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Biomedical subjects

A D Sherman

Publications and source records attributed to A D Sherman.

At least 19 recordsLinked to original sources
PubMed1993

Abnormal serine-glycine metabolism in the brains of schizophrenics.

The metabolism of serine and glycine as studied in the plasma is abnormal in schizophrenics and psychotics. There is a concomitant abnormality of the enzyme serine hydroxymethyl transferase (SHMT). To study the status of serine-glycine metabolism in brains of schizophrenics and controls, frozen autopsied brain tissues were obtained from medial and lateral temporal lobes. The results show that the apparent Km of SHMT and the concentrations of serine and glycine are significantly higher only in the medial temporal lobe areas of schizophrenics when compared to controls. These findings are discussed in the context of the role of glycine and serine as enhancers of glutamatergic excitotoxicity and consequent development of morphological abnormalities in the brains of schizophrenics.

Aged↗
PubMed1992

Presynaptic modulation of amino acid release from synaptosomes.

Using synaptosomes prepared from whole rat brain, the spontaneous, calcium-independent, and calcium-dependent release of glutamate and GABA was assessed. Time intervals of 1-30 seconds were studied. Spontaneous release of glutamate (but not GABA) was elevated by 10 microM NMDA or AMPA by thirty seconds. This stimulation was partially calcium-dependent. Calcium-dependent release induced by 30 mM KCl was biphasic, confirming previous findings. This release was stimulated at all time periods by the presence of 10 microM NMDA or AMPA in an antagonist-sensitive manner. These data suggest that glutamate and GABA are released from vesicular stores in rat synaptosomes and that some of this release is modulated by presynaptic glutamate receptors.

2-Amino-5-phosphonovalerate↗
PubMed1991

Deficient NMDA-mediated glutamate release from synaptosomes of schizophrenics.

Previous studies from our laboratory indicated that the veratridine-induced release of glutamate and GABA from synaptosomes derived from brains of schizophrenics was decreased. In the present study, synaptosomes were prepared from frozen brain samples from schizophrenics and from controls. Stimulation by 10 mumol/L 2-amino-3-hydroxy-5-methoxylisoxazole-4-propionic acid (AMPA) produced equal glutamate release from both groups. Release induced by either 10 mumol/L kainic acid (KA) or n-methyl-d-asparate (NMDA) was reduced significantly in the preparations derived from schizophrenics. Similarly, the amount of GABA released by 50 mumol/L glutamate was also reduced in the schizophrenic-derived synaptosomes. However, in membranes derived from the crude synaptosomal pellet, no differences between the controls and schizophrenics were observed in measures of total glutamate binding or its displacement by NMDA. The data demonstrate a deficiency in NMDA (and possibly KA) receptor functioning schizophrenics and support the "second-generation" theories of schizophrenia as a glutamatergic deficiency disorder.

Brain↗
PubMed1991

Evidence of glutamatergic deficiency in schizophrenia.

Studies of amino acid release were carried out using frozen sections from brains of schizophrenics and controls. Synaptosomes were prepared via differential centrifugation in Ficoll allowing the veratridine-induced release of aspartate, glutamate, glycine, and GABA to be measured. The release of glutamate and gamma-aminobutyric acid (GABA) was reduced in the synaptosomes from schizophrenics. This decrease could be reversed partially by pre-incubation of the synaptosomes with haloperidol. Additionally, the activity of glutamate decarboxylase was decreased and partially restored by haloperidol pre-incubation. These data are consistent with the hypothesis of a glutamatergic/GABAergic deficit in schizophrenia.

Aged↗
PubMed1991

Depolarization and synaptosomal glutamine utilization.

Synaptosomes prepared by discontinuous Ficoll gradient centrifugation were either pre-incubated with glutamine or incubated with releasing agents in the presence of glutamine. Under both conditions, KCl and 4-aminopyridine (agents with specificity toward the calcium-dependent pool) produced elevated glutamate (but not GABA) release when glutamine was included. AMPA and veratridine produced the same glutamate release in the presence or absence of glutamine. These data support the hypothesis that glutamine utilization is involved in the release of glutamate from calcium-dependent pools.

4-Aminopyridine↗
PubMed1990

Abnormal serine hydroxymethyl transferase activity in the temporal lobes of schizophrenics.

We studied the kinetics of the enzyme serine hydroxymethyl transferase (SHMT) and the concentration of its metabolic substrates serine and glycine, in the postmortem brains of controls and schizophrenics. The Km of SHMT, and the concentration of serine and glycine were all significantly higher in the temporal lobes of brain tissues from schizophrenics than in those from controls. These differences were not observed in the frontal lobe specimens. Neuroleptics, age, sex and autolysis time did not contribute to these differences. The role of SHMT deficiency in schizophrenia is discussed in relation to the production of glycine and 1-carbon units from which purines and thereby adenosine is produced. Both glycine and adenosine are potent neuromodulatory substances for the release of dopamine and glutamate, neurotransmitters which have been implicated in the pathophysiology of schizophrenia.

