Frank R. Ervin

Tryptophan depletion causes a rapid lowering of mood in normal males

Normal male human subjects ingested amino acid mixtures which were tryptophan-free, balanced or contained excess tryptophan. The tryptophan-free mixture causes a marked depletion of plasma tryptophan by 5 h. At this time the subjects in the tryptophan-free group had significantly elevated scores on the depression scale of the Multiple Affect Adjective Checklist. The tryptophan-free group also performed worse than the other two groups in a proofreading task carried out while listening to a tape with themes of hopelessness and helplessness (dysphoric distractor). Cognitive theories of depression predict greater distractability of depressed individuals by dysphoric themes. Thus, both measures indicate a rapid mood lowering effect of tryptophan depletion in normal males. This effect is probably mediated by a lowering of brain 5-hydroxytryptamine. Although the mood-lowering effect was not as great as that seen in depressed patients, our results suggest that low brain 5HT might be one factor precipitating depression in some patients.

Alzheimer's Disease Aβ Vaccine Reduces Central Nervous System Aβ Levels in a Non-Human Primate, the Caribbean Vervet

Amyloid β (Aβ) protein immunotherapy lowers cerebral Aβ and improves cognition in mouse models of Alzheimers disease (AD). Here we show that Caribbean vervet monkeys ( Chlorocebus aethiops, SK ) develop cerebral Aβ plaques with aging and that these deposits are associated with gliosis and neuritic dystrophy. Five aged vervets were immunized with Aβ peptide over 10 months. Plasma and cerebral spinal fluid (CSF) samples were collected periodically from the immunized vervets and five aged controls; one monkey per group expired during the study. By Day 42, immunized animals generated plasma Aβ antibodies that labeled Aβ plaques in human, AD transgenic mouse and vervet brains; bound Aβ1–7; and recognized monomeric and oligomeric Aβ but not full-length amyloid precursor protein nor its C-terminal fragments. Low anti-Aβ titers were detected in CSF. Aβx-40 levels were elevated ∼2- to 5-fold in plasma and decreased up to 64% in CSF in immunized vervets. Insoluble Aβx-42 was decreased by 66% in brain homogenates of the four immunized animals compared to archival tissues from 13 age-matched control vervets. Aβ42-immunoreactive plaques were detected in frontal cortex in 11 of the 13 control animals, but not in six brain regions examined in each of the four immunized vervets. No T cell response or inflammation was observed. Our study is the first to demonstrate age-related Aβ deposition in the vervet monkey as well as the lowering of cerebral Aβ by Aβ vaccination in a non-human primate. The findings further support Aβ immunotherapy as a potential prevention and treatment of AD.

Biochemical aspects of tryptophan depletion in primates.

We studied the degree of plasma tryptophan depletion produced by giving normal human males different amounts of a tryptophan-free (T-) amino acid mixture. From the results of this and other studies we concluded that the maximum degree of tryptophan depletion can be produced by a 31.5 g mixture of seven essential amino acids. Administration of a T−amino acid mixture to vervet monkeys lowered tryptophan and 5-hydroxyindoleacetic acid in the cerebrospinal fluid. Levels of tyrosine and the catecholamine metabolites were unchanged. These data support the idea that the effects of T−mixture on mental function in humans which have been reported previously are due to a decrease in 5-hydroxytryptamine.

A test of possible cognitive and environmental influences on the mood lowering effect of tryptophan depletion in normal males.

