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Biomedical subjects

W T McKinney

Publications and source records attributed to W T McKinney.

At least 37 records · Page 2Linked to original sources

Effects of alcohol on the despair response to peer separation in rhesus monkeys.

In humans, alcoholism and depression are often interrelated. This study examines the effects of alcohol on peer separation-induced despair in rhesus monkeys, a proposed nonhuman primate model of depression. Alcohol, at three different dose levels, or placebo was administered to rhesus monkeys undergoing repeated peer separation. Low-dose alcohol (1 g/kg/day) decreased separation-induced despair, whereas high-dose alcohol (3 g/kg/day) exacerbated the despair response as compared to placebo. This biphasic effect of alcohol on the despair response may be analogous to similar effects of alcohol on depression in humans.

Animals↗

Use of 6-hydroxydopamine to deplete brain catecholamines in the rhesus monkey: effects on urinary catecholamine metabolites and behavior.

The purpose of this study was to determine: 1) whether 6-hydroxydopamine (6-OHDA), previously shown to deplete brain catecholamines (CA) in rodents, depletes brain CA in rhesus monkeys; 2) whether depletion of brain CA produces changes in behavior; and, 3) whether urinary output of 3-methoxy-4-hydroxyphenylglycol (MHPG) reflects brain norepinephrine (NE) depletions. Repeated intracerebroventricular (ICV) injection of 6-OHDA (N = 20; 15.5-73.3 mg/subject) produced chronic changes in social behavior and, at higher dosages, reduced output of urinary MHPG. However, 4 weeks after the last ICV 6-OHDA injection, urinary MHPG excretion returned to baseline values and whole brain CA content was not reliably different from control. A single treatment with 6-OHDA microinjected into the substantia nigra (SN) (N = 12; 120-240 microgram/subject) produced chronic whole brain depletions of brain CA without depleting serotonin. Reductions in brain CA were associated with a specific set of motor behaviors, aphagia, and adipsia. SN 6-OHDA produced greater brain NE depletions than ICV 6-OHDA, but urinary MHPG output was not reduced. SN 6-OHDA treated subjects showed chronic changes in social behavior and were more sensitive to the operant response rate decreasing effects of alpha-methyl-para-tyrosine (AMPT) than control subjects. Subjects with the largest depletions of brain dopamine (DA) (greater than 90%) were hypokinetic, rigid, and had a distal limb tremor. These results show that SN but not ICV injection of 6-OHDA can deplete brain CA in the rhesus monkey. The most prominent behavioral changes were characterized by disturbances in motor function. Urinary MPHG output does not reflect depletions of brain NE in this species.

Animals↗

The dexamethasone suppression test as a measure of hypothalamic-pituitary feedback sensitivity and its relationship to behavioral arousal.

A nonhuman primate model was used to evaluate the value of the dexamethasone suppression test as an index of hypothalamic-pituitary-adrenal responsiveness to arousal. In 8 rhesus monkeys plasma cortisol was suppressed by dexamethasone in a dose-dependent fashion at doses between 0.75 and 33 microgram/kg. A replication study was performed 5 months later using a single dexamethasone dose (17 microgram/kg) known to produce maximal plasma cortisol suppression. This yielded highly correlated results (r = 0.91, p less than 0.005) suggesting that dexamethasone suppressibility may be a stable characteristic of individual animals. In 9 other animals whose arousal responses to a stressful procedure (nasogastric tube insertion) had been rated daily over a previous 3-month period, baseline plasma cortisol levels and the percent suppression of plasma cortisol by dexamethasone were evaluated. Baseline plasma cortisol levels did not significantly correlate with the degree of dexamethasone-suppression and the mean arousal ratings within animals. However, the postdexamethasone percent of baseline cortisol did correlate significantly (r = 0.75, p less than 0.025) with individual mean arousal ratings. These preliminary results suggest that assessment of the sensitivity of an individual's hypothalamic-pituitary glucocorticoid feedback system may be a better predictor than its baseline cortisol concentrations of its degree of behavioral arousal to stress.

Animals↗

Animal models of schizophrenia.

The authors review some general issues concerning the development and use of animal models of schizophrenia and present a summary of the criteria necessary for validating models. They also describe some of the major attempts at creating animal models of schizophrenia, including drug and nondrug methods. They comment on the etiologic, phenomenologic, and treatment relevance of the various systems and suggest approaches that might produce improved animal models of schizophrenia.

Amphetamine↗

Long-term chlorpromazine in rhesus monkeys: production of dyskinesias and changes in social behavior.

The daily administration of chlorpromazine (CPZ) in doses of 8--40 mg/kg over 113 weeks to four rhesus monkeys produced dyskinesias and alterations in social behavior. General activity and social interactions were reduced by CPZ treatment but social aggression was elevated during initial drug administration. These behaviors returned to normal when treatment was discontinued. Dyskinesias appeared during CPZ treatment, and two striking ones, gravel mouth and hand gesture, persisted for 12 weeks after drug withdrawal. These results indicate that dyskinesias which share major features of human tardive dyskinesia can be produced in nonhuman primates by long-term CPZ treatment.

