John B. Thurmond

Biochemical and behavioral correlates of chronic stress: Effects of tricyclic antidepressants

Using a chronic stress model of depression, the biochemical, hormonal, and neurochemical effects of chronic stress were determined in male CD-1 mice. The effects of chronic administration of three tricyclic antidepressants (TCA): chlorimipramine, amitriptyline and desmethylimipramine, as well as fluoxetine, a specific serotonin uptake inhibitor, were also evaluated. Exposure to acute noise/light stress dramatically increased motor activity (behavioral activation) in comparison with basal (unstressed) activity. However, animals with a history of chronic stress exhibited reduced basal activity levels as well as a decreased behavioral activation response to acute stress. There was also exaggerated corticosterone (CS) responding in both of these behavioral test situations attributable to prior chronic stress exposure. Chronic treatment with any of the TCAs significantly restored the behavioral activation response to acute stress and normalized CS responding in chronically stressed animals. Chronic fluoxetine treatment was ineffective. In chronically stressed, but behaviorally untested (quiescent) mice, there were no changes in CS levels, but norepinephrine (NE) and 5-hydroxyindoleacetic acid (5-HIAA) levels were increased. However, chronically stressed mice tested for basal motor activity showed large NE decreases, while those receiving acute stress exposure prior to testing showed large NE decreases and further 5-HIAA increases. There were no alterations on neurochemical parameters due to any drug treatment which could be correlated with a possible mechanism for their efficacy, although evidence suggested NE involvement. It was further proposed that the chronic stress paradigm induced conditioned neuroendocrine and neurochemical responses.

Technique for producing and measuring territorial aggression using laboratory mice

A method was developed for producing and measuring territorial aggression in male CF-1 laboratory mice using a simple apparatus. The technique is based on data collected from approximately 1000 CF-1 mice in order to establish the parameters and optimize the procedures. In this technique the mouse takes up lone residence for 24 hr in a 60 cm square box attached by a tubular runway to a standard mouse (home) cage with food, water, and bedding. After this interval, a naive intruder male CF-1 mouse of the same age is introduced. Under control (no treatment) conditions, 85-90 percent of the resident mice will attack the intruder with a latency of about 5 min and all residents attacking the intruder are dominant. Dominance or submission is typically decided within the first 20 min of the test. Data on 10 pairs of mice can be collected simultaneously by one observer. Treatments can be assessed in terms of their effects on the production of aggression (percentage of animals attacking) in either the resident or the intruder, and on the level of aggression produced by recording the latency to attack, the frequency of attacks, and the number of animals wounded (showing blood) during the 20 min observation period. The advantages of the technique include the use of a naturally occurring aggressive behavior (as opposed to techniques empolying long periods of isolation, shock, or drugs), the highly reliable occurrence of aggression, the ability to study animals exposed to either aggression or defeat, the clear and valid measures of aggression produced, the simple and sturdy apparatus, and the convenience and economy of data collection.

Behavioral and neurochemical effects of dietary tyrosine in young and aged mice following cold-swim stress.

Abstract The effects of dietary supplements of L-tyrosine on aggressive behavior, locomotor activity, and brain neurochemical changes were assessed in young and aged mice following cold-swim stress. Male CF-1 mice, ages 3 months and 21 months, were maintained on a semi-synthetic basal diet for one week, pretested for aggressive behavior and locomotor activity, then switched to diets modified by the addition of tyrosine or casein (control). After one week on the diet supplements, half of the mice were stressed by cold water swim and all were again subjected to behavioral testing. Members of each group were sacrificed for analysis of amino acids and monoamines in brain tissue and corticosterones in blood. It was found that tyrosine supplementation induced a marked increase in aggressive behavior in young, nonstressed mice but not in aged mice. Stress decreased the aggressiveness of both young and aged mice, and tyrosine prevented this stress-induced decrease in both groups. Young mice exhibited no changes in locomotion as a function of stress or diet. However, tyrosine prevented decreases in locomotion observed on second testing of both stressed and nonstressed older mice. The effect of stress was to lower levels of brain norepinephrine (NE) and dopamine (DA) in both young and aged mice. Tyrosine supplementation increased brain tyrosine and DA in both groups. Brain serotonin levels were lower in the aged mice compared to the younger ones, and this was associated with relatively higher concentrations of 5-hydroxyindoleacetic acid. It appears that tyrosine supplementation was effective in reducing the effects of stress in the aged animals, possibly by virtue of its relationship to catecholamine metabolism.

