured the outward transport of endogenous Ch (DoCh efflux) and the concomitant inward transport of deuterated Ch (D4Ch influx), in RBCs that were incubated in physiologic media for 24 min at 17 degrees C. Transport of the Ch isotopes was linear during these incubations. In drug-free, psychiatrically normal control subjects, DoCh efflux was inversely correlated with the natural logarithm of in vivo RBC Ch content (r = -0.97, p less than 0.001), and there was a nearly significant correlation between D4Ch influx and in in vivo RBC Ch content (r = -0.81, p less than 0.06). In patients with bipolar affective disorder, lithium treatment both inhibited DoCh and D4Ch transport, and substantially elevated in vivo RBC Ch content. However, varying degrees of transport inhibition were produced by this drug in different subjects. Our findings suggest that membrane Ch transport may have a role in the regulation of endogenous RBC Ch content. Studies of membrane Ch transport in RBCs or other types of cells could potentially help to increase our understanding of cholinergic function in psychiatric or neurologic disorders.

Bipolar Disorder↗

PubMed1984

Elevated red blood cell/plasma choline ratio in dementia of the Alzheimer type: clinical and polysomnographic correlates.

In a prospective study we have observed a shift in distribution of red blood cell (RBC)/plasma choline ratios among patients with probable dementia of the Alzheimer type (DAT), compared with healthy controls and depressed patients. Fifteen of 22 DAT patients (68%) showed RBC/plasma choline ratios greater than 1.9, in contrast to 9 of 26 healthy controls (35%) and 7 of 20 depressives (35%). These significant differences confirm and expand earlier observations. The subgroup of DAT patients with elevated RBC/plasma choline ratios is older and more cognitively impaired, shows later onset of dementia, and has less rapid eye movement (REM) sleep than the DAT subgroup with normal RBC/plasma choline ratios. Within the entire group of DAT patients, moreover, the RBC/plasma choline ratio shows a significant inverse correlation with REM sleep latency. These findings are discussed in relation to abnormalities in other nonneural Alzheimer tissues and within the context of cholinergic involvement in both DAT and the timing of REM sleep.

Aged↗

PubMed1984

Cholinergic lesion of the striatum impairs acquisition and retention of a passive avoidance response.

Significant impairments in the acquisition and retention of a step-down passive avoidance task were found in rats with striatal lesions induced by the cholinergic neurotoxin AF64A. No significant differences between control and AF64A-injected rats were found in sensitivity to electric shock or in various measures of spontaneous locomotor activity. Striatal choline acetyltransferase (CAT) activity was significantly decreased in AF64A-treated rats compared with controls, whereas glutamic acid decarboxylase (GAD) activities were not. Furthermore, there were no significant differences between groups in activities of CAT and GAD in either the cortex or the hippocampus, results that support the specificity of the lesion to the striatum. The passive avoidance deficits found in these rats after intrastriatal injection of AF64A support a role for the striatal cholinergic system in complex behavioral processes.

Animals↗

PubMed1984

Central neurotransmitter effects of organotin compounds: trials, tribulations and observations.

Administration of trimethyltin (TMT) or triethyltin (TET) compounds to rats during postnatal development has known behavioral and neuropathological consequences. By measuring the concentrations of dopamine, norepinephrine, homovanillic acid, dihydroxyphenylacetic acid, gamma-aminobutyric acid, acetylcholine, and choline in different brain areas of TMT and TET-treated animals, an attempt was made to correlate these functional deficits with changes in CNS neurotransmitter alterations in vivo. TET had no effect on any of the substances measured whereas TMT significantly decreased gamma-aminobutyric acid and dopamine levels, but only in hippocampus and striatum, respectively. All other neurotransmitter substances measured were not affected. These findings illustrate the complexity inherent in attempting to use neurochemical techniques alone as an index of toxicity in the absence of specific defined hypotheses.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1983

CSF and urinary biogenic amines and metabolites in depression and mania. A controlled, univariate analysis.

Levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF, and norepinephrine (NE), epinephrine (E), vanillylmandelic acid, normetanephrine, metanephrine, and MHPG in the urine, were measured in 151 hospitalized patients with affective disorders and in 80 healthy controls following a two-week drug-free period. Unipolar and bipolar depressed subjects differed only in NE and E levels. Compared with controls, depressed subjects had higher CSF MHPG levels, women had higher 5-HIAA levels, and men had lower HVA levels. All urinary metabolites were elevated in depression and mania, with the exception of MHPG. The patterns of NE-E differences discriminated among the forms of affective disorders. These data suggest an imbalance of monoamine transmission in depression, characterized by the hyperactive sympathetic nervous system and adrenal medulla. However, MHPG may not be the measure of choice to reflect this imbalance, necessitating measurement of total body monoamine output.

Adult↗

PubMed1983

Essential hypertension and membrane lithium transport in depressed patients.

Na+-Li+ countertransport activity in erythrocytes has previously been reported to be decreased in certain patients with mood disorders, but increased in essential hypertensives and possibly their first-degree relatives. The present investigation examines specific parameters of Na+-Li+ countertransport in relation to both affective disorder and essential hypertension. Depressed patients having a personal or family history of essential hypertension had significantly higher Vmax and fractional lithium release values than did other patients or control subjects. Values of K 1/2 did not differ among the groups. Essential hypertension in experimental subjects or their families may complicate attempts to study human erythrocyte (RBC) lithium transport in depressed patients.

Adult↗

PubMed1983

Selective presynaptic cholinergic neurotoxicity following intrahippocampal AF64A injection in rats.

Compound AF64A, ethylcholine mustard aziridinium ion (0.4-8 nmol) was stereotaxically administered into rat dorsal hippocampus, and neurochemical changes were determined 5 days later. AF64A treatment, over an almost 10-fold dose range, resulted in a significant (up to 70%) decline in choline acetyltransferase activity. In the same tissue samples, Na+-dependent choline transport activity was also lowered, with most decreases ranging between 10 and 50% of controls; however, there was no significant correlation (r = 0.39) between these two parameters. Acetylcholinesterase activity was not affected by AF64A treatment when assayed by either histochemical or enzymatic methods. AF64A reduced acetylcholine levels by 43%, but did not alter norepinephrine content or serotonin uptake. These results demonstrate that AF64A can induce a specific, long-term reduction of cholinergic presynaptic biochemical markers in rat hippocampus. Thus, AF64A can serve as a useful new tool to study the cholinergic system and as an important agent to help develop animal models representing disorders of central cholinergic hypofunction.

Acetylcholine↗

PubMed1983

Effects of postnatal trimethyltin or triethyltin treatment on CNS catecholamine, GABA, and acetylcholine systems in the rat.

The effects on brain neurochemistry of two neurotoxic tin compounds, trimethyltin (TMT) hydroxide and triethyltin (TET) sulfate, were examined. Long-Evans rats were treated with TMT hydroxide (1 mg/kg, i.p.) on alternate days from day 2 to 29 of life. These treatments caused a weight deficit of 10-20% by the time the animals were killed on day 55 by head-focused microwave irradiation. These TMT treatments are known to cause severe neuronal loss in the hippocampus and lesser damage in other brain regions. Accordingly, the concentration of gamma-aminobutyric acid (GABA) was decreased in the hippocampus; however, acetylcholine and choline concentrations were unaffected. These data suggest that TMT-induced effects on GABA systems are greater than that due simply to generalized neuronal loss. The TMT treatments also caused a significant decrease in dopamine concentrations in the striatum, but did not alter the concentrations of dihydroxyphenylacetic acid or homovanillic acid, the acidic metabolites of dopamine. Conversely, concentrations of dopamine and norepinephrine in the brain stem and norepinephrine in the cerebellum were not altered. Despite reports in the literature of TMT-induced neuronal damage in areas of the cortex, no effects on GABA, acetylcholine, or choline levels were found in the cortical areas examined, or in the hypothalamus. TET sulfate (0.3 mg/kg/day) was administered for 6 consecutive days of every week during days 2-29 of life. This dose is lower than that needed to cause intramyelin edema, yet it does result in long-term behavioral changes. Despite this, no changes in the concentration of any of the measured neurotransmitters or their metabolites were detected. In concert, these data demonstrate that neurochemical methods should not be used as neurological "screens," but rather to define specific mechanisms suggested by detailed behavior, pharmacological, and/or physiological studies.