Aggression↗

Mutual antagonism of behavioral effects of TRH and thiobarbiturate on an operant task in rhesus monkeys.

Similar excitatory or depressant response rate dependent effects on monkeys responding on a variable interval reinforcement schedule were observed following intravenous administration of either thyrotropin releasing hormone (TRH) or thiobarbiturate. However, these agents were mutally antagonistic when given together even though the response rate altering effects of each agent were in the same direction. These findings establish an additional behavioral effect of exogenously administered TRH in primates and suggest that barbiturates might alter behavior in part through an interaction with brain TRH receptive mechanisms.

Animals↗

Interactions of pharmacological agents which alter biogenic amine metabolism and depression--an analysis of contributing factors within a primate model of depression.

The observation that the biogenic amine depleting agent, reserpine, could induce severe depression in a small proportion of the patients treated with it has proved to be seminal finding in what is now a much larger field of research relating the function brain biogenic amine systems to emotions and behavior. A review of the human reserpine literature suggests, however, that factors other than pharmacologically produced alterations in brain biogenic amine metabolism must have been critical determinants of the eventual mood alterations observed in conjunction with reserpine treatment. While some of these factors, such as previous history of depression, ongoing psychosocial and environmental stress, can be intuitively identified, there are practical as well as ethical problems involved in actually testing the relative contribution of these factors in precipitating human depression and thereby determining their importance in a quantitative fashion. In the present paper we have attempted to examine, in a nonhuman primate model of depression, the degree to which factors such as prior rearing condition, repeated peer separation, and housing environment can intact with the behavioral effects produced by biogenic amine depleting agents. Major emphasis will be placed on studies utilizing alpha-methyl-para-tyrosine, an inhibitor of tyrosine hydroxylase, to ostensively reduce levels of the catecholamine neurotransmitters norepinephrine and dopamine. The results of these studies provide quantitative estimates, in terms of dose-effect relationships, of the degree to which a number of factors can combine to produce despair-like behavior in rhesus monkeys. These data may be of practical importance in evaluating the contribution of similar factors to the precipitation of human depression. Analysis of some of the existing literature relating alterations in behavior to changes in biogenic amine metabolism in animals suggests that there are important differences between rodent and primate species. These differences, when fully established, may indicate that additional research examining the mechanisms whereby modest alterations in biogenic amine metabolism can interact with environmental and social stress is needed.

Animals↗

The overlapping territories of psychiatry and ethology.

There have been numerous attempts since 1965 to stimulate more utilization of ethological methods and concepts in psychiatry. This literature is reviewed and an attempt is made to identify the factors which have inhibited an enhancement of this interaction to date. Most of the previous articles on this subject have appeared in edited collections, rather than in more widely circulated psychiatric or medical journals. Some of the articles focus on ethological theory, others on ethological research findings, and several on clinical analogies between animal and human situations. Regarding the specific way in which to integrate ethological thought into psychiatry, most frequently a phylogenetic approach is emphasized, however a few authors stress methodological considerations. In this paper, it is argued that artifactual differences have been the primary impediment to more interaction between these two rather similar fields. Scientific language difficulties, educational differences, and personal factors are described in this regard. Also, the real differences in approach and methodology, relative interest in normal vs. abnormal behavior, the degree of willingness to accept a phylogenetic approach, and the breadth of behavior being studied by the two fields are described. Examples of current areas of applicability of ethology to psychiatry are given: the attachment systems, early infantile autism, methodology, social psychiatry, and psychiatric education. Of these, the area where the most utilized is that of the occurred and in which the findings of ethology have been the most utilized is that of the attachment systems. Clinically applicable studies based upon the premise that attachment systems exist as understood ethologically are reviewed. These include study of extra physical contact between mothers and infants at birth, the prediction of child abuse and neglect utilizing observations from the immediate postpartum period, the treatment of failure to thrive by teaching attachment behavior, and developmental differences at 1 year correlated with differences in maternal responsiveness at 3 months. The usefulness of a biological approach to behavior is discussed, particularly in terms of utilizing operational criteria and from the point of view of differentiating etiological, phenomenological, and treatment models. A curriculum stressing the writings of Tinbergen, Lorenz, Bowlby, and Hailman is presented for possible use in psychiatric training programs interested in teaching an ethological approach to psychiatry. A briefer curriculum is also suggested from the psychiatric literature for use by ethologists. The epistemology and methodology of ethology possible will be of more use to psychiatry than the content. It is the opinion of the authors that the difficulties which have inhibited significant cooperation between psychiatry and ethology in the past are mostly artifactual, that such cooperation could be useful to both fields, and that a beginning to such interaction will require mutual familiarity with the literature.