Maternal aggression in mice: effects of treatments with PCPA, 5-HTP and 5-HT receptor antagonists.

Drug treatments which influence brain serotonergic systems were administered to lactating female mice during the early postpartum period, and their effects on aggressive behavior, locomotor activity and brain monoamines were examined. P-chlorophenylalanine (200 and 400 mg/kg) and 5-hydroxytryptophan (100 mg/kg) inhibited fighting behavior of postpartum mice toward unfamiliar male intruder mice. These drug-treated postpartum females showed increased latencies to attack male intruders and also reduced frequencies of attack. In addition, postpartum mice treated with the serotonin receptor antagonists, mianserin (2 and 4 mg/kg), methysergide (4 mg/kg) and methiothepin (0.25 and 0.5 mg/kg), displayed significantly less aggressive behavior than control mice, as measured by reduced number of attacks. Whole brain monoamine and monoamine metabolite levels were measured after drug treatments. The behavioral results are discussed in terms of drug-induced changes in brain chemistry and indicate a possible role for serotonin in the mediation of maternal aggressive behavior of mice.

Effects of dietary tyrosine, phenylalanine, and tryptophan on aggression in mice

Dietary amino acid regimens designed to enhance catecholaminergic and serotonergic functioning were found to differentially affect territorial-induced attacks in mice. Male albino mice were maintained on a semi-synthetic 12% casein protein diet for 2 weeks, then switched to diets modified by the addition of a 4% L-amino acid supplement, or 4% casein (control). Measures of aggressive behavior and open-field locomotor activity were obtained before and after the dietary supplements were administered. Resident mice fed supplements of L-tyrosine displayed a marked increase in the number of attacks on intruders and shorter attack latencies, but their locomotor activity was unaffected. L-phenylalanine supplements alone or in combination with L-tyrosine reduced the latency to attack and increased motility but did not affect the number of attacks. As a whole, the group of animals fed L-tryptophan showed no changes in aggression or motility.

Interaction of dietary tryptophan and social isolation on territorial aggression, motor activity, and neurochemistry in mice

This study examined the interaction of dietary tryptophan (TRP) and differential housing on territorial-induced aggression, locomotor activity, and monoamine neurochemistry in mice. Groups of male CF-1 mice were singly-housed or group-housed and administered a semisynthetic basal diet supplemented with TRP (0.25–1.0%). Behavioral measures were taken at various intervals up to 2 weeks after dietary administration was instituted. Separate groups of mice were given the same experimental treatment and sacrificed for whole brain determination of the monoamines and their metabolites. Isolated mice were consistently more aggressive than grouped animals, suggesting that territorial-induced aggression is synergistic with intermale aggression based on social isolation. The combination of isolation and 0.50% TRP was particularly effective in producing increases in aggression that reached maximal levels after 10 days of diet administration. However, motor activity of singly-housed mice was unaffected by TRP, while that of grouped mice was decreased after 5 days of 0.50% TRP. By day 14 of administration behavioral changes tended to return to baseline levels. Neurochemical measures indicated increased DA and 5-HT turnover in isolated mice, with the 5-HT system most affected by dietary TRP. Because housing conditions were a prominent factor in the aggression and neurochemistry, the results suggest the involvement of both transmitter systems in this behavior. However, there were no changes in monoamine turnover that could account for the development of behavioral tolerance.

Form identification in peripheral vision

Outlined and solid-surfaced metric histoforms and polygons we;e employed in an identification task where choice forms were fixed at 0 deg and target forms at six points along the temporal horizontal meridian in the periphery (nasal retina). Accuracy in the identification of solid-surfaced polygons in the far periphery (80 deg from the fovea) was much higher than has been previously reported. Polygons were identified more quickly than histaforms, but a significant difference was not obtained between the speed of identification of outlined and solid shapes. Combined speed and error data indicated that shape (histoform or polygon) is the most salient dimension of a form less than 50 deg from the fovea. whereas beyond 50 deg from the fovea the surface (outlined or solid) of a form is its most salient dimension. Finally. comparisons of the functional relations provided by these performance data with anatomical and physiological data produced the following hypothesis: Spatial summation of rod receptors beyond 20 deg of angular eccentricity in the nasal retina is directly proportional to the density of rod receptors.