In a previous study we found that a tryptophan-deficient amino acid mixture, designed to lower tissue tryptophan and thus brain 5-hydroxytryptamine (5HT) levels, caused a rapid (5 h) lowering of mood in normal males. Because of the importance of this evidence indicating a direct causal connection between low 5HT and low mood, we have now investigated other possible explanations for the mood lowering effect. Research strongly supports the involvement of environmental setting and cognition in the production and experience of emotions. Therefore we investigated how these factors might influence the mood-lowering effects of tryptophan depletion. In an instructional manipulation subjects were either supplied or not supplied with information designed to account for any possible peripheral sensations that might be related to depressive affect. In an environmental manipulation subjects were exposed either to a supportive and comfortable atmosphere (positive environment), or an unrewarding and unstimulating environment (negative environment). In the control group, which received a balanced amino acid mixture, the positive and negative environments had the expected effects on the scores of the Multiple Affect Adjective Checklist, thus indicating the effectiveness of these procedures. In the tryptophan depletion group neither the instructional nor the environmental manipulation had any influence on the mood lowering effect. It may be that tryptophan depletion lowers mood in normal males because low 5HT influences mood directly rather than via cognitive processes. Our data strongly support the idea that 5HT exerts an effect on mood and that low 5HT may, in some patients, be an important factor contributing to the etiology of clinical depression.

Acute effect of altered tryptophan levels and alcohol on aggression in normal human males

Normal males received amino acid mixtures designed to raise or lower tryptophan availability, and thus to raise or lower brain serotonin synthesis. They also received alcoholic or non-alcoholic drinks. The subjects were tested in the Taylor Competitive Reaction Time Task in which they competed against a (non-existent) partner in a reaction time task. The magnitude of electric shocks that the subjects were willing to give to their bogus partner was used as a measure of aggression. Lowered tryptophan levels and ingestion of alcohol were associated with increased aggression. Our data support the idea that low serotonin levels may be involved in the etiology of aggression. They suggest that subjects with low brain serotonin levels may be particularly susceptible to alcohol-induced violence.

Host Response to Human Acellular Dermal Matrix Transplantation in a Primate Model of Abdominal Wall Repair

Commercially available human acellular dermal matrix (HADM), AlloDerm((R)), was implanted as an interpositional graft in the abdominal wall of adult vervet monkeys. Host response to implanted HADM was evaluated and compared with a human cellular dermal matrix (HCDM) and a primate acellular dermal matrix (PADM). Clinical acceptance of the acellular grafts (HADM and PADM) and graft remodeling were evidenced by fibroblast repopulation and neoangiogenesis. A mild inflammatory response marked predominantly by macrophages and T-cells was present in both HADM and PADM during the first month but was absent by 3 months. Similarly, antibody and complement deposition into the grafts as well as in the serum was evident only at the early time points. Interleukin-6 (IL-6) or IL-10 was induced in some acellular graft-implanted monkeys at the early time points, but tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), or IL-2 was not detected over the study period. In contrast, significant inflammation was observed in HCDM-implanted animals, as evidenced by immune cell infiltration (p </= 0.0001), immunoglobulin G (IgG) binding (p < 0.001), complement (C5b) deposition (p < 0.05), TNF-alpha deposition (p < 0.001), and macrophage activation (p < 0.05). Abdominal wall repair in the vervet monkey is an immunologically relevant model to evaluate functional efficacy and host immune response to implanted biomaterials and may be predictive of clinical response and surgical outcomes in humans.

The effect of raising or lowering tryptophan levels on aggression in vervet monkeys

Social groups of vervet monkeys (Cercopithecus aethiops) were given amino acid mixtures that were tryptophan-free (T-), nutritionally balanced (B), or contained excess tryptophan (T+). The T- mixture caused a marked decrease in plasma tryptophan and the T+ mixture a large increase. Behavioral observations were made on the animals after administration of the amino acid mixtures both during spontaneous activity and while the (fasted) animals were competing for food newly placed in the feeder. The only effect of the biochemical manipulations on spontaneous aggression was an increase in aggression of the male animals with the T- mixture. During competition for the food the T- mixture increased and the T+ mixture decreased aggression in the males, while the T+ mixture decreased aggression in females. These data indicate that brain 5-hydroxytryptamine can influence aggression in a primate and suggest that altered tryptophan levels can influence aggression more reliably at higher levels of arousal.

An amino acid mixture deficient in phenylalanine and tyrosine reduces cerebrospinal fluid catecholamine metabolites and alcohol consumption in vervet monkeys.

