Department of Biomedical Sciences

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    The role of corticotropin-releasing factor in anxiety disorders
    (Stellenbosch : Stellenbosch University, 2001-12) Pietersen, Charmaine Y.; Daniels, W. M. U.; Stein, D. J.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine.
    ENGLISH ABSTRACT: SEPARATION STUDY Traumatic experiences during childhood can have a negative impact on behaviour later in life. Kendier et al. (1992) found that the loss of a parent during childhood increased the risk to develop major anxiety disorders and could also lead to depressive-like behaviour (Furukawa et al., 1999). Methods: We subjected rat pups to maternal separation and determined the effects thereof on adult behaviour. We removed rat pups from their mothers for 3 hours daily from postnatal day 2 to 14. On day 60, the behaviours of the rats were tested using the elevated plus-maze and the open field test. Controls were reared normally. Behaviours: Amount of time spent and the number of entries into the arms of the maze were noted on the elevated plus-maze, while the total time spent in each zone (inner versus outer) and the number of zone crossings were noted for each rat on the open field arena. The latency to move from the initial placement in the outer zone to the inner zone as well as the number of quadrant crossings was also determined. Defecation, freezing, rearing and grooming behaviours were also noted. Neurotransmitter levels: Noradrenaline, serotonin and their metabolites were evaluated in maternally separated rats and compared to controls. Their concentrations at basal level, immediately after restraint stress and 15 minutes after restraint stress, were also determined. A HPLC method was followed in these determinations. ACTH Determinations: All rats were subjected to restraint stress for a lO-minute period. Trunk blood was collected for basal, as well as 15 and 60 minutes postrestraint stress for ACTH determinations. Results: Behaviours: The amount of entries was significantly reduced in the separated animals, indicating decreased locomotion. They spent significantly more time in the closed maze arms. A significant increase in defecation frequency and rearing behaviour was noted. These observations are typical of anxious behaviour. In the open field test, the behavioural results were less convincing. Only a significant increase in defecation frequency and a significant decrease in rearing behaviour in separated animals, were observed. Neurotransmitter levels: No significant differences were noted between separated animals and controls with respect to basal monoamine levels. However, noradrenaline levels were significantly decreased in the frontal cortex 15 minutes after restraint stress and immediately after restraint stress in the hypothalamus and hippocampus in separated animals. MHPG levels were significantly decreased in the frontal cortex immediately after restraint stress. No significant differences were found with respect to serotonin levels. However, significant increases were found in 5HIAA levels in the frontal cortex and hippocampus of separated rats, 15 minutes after restraint stress. The basal turnover ratios of serotonin (5HIAA/5HT) and noradrenaline (MHPGINA) did not yield significant results. However, immediately after restraint stress, a significant increase was found in serotonin turnover in the hypothalamus of separated rats when compared to controls. This turnover rate was also increased in separated rats, 15 minutes after restraint stress in the frontal cortex and hypothalamus. ACTH Determinations: Basal ACTH levels were significantly higher in separated animals. At 15 minutes post-restraint stress, the levels were significantly lower than controls, indicating a blunted stress response. Our results therefore showed that maternal separation could lead to anxious behaviours in adult life. These behavioural abnormalities were associated with alterations in the central nervous and neuroendocrinological systems, particularly in response to stressful situations. CRF STUDY The maternal separation study indicated that elevated CRF levels could possibly be causally related to abnormalities observed in the anxious animals. We therefore hypothesised that adverse development factors, such as maternal separation, predisposes individuals to develop psychopathologies later in life and that this process was driven by a presence of high CRF levels. Methods: Cannulas were implanted into the left lateral ventricles of normal rats, making use of stereotaxic procedures. CRF (3 flg/fll) was injected into the ventricles daily for 5 days. Saline controls were handled similarly, but only injected with saline for the same time period. Both groups of animals were then compared to naïve controls. Histology was performed to determine the correct placement of the cannulas. Behaviours: The Elevated Plus-maze was employed to determine whether their behaviours were anxious. The number of entries into the various arms of the maze as well as the amount of time spent in the open and closed arms was accumulated. Rearing, freezing, defecation and grooming were also noted. ACTH Determinations: The ACTH levels ofCRF-injected, saline-injected and naïve rats were determined 15 minutes after restraint stress. Results: Behaviours: A decrease in the number of entries into the closed arms of the maze was noted in the CRF-injected rats when compared to naïve controls. No significant differences were found between the groups with respect to the amount of time spent in the various arms and the behaviours noted during the experiment. ACTH Determinations: A decrease in ACTH levels was noted in CRF-injected rats 15 minutes after restraint stress when compared to naïve controls. Therefore, although the CRF injections did not alter the behaviour of the rat, they did exhibit a blunted stress response to the stressor. Conclusion: Our experiments led us to conclude that early adverse experiences, such as maternal separation, can lead to the development of psychopathologies later in life. CRF, however, is not pivotal in the development of these abnormalities; rather it seems that the neurochemical abnormalities (serotonin and noradrenaline) play a more important role in the development of these mental disturbances. Finally, we hypothesise that combination drug therapy that targets both the noradrenergic and serotonergic neurotransmitter systems could be preferred above those aimed at rectifying the individual neurotransmitter systems in the treatment of psychopathologies, such as anxiety disorders.