Stefan Tiefenbacher

Pharmacological blockade of α2-Adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys

Converging evidence suggests a role for noradrenergic mechanisms in stress-induced reinstatement of cocaine seeking in animals. Yohimbine, an α2-adrenoceptor antagonist, is known to be anxiogenic and induce stress-related responses in humans and animals. Here, we tested the ability of yohimbine to reinstate cocaine-seeking behavior and induce behavioral and physiological signs characteristic of stress in squirrel monkeys. Monkeys were trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Drug seeking subsequently was extinguished by substituting saline for cocaine injections and omitting the cocaine-paired stimulus. The ability of yohimbine and the structurally distinct α2-adrenoceptor antagonist RS-79948 to reinstate cocaine-seeking behavior was assessed by administering priming injections immediately before test sessions in which the cocaine-paired stimulus was either present or absent. Priming injections of yohimbine (0.1–0.56 mg/kg, i.m.) or RS-79948 (0.01–0.1 mg/kg, i.m.) induced dose-related reinstatement of cocaine-seeking behavior. The magnitude of yohimbine-induced reinstatement was similar regardless of the presence or absence of the cocaine-paired stimulus. Yohimbine also significantly increased salivary cortisol levels, a physiological marker of stress, as well as scratching and self-grooming, behavioral markers of stress in nonhuman primates. In drug interaction experiments, pretreatment with the α2-adrenoceptor agonist clonidine (0.1–0.3 mg/kg, i.m.) dose-dependently inhibited yohimbine-induced reinstatement of cocaine seeking. In contrast, pretreatment with the dopamine receptor antagonist flupenthixol failed to inhibit yohimbine-induced reinstatement of cocaine seeking. The results show that pharmacological blockade of α2-adrenoceptors can induce reinstatement of cocaine-seeking behavior and characteristic stress responses in squirrel monkeys, providing a potentially useful model of stress-induced relapse to drug seeking.

A Rhesus Monkey Model of Self-Injury: Effects of Relocation Stress on Behavior and Neuroendocrine Function

BACKGROUND Self-injurious behavior (SIB), a disorder that afflicts many individuals within both clinical and nonclinical populations, has been linked to states of heightened stress and arousal. However, there are no published longitudinal data on the relationship between increases in stress and changes in the incidence of SIB. This study investigated the short- and long-term behavioral and neuroendocrine responses of SIB and control monkeys to the stress of relocation. METHODS Twenty adult male rhesus macaques were exposed to the stress of relocation to a new housing arrangement in a newly constructed facility. Daytime behavior, sleep, and multiple measures of hypothalamic-pituitary-adrenocortical (HPA) axis function were investigated before and after the move. RESULTS Relocation induced a complex pattern of short- and long-term effects in the animals. The SIB animals showed a long-lasting increase in self-biting behavior, as well as evidence of sleep disturbance. Both groups exhibited elevated cortisol levels in saliva, serum, and hair, and also an unexpected delayed increase in circulating concentrations of corticosteroid binding globulin (CBG). CONCLUSIONS Our results indicate that relocation is a significant stressor for rhesus macaques and that this stressor triggers an increase in self-biting behavior as well as sleep disturbance in monkeys previously identified as suffering from SIB. These findings suggest that life stresses may similarly exacerbate SIB in humans with this disorder. The HPA axis results underscore the potential role of CBG in regulating long-term neuroendocrine responses to major stressors.

The physiology and neurochemistry of self-injurious behavior: a nonhuman primate model.

Self-injurious behavior (SIB) is a serious behavioral condition that afflicts millions of individuals in the United States alone. The underlying factors contributing to the development of self-injury in people are poorly understood, and existing treatment strategies for this condition are limited. A low but persistent percentage of socially reared individually housed rhesus monkeys also spontaneously develop SIB. Data obtained from colony records suggest that the risk of developing SIB in socially reared rhesus monkeys is heightened by adverse early experience and subsequent stress exposure. The present review summarizes the physiological and neurochemical findings obtained in this nonhuman primate model of SIB, focusing on monoamine neurotransmitters, neuropeptides, and neuroendocrine systems. The results indicate that monkeys with SIB exhibit long-lasting disturbances in central and peripheral opioid and stress response systems, which lead to increased levels of anxiety. Based on these findings, we propose an integrated developmental-neurochemical hypothesis in which SIB arises from adverse life events in a subset of vulnerable monkeys, is maintained by a persisting dysregulation of several neurochemical and physiological systems, and functions to periodically reduce anxiety when the levels of anxiety become excessive. Implications of this hypothesis for understanding self-injury in patients with borderline personality disorder and members of the general population are discussed.

