We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.

The measurement of monkey cisternal CSF 5-HT appears to provide a useful index of central 5-HT release. Initial results tend to support a role for increased extracellular 5-HT in the mechanism of action of chronically administered SSRIs.

Two studies were conducted to examine the effects of oral L-tryptophan (TRP) supplementation as a treatment for self-injurious behavior (SIB) and to investigate behavior and central serotonin turnover of male rhesus monkeys. In Study One, TRP was administered to seven individually housed rhesus monkeys with a recent history of spontaneous SIB. While the monkeys were on TRP treatment (100 mg/kg twice a day), cisternal cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid increased markedly (p .0013) above baseline (baseline mean 207.6 pmol/ml 39; TRP mean 320.3 pmol/ml 83.4), and the duration of self-biting behavior decreased below baseline (p .03). In Study Two, 14 individually housed rhesus monkeys without a history of SIB were placed on three different doses of TRP in random order (50, 100, and 200 mg/kg twice a day). TRP had no effect on any behavioral or biochemical variables in the normal monkeys. Conclusions: Supplemental tryptophan in well-tolerated doses reduced self-biting and increases serotonin turnover rate in male monkeys with a recent history of SIB. The same doses of TRP do not affect behavior or serotonin metabolism in male monkeys without a history of SIB. [Neuropsychopharmacology 19:314-321, 1998] Published by Elsevier Science Inc. Self-injurious behavior (SIB) occurs in humans (re-viewed by Winchel and Stanely 1991; Favazza and Rosenthal 1993) and other species (see Meyer-Holzapfel 1968; Jones and Barraclough 1978). In humans, SIB has been described as representing a continuum of behavior ranging from occasional noninjurious biting, scratching , and head banging to persistent self-biting and cutting associated with severe physical injuries (Harris 1995; Walsh and Rosen 1988). SIB also occurs in rhesus monkeys, most often as a result of self-biting (Tinkle-paugh 1928; Erwin et al. 1973; Capitanio 1986). A retrospective study documenting the incidence of wounding in three primate colonies (Bayne et al. 1995) showed that, of 253 monkeys studied, 0.8% engaged in self-inju-rious behavior that resulted in wounds requiring veterinary treatment. Although severe self-biting in nonhu-man primates is a relatively uncommon phenomenon, it nevertheless remains a serious concern, because it can lead to severe and sometimes fatal injuries.