Acetylcholine↗

PubMed1983

CSF monoamine metabolites in mania.

As part of the National Institute of Mental Health Clinical Research Branch Collaborative Program on the Psychobiology of Depression, the authors compared concentrations of CSF monoamine metabolites (the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol [MHPG], the dopamine metabolite homovanillic acid [HVA], and the serotonin metabolite 5-hydroxyindoleacetic acid [5-HIAA]) from 14 hospitalized manic patients with concentrations from 62 healthy comparison subjects. The manic patients had significantly higher levels of MHPG. Levels of 5-HIAA and HVA did not differ between the manic patients and the comparison male subjects, but they were elevated in the female manic patients. MHPG was the only metabolite that correlated significantly with mania symptom ratings. These data are consistent with findings that have shown abnormal, perhaps excessive, central noradrenergic activity in patients with mania, but not with those suggesting deficits in serotoninergic function.

Adult↗

PubMed1983

Selective inhibition of peripheral cholinergic transmission in the cat produced by AF64A.

The neuropharmacologic effects of ethylcholine aziridinium ion, AF64A, were studied in cats, using various physiological techniques, to ascertain its synaptic site of action and to determine whether it may act as a cholinergic specific neurotoxin in vivo. Nictitating membrane contractions elicited by preganglionic nerve stimulation (1-16 Hz) were diminished in a dose-dependent manner after injection of AF64A into the carotid artery. Contractions due to injection of l-norepinephrine, tetramethylammonium or acetylcholine were not changed. Postganglionic action potentials from the superior cervical ganglion evoked by preganglionic stimulation were also abolished by AF64A, whereas the postganglionic firing produced by tetramethylammonium was unchanged. Neither the nictitating membrane nor ganglionic responses on the contralateral side of the animal were affected by AF64A treatment. In the same animals, twitch tension in the tongue produced by stimulation of the ipsilateral hypoglossal nerve (1-16 Hz) was gradually reduced and in most experiments completely blocked by AF64A. Repetitive stimulation of either the autonomic or somatic nerves at high frequencies (greater than 10 Hz) magnified and accelerated the onset of neurotoxic effects of AF64A. The suppression of ganglionic and neuromuscular transmission by AF64A was irreversible during the course of the experiments (12-18 hr). From these results, we can conclude that AF64A produces in the peripheral nervous system a longlasting inhibition of cholinergic transmission, without interfering with adrenergic transmission. Moreover, because AF64A did not block the postganglionic responses elicited by cholinergic nicotinic and muscarinic agonists, the inhibitory effects of AF64A must be mediated by a presynaptic action on cholinergic nerve terminals.

Acetylcholine↗

PubMed1983

Lithium treatment during pregnancy: a case study of erythrocyte choline content and lithium transport.

Lithium treatment can affect the transport of choline and lithium ions across cell membranes, but little is known about these effects during pregnancy. In a patient treated with lithium carbonate during the final month of pregnancy, maternal erythrocyte (RBC) lithium transport and the choline content of maternal and fetal blood were measured. Fetal RBC choline levels appeared to be substantially elevated by maternal lithium treatment, and cellular lithium transport in the mother was affected by pregnancy. These observations, although preliminary, suggest interactions of lithium with both fetal and maternal physiology during pregnancy.

Adult↗