Abstract An amino acid mixture devoid of tryptophan, given orally, was previously shown to reduce cerebrospinal fluid levels of tryptophan and 5-hydroxyindoleacetic acid in vervet monkeys, as compared to a control mixture containing all essential amino acids. In the present study, we tested the possibility that a similar amino acid mixture containing tryptophan, but devoid of phenylalanine and tyrosine (the amino acid precursors of catecholamine neurotransmitters), would influence dopamine and noradrenaline metabolism. Five hours after the administration of this mixture to vervet monkeys, cerebrospinal fluid levels of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol were reduced by 27.4% and 26.9%, respectively. Both effects were statistically significant. Plasma tyrosine (-30%) and the ratio of tyrosine to the sum of other large neutral amino acids (ΣLNAA) were also significantly reduced. The behavioral efficacy of phenylalanine/tyrosine depletion was compared with that of tryptophan depletion in a primate model of voluntary alcohol consumption. All three drinks lowered alcohol consumption, but the effects of the tryptophan-deficient amino acid mixture were not different from those of the balanced amino acid control. The phenylalanine/tyrosine-deficient drink differentially lowered alcohol consumption, consistent with other data in this species and elsewhere implicating dopamine in the rewarding effects of alcohol.

Chapter 8 Ibogaine in the treatment of heroin withdrawal

Publisher Summary The chapter presents a study on the role of ibogaine in the treatment of heroin withdrawal. Pharmacological treatments for heroin addiction currently employ two treatment strategies: detoxification followed by drug-free abstinence or maintenance treatment with an opioid agonist. Because agonist maintenance with methadone usually has the goal of eventual detoxification to a drug-free state, the use of medications to facilitate this transition is a clinically important treatment strategy. Anecdotal reports suggest that ibogaine has promise as an alternative medication approach for making this transition. Ibogaine has an added benefit to other detoxification strategies in that the treatment experience seems to bolster the patients own motivational resources for change. Ibogaine is a drug with complex pharmacokinetics and an uncertain mechanism of action with regards to its alleged efficacy for the treatment of opiate dependence. Ibogaine is metabolized to noribogaine, which has a pharmacological profile that is different from that of the parent drug. The chapter presents that ibogaine is effective in blocking opiate withdrawal, providing an alternative approach for opiate-dependent patients who have failed other conventional treatments. Identifying noribogaines mechanism of action may explain the way ibogaine promotes rapid detoxification from opiates after only a single dose. Ibogaine, like most central nervous system (CNS) drugs, is highly lipophilic and is subject to extensive biotransformation. The Opiate-Symptom Checklist (OP-SCL) was developed for the present study as a subtle assessment of withdrawal symptoms.

Monoamine oxidase inhibition during brain development induces pathological aggressive behavior in mice

BACKGROUND Monoamine oxidase (MAO) is historically a focus of concern in research on impulsive and aggressive behavior. Recent studies in a single kindred with a point mutation in the MAO-A gene, together with phenotypic evaluations of MAO-A knockout mice, have sharpened this interest. The goal of this study was to investigate the behavioral consequences of MAO inhibition during brain development and to determine the extent to which specific effects could be attributed to MAO- A versus MAO-B. METHODS MAO-A and B inhibitors were administered, separately or in combination, during gestation and lactation. Behavioral evaluations included neurologic testing, delay of rewarded response, and the resident-intruder aggression paradigm, conducted before and after an acute pharmacologic challenge. RESULTS Total prenatal MAO inhibition produced a pervasive increase in aggressive behavior, whereas MAO-B inhibited mice demonstrated a similar pattern of lower intensity. Aggression was elevated in MAO-A inhibited mice only after acute pharmacologic challenge, suggesting prenatal sensitization. CONCLUSIONS Developmental inhibition of MAO activity engenders behavioral effects that parallel those observed in animals with genetic ablation of MAO function. These data underscore the importance of neurochemical changes during development and provide a possible model for disinhibited aggression, common in clinical populations.