Altered hypothalamic-pituitary-adrenocortical function in rhesus monkeys (Macaca mulatta) with self-injurious behavior

Individually housed rhesus monkeys sometimes spontaneously develop self-injurious behavior (SIB) in the form of self-directed biting that, on occasion, results in severe tissue damage and mutilation. We previously demonstrated lower levels of plasma cortisol in rhesus monkeys with a history of self-wounding (SW) when compared to non-wounders (NW). Furthermore, cortisol levels were negatively correlated with rates of self-directed biting. The present study was designed to further characterize the relationships between hypothalamic-pituitary-adrenocortical (HPA) activity, self-wounding, and self-directed biting. Basal 24-h urinary free cortisol excretion, the urinary free cortisol response to a low dose of dexamethasone, and the plasma cortisol response to ACTH were examined in 24 individually housed rhesus monkeys, based on wounding history, i.e. the presence/absence of a veterinary record of self-wounding, and current rates of self-directed biting, i.e. the median split of self-directed biting frequency (independent of wounding status). There were no reliable group differences on any of the physiological measures when analyzed by wounding history. However, the plasma cortisol response 30 min post-ACTH stimulation was significantly correlated with wounding recency, such that lower responsivity was associated with more recent wounding episodes. When the results were analyzed on the basis of biting frequency, high frequency biters (HFB) compared to low frequency biters (LFB) showed decreased HPA negative feedback sensitivity to dexamethasone and a trend towards an attenuated plasma cortisol response to ACTH stimulation. These findings suggest that SIB in socially reared monkeys is associated with complex changes in HPA axis function that are related to the expression of the pathology, i.e. self-directed biting, and to the recency of a wounding episode. It remains to be determined whether humans who exhibit SIB show similar alterations in HPA function.

Continuity and Change in Emotional Reactivity in Rhesus Monkeys Throughout the Prepubertal Period

We examined continuity and change in emotional reactiviy as assessed by hypothalamic–pituitary–adrenal (HPA) activity in rhesus monkeys. Plasma samples were obtained from mother-peer–reared and surrogate-peer–reared monkeys and assayed for cortisol concentrations at 5 time points in infancy. Both plasma and saliva samples were collected for cortisol assay from the same monkeys as 1-, 2-, and 3-year-old juveniles, respectively. Plasma cortisol concentrations increased during the first 5 months of life and decreased from 1 to 3 years of age. Females consistently had higher plasma cortisol concentrations than males. Plasma cortisol concentrations were lower in surrogate-peer–reared than mother-peer–reared monkeys during the first month of life. Juvenile plasma cortisol concentrations were significantly correlated with infant cortisol levels at all but the earliest time point. Analysis of salivary cortisol from a subset of animals showed a similar age-related decline and the presence of a significant rearing effect, with lower concentrations in surrogate-peer–reared juveniles, but no sex difference. Salivary and plasma cortisol concentrations in these animals were significantly correlated.

Fenfluramine challenge, self-injurious behavior, and aggression in rhesus monkeys

Self-injurious behavior (SIB) and aggression have been linked to reduced serotonergic (5-HT) functioning in both humans and nonhuman primates. The present study examined serum prolactin and cortisol responses to the 5-HT releasing agent D,L-fenfluramine (FEN) in 24 individually housed rhesus monkeys (Macaca mulatta), 15 of which carried a veterinary record of self-wounding (SW). Subjects received two doses of FEN, 4 and 2 mg/kg, separated by an interval of at least 2 months. For control purposes, monkeys were given an intramuscular saline injection 1 week prior to each FEN challenge. The relationship between the hormonal responses to FEN, wounding history, the rates of self-directed biting and aggression were determined for each animal based on 100 five-minute observations conducted over a period of 12 months surrounding the challenge procedures. Prolactin and cortisol responses to FEN were unrelated either to wounding history or to rates of self-directed biting. However, there were significant inverse correlations between levels of aggression and the prolactin response to both doses of FEN. The present findings provide no evidence for reduced 5-HT system function in rhesus monkeys with SIB under the present challenge conditions. However, the results are consistent with a previously reported inverse relationship between serotonergic activity and aggression. Moreover, a dose-dependent response to FEN was observed only for prolactin, suggesting that this variable is more appropriate than cortisol as an endpoint for FEN challenge in monkeys.