A.D. Sherman

Specificity of the learned helplessness model of depression

The learned helplessness model of depression was tested for its responsiveness to several types of antidepressant therapies, and to a number of psychoactive drugs which are not effective in treating depression in humans. Chronic administration of tricyclic antidepressants (imipramine, desipramine, amitryptyline, nortryptyline, or doxepin), atypical antidepressants (iprindole or mianserin), monoamine oxidase inhibitors (iproniazid or pargyline), or electroconvulsive shock was effective in reversing learned helplessness. Chronic treatment with anxiolytics (diazepam, lorazepam, or chlordiazepoxide), neuroleptics (chlorpromazine or haloperidol) stimulants (amphetamine or caffeine), or depressants (phenobarbital or ethanol) was not. Thus, this model provides a reasonable degree of specificity toward therapies which are successful in humans.

l-Kynurenine Its synthesis and possible regulatory function in brain

One pathway by which tryptophan is metabolized in the brain as well as in the periphery is through cleavage of the indole ring to formylkynurenine and then kynurenine. Indoleamine-2,3-dioxygenase, the enzyme that catalyzes this clavage, and kynurenine are distributed all across the different anatomic regions of brain. Approximately 40% of the kynurenine in brain is synthesized there, the remainder having come from plasma. Tryptophan loading, which has been used both experimentally and therapeutically as a means of increasing tryptophan conversion to serotonin, also increases kynurenine formation in the brain and in the periphery. Because of the formation of kynurenine, which competes for cerebral transport and cellular uptake ofl-tryptophan, and because of substrate inhibition on tryptophan hydroxylase, excessively high doses of tryptophan may actually decrease the production of cerebral serotonin and 5-hydroxyindoleacetic acid.

A neuropharmacologically-relevant animal model of depression.

Abstract The phenomenon of “learned helplessness” was evaluated as a potential animal model of depression. Imipramine, but not chlorpromazine or lorazepam, had a delayed protective effect on the development of this behavior although lorazepam was effective after a single dose. Dose-response curves related either to concentration of imipramine in drinking water or to free drug levels in brain were linear with higher drug levels associated with a lowered degree of learned helplessness following chronic administration. The effects of imipramine on the development of learned helplessness were seen following four days of access to drug in drinking water, but not after 1, 2 or 3 days. This model, although clearly not a perfect fit with depression in humans, has many characteristics which suggest its utility in further studies of the mechanism of action of antidepressants.

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.

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.

Regional aspects of the prevention of learned helplessness by desipramine

Abstract Desipramine injected directly into the hippocampus, frontal neocortex, or lateral geniculate body prevented the development of learned helplessness in rats. It did not have this protective effect when injected into the septum, entorhinal cortex, posterior neocortex, nucleus candatus, nucleus accumbens, or amygdala. Neocortical levels of 5-hydroxyindoleacetic acid were significantly higher in rats receiving desipramine in the three behaviorally active ares than in the six other areas or than in saline injected controls.

The treatment of tricyclic antidepressant overdose with repeated charcoal.

Activated charcoal given repeatedly through a nasogastric tube to three patients in coma from amitriptyline overdose greatly accelerated tricyclic elimination: the apparent half-life fell below 10 hours for each patient to as low as 4 hours. This contrasts with extended half-lives for amitriptyline elimination averaging 36.8 hours and regularly over 60 hours previously reported for overdoses treated without repeated charcoal. The enterohepatic recirculation of amitriptyline and nortriptyline appears to be a major influence on keeping their blood levels up. In one case, intravenous diazepam inhibited tricyclic elimination.

Learned helplessness induction decreases in vivo cortical serotonin release

Abstract Frontal neocortices of freely moving, unanesthetized rats were perfused before, during, and after exposure to 40 min of uncued pulsed random footshock. Animals developing nontransient learned helplessness had lower levels of serotonin in cortical perfusate than those failing to develop helplessness.

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.

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.