Preattentive and cognitive effects on perceptual completion at the blind spot

Our findings indicate that preattentive processes, such as the filling in of homogeneously colored areas, discrete dots, or bars across the blind spot, take into account both the color and the form that stimulate the retina around the optic disk. Perceptual completion of the “junction” of two opposite colors facing each other on opposite sides of the blind spot was resolved by simultaneous segregation of the two colors at the location of a filled-in perpendicular line that suggested a boundary separating the two colors. Orientation preference and relative salience of one color versus the other determined which color was perceptually completed in a forced-choice situation that involved perceptual completion at the intersection of a cross formed by bars of opposite colors. A 1-min exposure to these stimuli presented an ambiguous situation for perceptual completion of either color within the blind spot, and resulted in a perceptual “flip-flop” from one color to the other, much like the phenomenon that occurs in figure reversal. Instructions to speed up this reversal process led to a fivefold reduction in latency to first reversal.

Dietary amino acid precursors: Effects on central monoamines, aggression, and locomotor activity in the mouse

Abstract Behavioral and brain neurochemical changes were assessed in mice maintained on amino acid supplemented 12% protein diets for two and six weeks. Addition of 1,2, or 4% L-phenylalanine increased aggression but only the 1% supplement increased locomotion. Addition of 0.25 or 0.5% L-tryptophan of the basal diet also increased aggression. All behavioral effects were noted after two weeks but not after six weeks on the diets, suggesting the development of behavioral tolerance. All groups of mice gained the same amount of weight on the various diets over a seven-week period and no ill effects were observed. Mice on 16% protein diets displayed only marginal differences in brain concentrations of phenylalanine, tyrosine, tryptophan, dopamine, norepinephrine, serotonin or 5-hydroxyindoleacetic acid. Brain concentrations of tyrosine, phenylalanine and tryptophan were significantly reduced in animals receiving supplements of leucine for two and six weeks. L-phenylalamine supplementation caused marked increases in brain phenylalanine and tyrosine concentrations after two and six weeks. Changes in brain dopamine and 5-hydroxyindoleacetic acid also were noted. Supplements of 0.25, 0.5, and 1.0% L-tryptophan increased brain indoles, and these changes also appeared to be sustained over the six-week period.

Effect of brain monoamine precursors on stress-induced behavioral and neurochemical changes in aged mice.

Male CF-1 mice aged 22 months showed approximately the same level of motor activity and aggressive behavior as 3-month-old mice under control (no stress) conditions, or 45 min following cold swim stress. Increasing brain catecholamine activity by dietary L-tyrosine treatment had no effect on these two age groups either under control conditions or after stress. In contrast, 30-month-old mice showed lower motor activity under control conditions which was raised significantly by supplementation of the diet with L-tyrosine. However, marked reductions in activity and aggression following stress were observed in the 30-month-old animals and these deficits were not reversed by L-tyrosine treatment prior to stress. Reduction in motor activity was greatest in stressed, 30-month-old mice on L-tyrosine supplemented diets. Compared to 3-month-old mice, the 30-month-old animals had lower brain tyrosine following dietary L-tyrosine treatment, lower brain tryptophan, norepinephrine (NE), dopamine (DA) and DOPAC, but higher HVA, serotonin (5-HT) and 5-HIAA levels. Under both control (no stress) and stress conditions, L-tyrosine pretreatment decreased brain 5-HT in the young animals, but increased 5-HT in the old mice. After stress the 30-month-old animals evidenced only slight increases in levels of blood corticosterone. Brain tyrosine was reduced by stress in the young animals but increased by stress in the old animals. Stress-induced decreases in brain NE and increases in serotonin and 5-HIAA levels were observed in both age groups. These results are consistent with hypotheses concerning age-related alterations in brain monoamine functions and adrenocortical control mechanisms.