Adult↗
PubMed1989

Isolation of metabolically distinct synaptosomes on Percoll gradients.

Synaptosomes were prepared from whole rat brain by six different methods based on gradients of sucrose, Ficoll or Percoll. In these, the synthesis and calcium-specific release of amino acids were assessed by two different procedures. Preparations based on sucrose showed the least calcium-specific release, followed by Ficoll-derived synaptosomes. As previously described, Percoll gave two separate populations of synaptosomes, both very active in terms of release of aspartate, glutamate, and GABA. The data involving release and synthesis were not identical, but did agree in the following: in low-density synaptosomes, haloperidol blocked both the release and synthesis of glutamate, but was without effect in the heavier population. 2-chloroadenosine and 2-oxoglutarate affected both release and synthesis only in the high-density population. Dopamine blocked aspartate release and synthesis only in the high-density population. These results suggest that haloperidol interferes with glutamate release and synthesis via a mechanism which may not involve adenosine, serotonin, or dopamine.

Animals↗
PubMed1989

Behavioral performance and seizure activity of lithium-intoxicated Sprague-Dawley rats treated with theophylline.

Male Sprague-Dawley rats were divided into four groups that were treated with various combinations of lithium, saline, and theophylline, i.e., saline/saline, saline/theophylline, lithium/theophylline, and lithium/saline. Neurobehavioral testing of cerebellar and neuromuscular functioning, and determination of the effect of the drug combinations on the animals' seizure threshold concluded that while theophylline increases lithium clearance, it does not exacerbate lithium neurotoxicity.

3-Mercaptopropionic Acid↗
PubMed1988

Effects of neuroleptics on glutaminase from rat synaptosomes.

Phosphate-activated glutaminase was isolated from synaptosomes from three areas of rat brain. Glutamine utilization phosphate activation and inhibition by glutamate or ammonia were assessed in the absence or presence of haloperidol, chlorpromazine, or clozapine. All three drugs (at 1 micromolar concentration) elevated the Km for glutamine using preparations from the amygdala, hippocampus, or striatum. They interfered with phosphate activation only in the amygdala preparation. No drug affected end-product inhibition. The data suggest that neuroleptics may depress the release of glutamic acid from synaptosomes by interfering with the activation of glutaminase by phosphate.

Amygdala↗
PubMed1986

Effects of glutaminase inhibition on release of endogenous glutamic acid.

The effects of four inhibitors of glutamine hydrolysis on synaptosomes derived from several regions of the brain were studied. The calcium-specific release of endogenous glutamic acid was determined in the presence of varying concentrations of 6-diazo-5-oxo-norleucine (DON), N-ethyl-maleimide (NEM), 2-chloroadenosine (2-CA) or haloperidol. Both DON and NEM reduced the calcium-specific release in a concentration-dependent manner, equally in all regions tested. 2-Chloroadenosine also decreased release and the effect was most evident in the amygdala. As reported earlier, haloperidol blocked release of glutamic acid only in the amygdala. In synaptosomes from the amygdala, both DON and NEM failed to affect the calcium-specific release of aminobutyric acid (GABA), glycine or serotonin at concentrations which reduced release of glutamate by 50%; NEM, but not DON, elevated the release of dopamine. Dopamine itself affected neither the release of glutamate nor its blockade by haloperidol even in extremely large concentrations.

2-Chloroadenosine↗
PubMed1985

Amphetamine stimulation of glutaminase is blocked by neuroleptics.

The ability of several classes of neuroleptics to inhibit the activity of phosphate-activated glutaminase was studied in several brain regions. These agents decreased glutaminase activity only in the amygdala. Amphetamine elevated glutaminase activity in this region. This stimulation was not blocked by (-) butaclamol, but was blocked by (+) butaclamol, haloperidol, chlorpromazine or clozapine.

Amphetamine↗
PubMed1985

Relationship of free nortriptyline levels to therapeutic response.

The relationship between the free plasma concentration of nortriptyline and therapeutic response was examined. Eighteen depressed inpatients were treated for 21 days with steady state total nortriptyline plasma concentrations between 50-150 ng/ml. Steady state free nortriptyline concentrations were measured. The therapeutic nortriptyline response was measured by administering the Hamilton and the Carroll Rating scales at day zero and day 21. Statistical relationships between free levels of drug and clinical response were found to be insignificant. Qualitative assessment of the data suggest that free serum levels of nortriptyline in excess of 10 ng/ml may have an inhibitory effect on clinical response.

