Joseph J. Schildkraut

Biogenic Amines and Emotion

The studies discussed here have shown a fairly consistent relationship between the effects of drugs on biogenic amines, particularly norepinephrine, and affective or behavioral states. Those drugs which cause depletion and inactivation of norepinephrine centrally produce sedation or depression, while drugs which increase or potentiate brain norepinephrine are associated with behavioral stimulation or excitement and generally have an antidepressant effect in man (Table 1). From these findings, a number of investigators have formulated the concept, designated the catecholamine hypothesis of affective disorders (6), that some, if not all, depressions may be associated with a relative deficiency of norepinephrine at functionally important adrenergic receptor sites in the brain, whereas elations may be associated with an excess of such amines. It is not possible either to confirm or to reject this hypothesis on the basis of currently available clinical data. Although there does appear to be a fairly consistent relationship between the effects of pharmacological agents on norepinephrine metabolism and on affective state, a rigorous extrapolation from pharmacological studies to pathophysiology cannot be made. Confirmation of this hypothesis must ultimately depend upon direct demonstration of the biochemical abnormality in the naturally occurring illness. It should be emphasized, however, that the demonstration of such a biochemical abnormality would not necessarily imply a genetic or constitutional, rather than an environmental or psychological, etiology of depression.Whereas specific genetic factors may be of importance in the etiology of some, and possibly all, depressions, it is equally conceivable that early experiences of the infant or child may cause enduring biochemical changes and that these may predispose some individuals to depressions in adulthood. It is not likely that changes in the metabolism of the biogenic amines alone will account for the complex phenomena of normal or pathological affect.Whereas the effects of these amines at particular sites in the brain may be of crucial importance in the regulation of affect, any comprehensive formulation of the physiology of affective state will have to include many other concomitant biochemical, physiological, and psychological factors. Although in this review of the relationship of biogenic amines to affective state relatively little has been said concerning the intricate set of environmental and psychological determinants of emotion, the importance of these factors must be stressed. The normally occurring alterations in affective state induced by environmental events is well known to all, from personal experience. The interactions between such environmental determinants of affect, various physiological factors, and the complexity of psychological determinants, including cognitive factors derived from the individuals remote and immediate past experiences, have received only limited study under adequately controlled conditions. It may be anticipated, however, that this will prove to be a particularly fruitful area for future research, for only within such a multifactorial framework may one expect to understand fully the relationship of the biogenic amines to emotional state.

Norepinephrine Turnover and Metabolism in Rat Brain after Long-Term Administration of Imipramine

The rate of disappearance of intracisternally administered tritiated norepinephrine from rat brain is decreased after a single dose of the tricyclic antidepressant imipramine. During long-term administration of imipramine, however, the rate of disappearance of tritiated norepinephrine from brain gradually increases, and there is a concurrent decrease in the content of endogenous norepinephrine in brain. These findings may help to explain why antidepressant effects are observed clinically only after long-termn treatment with imipramine.

The effects of lithium salts on the turnover and metabolism of norepinephrine in rat brain

SummaryAcute or chronic administration of lithium chloride increased the disappearance of intracisternally administered norepinephrine-H3 from rat brain. Tritiated deaminated catechol metabolites and free deaminated-O-methylated metabolites represented a larger fraction of the radioactivity present in the brain in animals treated with lithium chloride than in control animals. Statistically significant changes in the uptake of norepinephrine-H3 into brain were not observed after the chronic administration of lithium chloride. The findings suggest that chronic, as well as acute administration of lithium salts may increase norepinephrine turnover in brain and possibly increase the deamination of this amine.

Clinical experience with dihydroxyphenylalanine (DOPA) in depression

THIS is a report of the rGsults of a clinical trial of dihydroxyphenylalanine (DOPA), a precursor of catechol amines, in the treatment of depression. This experiment was undertaken as an indirect test of the catechol amine theory of affective disorders, which proposes that depressed patients have an absolute or relative deficiency of central nervous system (CNS) catechol amines, and that conversely, patients with elation have an excess of CNS catechol amines. The evidence in support of this theory derives from parallels between neuropharmacological investigations and clinical therapeutic experience with various psychopharmacologic agents, particularly reserpine and the MAO inhibitors. Soon after they were found effective in excited and psychotic patients, including manic patients,1 the Rauwolfia derivatives were discovered to alter CNS stored and free amines, particularly serotonin and norepinephrine. Reserpine, moreover, was found to induce severe depressive reactions in humans, especially hypertensive patients.2 Based on these considerations, BRODIE et al. proposed that the clinical and pharmacological effects of the Rauwolfia derivatives were related to their capacity to alter brain amines. The therapeutic effectiveness of iproniazid, a monoamine oxidase inhibitor, in depressions further supported the idea that depressive states might be associated with a deficiency of

MHPG Excretion in Depressive Disorders: Relation to Clinical Subtypes and Desynchronized Sleep

The urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was significantly lower in patients with manic-depressive depressions than in patients with chronic characterological depressions. There was an inverse relationship between MHPG excretion and the amount of time spent in desynchronized sleep, particularly in the manic-depressive disorders. Excretion of MHPG was not related to the degree of retardation, agitation, or anxiety in these patients.

