Presynaptic electrical coupling in Aplysia: effects on postsynaptic chemical transmission.

The large cholinergic interneuron L10 in the abdominal ganglion of Aplysia mediates both chemical and electrical synaptic transmission. The amplitudes of postsynaptic potentials produced by different branches of L10 are differentially affected when the electrically coupled neuron L20 is depolarized or hyperpolarized. Polarizations applied to L20 are transmitted to L10 branches by the "presynaptic"electrical synapse. Depolarization increases the amplitude of the postsynaptic potential, while hyperpolarization has the opposite effect. The differential effects occur because current supplied through the electrical synapse undergoes more electrotonic decrement for the distant branches than for branches closer to the electrical synapse. These findings indicate that the presynaptic electrically coupled neuron may have an integrative role in the modulation of chemical synaptic efficacy mediated by L10.

A familial/genetic study of plasma serine and glycine concentrations.

Plasma serine and glycine concentrations were assayed in a sample of 28 nuclear families (n = 108). Complex segregation analysis of these familial data reveals significant genetic control of concentrations via a single major gene locus. The serine and glycine metabolizing enzyme serine hydroxymethyltransferase (SHMT) is suggested as the most likely candidate for this single major gene locus.

Neuroleptic effects on serine and glycine metabolism.

The concentrations of serine and glycine and the activity of serine hydroxymethyltransferase (SHMT) are abnormal in plasma and brains of schizophrenics. To further elucidate the possible role of neuroleptics on the metabolism of serine and glycine and the activity of SHMT, we studied the plasma of controls and schizophrenics on and off medications, the brains of rats treated with haloperidol, and the activity of purified SHMT in the presence or absence of haloperidol and fluphenazine. Plasmas of neuroleptic-treated schizophrenics had nonsignificantly lower concentrations of serine and glycine. Brains of haloperidol-treated rats had significantly lower concentrations of serine and glycine. At therapeutic levels haloperidol and fluphenazine did not inhibit the activity of purified SHMT. The serine-glycine lowering effects of haloperidol and neuroleptics are discussed in the context of a possible neuroprotective potential of neuroleptics in schizophrenia.

Metabolism of an ingested serine load in psychotic and nonpsychotic subjects.

Our previous studies have shown that in psychotics, the plasma serine level is abnormally high and that plasma serine hydroxymethyltransferase (which cleaves serine to glycine) activity is abnormally low as compared with that in nonpsychotic subjects. In this study, psychotic and nonpsychotic subjects ingested a large bolus of L-serine (4 mM/kg) at breakfast and blood was drawn before breakfast, 2 hr, 4 hr, and 6 hr after serine ingestion. Baseline serine and SHMT activity differentiated between psychotics and nonpsychotics with high degrees of significance (p less than 0.0001) and p less than 0.01, respectively). Plasma serine levels 2 hr after serine ingestion were significantly higher (p less than 0.01) in nonpsychotics as compared with psychotics. Elimination of serine in psychotics was bimodal and was significantly different from that of nonpsychotics (p less than 0.0079, Moses test). These findings provide additional evidence for abnormal serine metabolism in psychotic patients.

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.

Effects of the Transcendental Meditation program on adaptive mechanisms: changes in hormone levels and responses to stress after 4 months of practice.

Stress has been implicated in both somatic and mental disorders. The mechanisms by which stress leads to poor health are largely unknown. However, studies in animals suggest that chronic stress causes high basal cortisol and low cortisol response to acute stressors and that such changes may contribute to disease. Previous studies of the Transcendental Meditation (TM) technique as a possible means of countering effects of stress have reported altered levels of several hormones both during the practice and longitudinally after regular practice of this technique. In this prospective, random assignment study, changes in baseline levels and acute responses to laboratory stressors were examined for four hormones-cortisol, growth hormone, thyroid-stimulating hormone and testosterone-before and after 4 months of either the TM technique or a stress education control condition. At pre- and post-test, blood was withdrawn continuously through an indwelling catheter, and plasma or serum samples were frozen for later analysis by radioimmunoassay. The results showed significantly different changes for the two groups, or trends toward significance, for each hormone over the 4 months. In the TM group, but not in the controls, basal cortisol level and average cortisol across the stress session decreased from pre- to post-test. Cortisol responsiveness to stressors, however, increased in the TM group compared to controls. The baselines and/or stress responsiveness for TSH and GH changed in opposite directions for the groups, as did the testosterone baseline. Overall, the cortisol and testosterone results appear to support previous data suggesting that repeated practice of the TM technique reverses effects of chronic stress significant for health. The observed group difference in the change of GH regulation may derive from the cortisol differences, while the TSH results are not related easily to earlier findings on the effects of chronic stress.

Lithium in diabetes mellitus: a paradoxical response.

An unusual hyperglycemic effect of lithium was observed in a patient suffering from diabetes mellitus and mania. In the presence of constant insulin dosage, high serum lithium levels were correlated with high fasting bloos sugar, while lowering of the lithium level led to a lowering the fasting blood sugar. These observations are discussed in terms of the effects of lithium on glucose metabolism and with particular emphasis on the ability of lithium to increase the release of glucagon.

The Capgras symptom and nondominant cerebral dysfunction.

Although the etiology of the Capgras symptom is still unknown, recent reports strongly support the role of organic factors. The authors present the case of a psychotic woman with Capgras symptoms who showed evidence of nondominant cerebral dysfunction, documented by neuropsychologic testing and electrophysiologic procedures. This observation lends credibility to the role of organic factors in the development of the Capgras phenomenon.

