Glucocorticoid receptor impairment alters CNS responses to a psychologicalstressor: an in vivo microdialysis study in transgenic mice

To study the consequences of impaired functioning of the glucocorticoid rec eptor (GR) for behavioural, neuroendocrine and neurochemical responses to a psychological stressor, a transgenic mouse expressing antisense RNA agains t GR was used. Previous studies on these transgenic mice have shown that im pairment of GR evolves in disturbed neuroendocrine regulation and certain b ehavioural responses to stress. Here we investigated putative disturbances on the level of brain neurotransmission in GR-impaired (GR-i) mice using an in vivo microdialysis method. Through a microdialysis probe in the hippoca mpus, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and free cortic osterone [as an index of hypothalamic-pituitary-adrenocortical (HPA) axis a ctivity] were monitored. Moreover, specific behaviours (e.g. grooming, eati ng/drinking, sniffing, nest building and locomotion) displayed by the mice during collection of the dialysates were scored. Measurement of dialysate c oncentrations of corticosterone on days 1 and 3 after insertion of the micr odialysis probe showed that the free levels of this glucocorticoid were sig nificantly lower in GR-i mice toward the evening. On day 2 after insertion of the microdialysis probe, baseline values of dialysate corticosterone, 5- HT and 5-HIAA were assessed, after which mice were exposed to a rat placed into their home cage. The rat and mouse were separated by a Plexiglas wall. A positive correlation between baseline hippocampal extracellular levels o f 5-HT and 5-HIAA and the time spent performing active behaviours was obser ved in both genotypes. The main active behaviour performed at the baseline was grooming behaviour. During the rat exposure period, control mice remain ed mostly sitting and/or lying with their eyes fixed on the rat. Moreover, they showed a profound rise in free corticosterone levels. In contrast, GR- i mice displayed significantly more activities along the separation wall an d a trend toward more grooming behaviour, but no increase of free corticost erone. In both mouse lines, exposure to a rat increased hippocampal extrace llular levels of 5-HT and 5-HIAA. The rise in 5-HT was, however, more prono unced in the GR-i mice. From these data it may be concluded that life-long GR impairment has profound consequences for behavioural and neuroendocrine responses to a psychological stressor. Moreover, long-term impaired functio ning of GR evolves in hyper-responsiveness of the raphe-hippocampal seroton ergic system.