Adolescent↗
PubMed1984

Direct effect of neuroleptics on glutamate release.

In studies designed to assess the pre-synaptic effects of neuroleptics in vitro, synaptosomes were prepared from several regions of rat brain. These preparations were incubated in the presence of a representative of each of the major classes of neuroleptic--chlorpromazine, haloperidol, or clozapine, or with (+) or (-)butaclamol. The calcium-specific release of endogenous glutamic acid was reduced only in synaptosomes derived from the amygdala. In this area, each of these agents [except (-)butaclamol] reduced the release of glutamic acid to a maximum of 40% in a concentration-dependent manner. When [3H]glutamine was included in the incubation media, a reduction in the released [3H]glutamate was present with 10(-8) M haloperidol, and 5 X 10(-8) M (+)butaclamol, clozapine, or chlorpromazine. (-)Butaclamol was inactive at 10(-5) M, a concentration producing complete blockade of the release of [3H]glutamic acid when active agents were included. Again, the effects were observed only in the amygdala. All agents, including (-)butaclamol blocked the uptake of [3H]glutamine into depolarized synaptosomes.

Amygdala↗
PubMed1984

Potential locus and mechanism of blockade of conditioned avoidance responding by neuroleptics.

In order to assess the possible loci of action of neuroleptics in blocking the acquisition of a one-way conditioned avoidance response, microinjections of three neuroleptics and seven putative neurotransmitters were made into several brain regions and their effects on this behavior were assessed. When injected into the amygdala, the ED50 values for haloperidol (0.128 nmol), chlorpromazine (1.04 nmol) and thioridazine (1.41 nmol) were appropriate in relation to their clinical potency. Injections of neurotransmitters were without effect except in a few cases. Most significantly, the intra-amygdaloid administration of glutamate diethyl ester (an antagonist at quisqualate-type receptors) produced a blockade of avoidance acquisition which, as in the case of the neuroleptics, was not diminished by pretreatment with atropine. Following intraperitoneal injection of chlorpromazine, a statistically-significant blockade of avoidance acquisition and of glutamate, released from slices of amygdala, was obtained at doses of 2 mg/kg or more. With haloperidol, comparable behavioral effects and release of glutamate were found at doses of 0.05 mg/kg or more. The depression of release of glutamate from amygdaloid slices could be attributed to glutamate derived from glutamine. These data suggest a possible role for glutamatergic transmission in the effects of neuroleptics.

Amygdala↗
PubMed1984

Learned helplessness decreases [3H]imipramine binding in rat cortex.

Specific binding of [3H]imipramine decreased in frontal neocortex from rats demonstrating learned helplessness, an animal model of depression. The decrease was in maximal binding but not in affinity for the receptor site. No change in [3H]imipramine binding was found in septum or hippocampus. The receptor changes found in frontal neocortex parallel behavioral and neurochemical changes produced by learned helplessness in this region. These changes are also similar to those found in the frontal neocortex from suicides and in platelets of patients with depression.

Animals↗
PubMed1984

Plasma GABA levels in psychiatric illness.

In two separate studies, we have obtained plasma levels of GABA in 134 psychiatric patients and 22 normal controls. Patients with a unipolar affective disorder had levels significantly lower than control (n = 58) as did patients with alcoholism (n = 10). Patients with a bipolar affective disorder had levels significantly higher than control when manic (n = 28) and also when euthymic on lithium prophylaxis (n = 17), but levels in the control range when depressed (n = 4). Patients with schizophrenia demonstrated a high degree of variability in their levels of plasma GABA but were not statistically different from control (n = 36). Patients with unipolar depression who received a dexamethasone suppression test had no correlation between nonsuppression of cortisol secretion and plasma levels of GABA. Diagnostic and research implication of plasma GABA in psychiatric illness are discussed.

Alcoholism↗
PubMed1984

Serine metabolism and psychosis.

Plasma serine levels (PSL) in a group of patients with the diagnosis of major or atypical psychoses were significantly higher than in patients with nonpsychotic diagnoses or nonpatient controls. The enzyme serine hydroxymethyltransferase (SHMT), which metabolizes serine to glycine, showed abnormal activity in the psychotics compared to nonpsychotics and controls. PSL differentiated psychotics from nonpsychotics with a high (95%) degree of confidence. PSL were highly correlated to SHMT activity, suggesting that the hyperserinemia in psychotics was due to the abnormality of the enzyme. Previously psychotic patients who had been treated and were psychosis free still manifested abnormal high PSL and abnormal enzyme activity. These findings suggest that disturbed serine metabolism may be a biological marker and a vulnerability factor for psychosis.

Adult↗