The effects of Δ9-tetrahydrocannabinol on the metabolism of norepinephrine in rat brain

AbstractΔ9-THC (approximately 80 mg/kg) was administered to rats by intraperitoneal injection. This dose was found to cause an accelerated rate of disappearance of intracisternally administered norepinephrine-H3 from the brain and a small increase in the uptake of norepinephrine-H3 in the brain. In contrast to most stimulants, euphoriants, or antidepressants (e.g., cocaine or amphetamine, monoamine oxidase inhibitors and tricyclic antidepressants), Δ9-THC appeared to cause no decrease in the deamination of norepinephrine-H3 in brain. Levels of endogenous norepinephrine in brain tended to be slightly lower, whereas levels of endogenous serotonin were slightly higher in animals treated with Δ9-THC than in matched control animals. Behavioral effects were observed and are described in the text.

Amphetamine withdrawal: effects on threshold of intracranial reinforcement.

In order to determine whether alterations in sensitivity to rewarding stimuli accompany the biochemical and behavioral changes induced by chronic amphetamine treatment and withdrawal, we explored the effects of chronic administration and withdrawal of d-amphetamine on thresholds of intracranial reinforcement in the rat. Rats were injected with d-amphetamine sulfate according to a chronic, escalating dose schedule. Marked decreases in threshold of intracranial reinforcement were observed immediately (0–1 h) following the last injection of d-amphetamine. In contrast, all animals showed marked increases in thresholds of intracranial reinforcement 24–48 h after the last injection of d-amphetamine. These findings were discussed in relation to amphetamine-induced and naturally occurring depressions in man.

EXCRETION OF 3-METHOXY-4-HYDROXYMANDELIC ACID (VMA) IN DEPRESSED PATIENTS TREATED WITH ANTIDEPRESSANT DRUGS.

Abstract Urinary excretion of 3-methoxy-4-hydroxymandelic acid (VMA), the major metabolite of norepinephrine, was measured in depressed patients before and during treatment with phenelzine (45–60 mg/day), imipramine (100–200 mg/day) and placebo. A statistically significant decrease in VMA excretion was observed in both the group of patients receiving phenelzine and those receiving imipramine. A significant change in VMA excretion did not occur in the placebo control group. These findings are discussed in the context of recent studies of the uptake, storage, release and metabolism of norepinephrine. Possible mechanisms of action to account for the decrease of VMA excretion with imipramine and phenelzine are considered. Based on the findings of this study and the interaction effects of imipramine with amine releasing agents, it is suggested that a common mechanism of action of monoamine oxidase inhibitors and the imipramine class of antidepressant agents may be to increase norepinephrine available for functional extracellular release.

Norepinephrine metabolism in the rat brain following acute and chronic administration of thyrotropin releasing hormone.

Synthetic thyrotropin releasing hormone (TBH) was administered to albino rats in order to determine the effects of this drug on norepinephrine-H3 metabolism in the brain. With the possible exception of a slight enhancement of release, acute or chronic administration of TRH had little effect on the disposition and metabolism of norepinephrine-H3 in rat brain. In addition, no significant changes were found in brain levels of endogenous norepinephrine, serotonin or dopamine following the injection of TRH. Thus, little evidence was found to support a possible relationship between the reported clinical antidepressant activity of TRH and its effects on norepinephrine metabolism in brain.

Alterations in brain norepinephrine metabolism and behavior induced by environmental stimuli previously paired with inescapable shock

After exposure to a single session of inescapable footshock, rats show deficits in escape performance 24 h later when required to lever press on a fixed ratio (FR-3) schedule. Footshock stress produces an immediate increase in brain levels of 3-methoxy-4-hydroxyphenylglycol sulfate (MHPG-SO4), a major metabolite of norepinephrine in rat brain. Twenty-four hours after a single or repeated session(s) of footshock stress, when levels of MHPG-SO4 returned to baseline, increases in brain levels of MHPG-SO4, crouching and defecation behavior were elicited in rats by neutral environmental stimuli that had been previously paired with inescapable footshock stress. These results suggest that sensitization or conditioning of noradrenergic neuronal systems may be induced by environmental stimuli previously paired with stress, and may help to explain, at least in part, the deficits in escape performance observed 24 h after exposure to inescapable shock.