Arthritis associated with lithium toxicity: case report.

A 33-year-old man developed transient polyarthritis associated with lithium toxicity. The arthritic symptoms resolved after lithium was discontinued. A link between lithium, autoimmune mechanisms, and arthritis is postulated.

Lateralization of neuroleptic-induced dyskinesia indicates pharmacologic asymmetry in the brain.

Since the two hemispheres of the human brain are asymmetrical for various cognitive and perceptual functions, a pharmacological as well as the known anatomical differentiation between the two hemispheres may underly the asymmetrical functions. A lateralization of the dyskinetic states consequent to long-term usage of large doses of neuroleptics would be indicative of a pharmacologic asymmetry in the brain hemispheres. Seven of eight right-handed psychiatric patients had greater right-than left-sided dyskinesias, a finding which pointed to pharmacological vulnerability in the left dominant hemisphere.

A hyperglycinergic rat model for the pathogenesis of schizophrenia: preliminary findings.

There is evidence of high glycine concentrations in the brains and periphery of schizophrenics. In the forebrain, glycine plays a major role as a co-agonist with glutamate at the excitatory N-methyl-D-aspartate (NMDA) receptors. This activity of glycine is involved in the normal functioning of the brain in adulthood and during neurodevelopment, and it may also cause neurotoxicity and brain abnormalities when its concentrations are high. To test the hypothesis that the high glycine concentrations observed in schizophrenics play an etiologic role in schizophrenia, an animal model was tested where rats were made hyperglycinic from life in utero to adulthood. The hyperglycinic rats showed abnormalities in sensory gating mechanisms, enlarged cerebral ventricles and diminished hippocampal dimensions. All of these abnormalities closely parallel observations reported in patients with schizophrenic psychoses. These results from a rat model suggest an etiologic role for high glycine concentration in the behavior and brain abnormalities of schizophrenic patients.

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.

Repetitive activity alters spike initiation locus and conduction velocity in Aplysia axons.

During a burst of spikes in the axon of neuron R2 of Aplysia, the spike initiation zone moves down the axon. The orthodromic latency of propagated spikes decreases as the trigger zone moves distally. At the same time, the conduction velocity of the spikes slows down, which leads to lengthening of interspike intervals, especially in remote regions of the axon. Similar timing changes are seen in the chemical and electrotonic postsynaptic potentials in some follower neurons of L10.

Long-term consequences of prenatal cocaine exposure on biogenic amines in the brains of mice: the role of sex.

Prenatal cocaine exposure leads to multiple abnormalities in the mature offspring. We explored the effects of gestational exposure to cocaine on neurotransmitter systems of adult mice. The subjects were the mature offspring of mice (a) prenatally fed cocaine between gestational day (G) 8 and G19, (b) pair-fed chow and water, or fed chow and water ad libitum. The forebrains of the mature offspring were assayed for monoamines and amino acids. Cocaine exposure particularly affected the dopaminergic system and in a sex-specific manner. In males dopamine concentrations were decreased and dopamine turnover was increased, whereas in females dopamine concentrations were increased and turnover was decreased. Neither norepinephrine, the serotonergic system, nor neuroactive amino acids (or their precursors) were affected by cocaine. Thus, in utero exposure to cocaine produces long-lasting, specific defects in the dopaminergic system.

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.

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.

Differentiation of psychotic from nonpsychotic depression by a biological marker.

In a study of fasting plasma serine levels (PSL) previously shown to be a biological marker for psychosis, we found significantly higher (P = 0.0008) PSL in 18 psychotic depressives when compared to 22 nonpsychotic depressives. Similarly the activity of the enzyme serine hydroxymethyltransferase (SHMT) which cleaves serine to glycine, was significantly lower (P less than 0.0001) in psychotics than in nonpsychotics. The difference between psychotic and nonpsychotic depressives were not attributable to age, sex or drug intake. This finding is in support of the hypothesis that these two types of depressions are qualitatively distinct from each other.

Drug effects on serine metabolism in psychiatric patients.

The question of whether neuroleptics can play a role in the hyperserinemia and low serine hydroxymethyltransferase (SHMT) activity previously reported in psychotic patients is investigated in this report. We find that in drug-free psychotics who had significantly higher plasma serine levels (PSL) and lower SHMT activity compared to nonpsychotics and normal subjects, more than 2 weeks of neuroleptic treatment decreased PSL and did not affect SHMT activity. This finding makes it unlikely that neuroleptics play an important role in the hyperserinemia of psychotics. The possible role of dietary factors in these patients is also discussed.

Plasma serine in schizophrenics and controls measured by gas chromatography-mass spectrometry.

In several previous studies, we reported significantly higher plasma serine concentrations in psychotic (and schizophrenic) subjects compared with nonpsychotic and control subjects. In those studies, we used a gas chromatography technique to assay the amino acids. Perry and Hanson (1985), using cation-exchange chromatography to assay plasma amino acids, found no differences in the plasma serine concentrations of controls compared with schizophrenic patients. They criticized our work on technical grounds and suggested that some other substance was co-eluting with the gas chromatographic serine peaks in our assays. We have now examined the plasma of schizophrenic and control subjects with gas chromatography-mass spectrometry (GC-MS), where accurate amino acid quantitation relative to a known internal standard can be achieved. The results show that the plasma serine concentrations of schizophrenic patients are significantly higher than those of controls. Also, plasma glycine concentrations are significantly higher in schizophrenic patients compared with controls.