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The effects of intracerebroventricular corticotropin-releasing factor (CRF) on the behaviour and cerebral glucose metabolism of non-human primates Strome, Elissa Marie

Abstract

Corticotropin-releasing factor (CRF) is a peptide neurotransmitter involved in the mammalian stress response, and also plays a key role in the mediation of fear and anxiety-like behaviours in animals. In rats, intracerebroventricular (ICV) CRF induces anxiety-like behaviour, and in rhesus monkeys, CRF administration produces distinct behavioural changes, including lying down, huddling, wallfacing and decreased locomotion. In humans, increased activity within CRF neurons has been associated with psychiatric disorders such as anxiety and major depression. The resemblance of the behavioural effects of CRF in monkeys to the symptoms of human depression suggests that this could be a new animal model of depression. This experiment examines the CRF model of depression more closely. CRF (434 pg in artificial cerebrospinal fluid) or vehicle alone were administered ICV over 40 min in a counterbalanced design to six adult rhesus monkeys, with each animal acting as its own control, and behavioural observations were taken. On a separate occasion, nine animals underwent two consecutive positron-emission tomography scans (baseline followed by an activation scan after CRF administration) under light anaesthesia using the tracer analog [18F]fluorodeoxyglucose to determine how the same dose of CRF altered regional cerebral glucose metabolism from baseline. Behaviourally, ICV CRF elicited a wide range of anxiety- and depressive-like behaviours in rhesus monkeys. These included increased passivity, huddling, stypics and decreased locomotion and grooming. In general, anxiety- and depressive-like behaviours increased after CRF, while externally-oriented behaviours decreased. Depressive-like behaviours were most obvious when the animals were in social groups, suggesting that these were a means of communication. Central administration of CRF increased the rate of glucose metabolism in the pituitary, one of its main targets during the stress response. CRF also increased the glucose metabolic rate in the amygdala, a key limbic region underlying anxious and fearful behaviour. The results of this study suggest that increased cerebral CRF tone specifically affects behaviour and cerebral glucose metabolism in limbic brain regions of rhesus monkeys. Because CRF can elicit depressive-like behaviour in monkeys and alter the function of brain regions implicated in depression, CRF antagonists may be an effective treatment for major depression in humans.

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