Adult↗

Effects of imipramine treatment of separation-induced social disorders in rhesus monkeys.

Two groups of young rhesus monkeys were subjected to repetitive peer separations, a procedure that has been shown to produce depressivelike reactions in infant monkeys. Midway through the procedure one group was treated with the antidepressant imipramine hydrochloride, the other with a saline placebo. In comparison with placebo treatment, the imipramine treatment yielded significant behavioral improvement in a form and with a time course similar to that seen when the drug is given clinically to human depressives. We discuss the implications of the findings.

Animals↗

Mother-infant separation in rhesus monkeys as a model of human depression. A reconsideration.

Nineteen rhesus monkeys between the ages of 5.9 and 8.5 months were separated from their mothers in five different studies. While in two of the studies, data indicated behavioral responses roughly parallel to Bowlby's protest-despair response to maternal separations, data across all five studies were sufficiently variable to bring this technique into serious question as a reliable and predictable animal model for neurobiologic and rehabilitative studies.

Animals↗

Thyrotropin releasing hormone: antagonism of pentobarbital narcosis in the monkey.

The effect of TRH on pentobarbital narcosis in 21 rhesus monkeys was examined. Vital signs monitored included respiration rate, heart rate, temperature, sleeping time,and time of reappearance of certain reflexes. Blood samples were obtained for pentobarbital assay. Two dose schedules for TRH administration were used. One group of 6 animals received a single dose of 20 mg/kg 30 min after barbiturate administration, while the other group were received 3 injections of 20 mg/kg spaced at 30, 40 and 50 min after injection of pentobarbital. Both groups were sex balanced. TRH administration resulted in dramatically increased respiration and heart rates and arrested the progress of barbiturate induced hypothermia. The extended dose schedule prolonged increased respiration rate and a differential effect of TRH on pentobarbital induced hypothermia across sexes was observed. All animals regained reflexes sooner and sleeping time was reduced by 22%. No differences in pentobarbital blood levels with TRH were observed. These results extend earlier work in rodents to primates and suggest a possible use of TRH in cases of acute barbiturate intoxication.

Animals↗

Diazepam treatment of socially isolated monkeys.

Four rhesus monkeys were reared for the first eight months of life in total social isolation. One animal died during this period; the three remaining subjects were treated with diazepam in an isolation chamber, in their home cages, and in a playroom testing situation. Diazepam significantly decreased the self-disturbance behaviors of two subjects, and there was even the appearance of some social behaviors, although they were limited and not of the same quality as in nonisolated subjects. The authors discuss the implications of the data for understanding the significance of the social isolation syndrome in monkeys as a model for human psychoses.

Aggression↗

The effect of electrically induced convulsions on the behavior of normal and abnormal rhesus monkeys.

The social behavior of six juvenile rhesus monkeys was studied in a playroom before, during, and after a series of electrically induced convulsive (EIC) treatments. Three subjects had been reared in a normal environment, and showed the usual levels of social activity for monkeys of this age. Three were socially deprived early in life and showed higher levels of self-directed behaviors and lower levels of social behaviors. At different times all animals received both EIC ad sham EIC, three times per week for 4 weeks, and were observed in a playroom. In general the experimental subjects showed an increase in environmental activity as a consequence of EIC treatments while the control subjects showed decreases in environmental activity and in several social behaviors. The control subjects showed clear increases in self-disturbance behaviors while the experimental animals tended to show a decrease. The patterns of these changes thus showed clearly different characteristics of response to EIC and sham EIC as a function of early rearing condition. The results are discussed in terms of possible models for further study of the effects of EIC on physiological and social variables in a controlled laboratory setting.

Aggression↗

Overview of recent research in depression. Integration of ten conceptual models into a comprehensive clinical frame.

Disciplinary fragmentation and nosological and semantic controversies have obscured the impressive advances made in the area of depressive disorders during the past decade. This article is an attempt to translate data derived from psychodynamic, sociobehavioral, and neurobiologic research into a clinically meaningful framework. We review ten models of depression with special emphasis on newer models supported by empirical and experimental studies, and present a new model, which incorporates and synthesizes findings from different schools. Depressive illness is conceptualized as the feedback interaction of three sets of variables at chemical, experiential, and behavioral levels with the diencephalon serving as the field of action.

Anger↗

Effects of chlorpromazine on the vertical chamber syndrome in rhesus monkeys.

In an attempt at social rehabilitation, chlorporomazine was given to three groups of rhesus monkeys that had been confined to the vertical chambers apparatus early in their development. Previous studies have shown that such periods of deprivation produce severe deficits in social behavior. There were no substantial beneficial effects of chlorpromazine treatment; however, there was a notable amount of spontaneous improvement seen in all three groups. We discuss these data in terms of their implications for the use of the vertical chamber as a tool in experimental research of psychopathological disorder.

Animals↗