Differences in central noradrenergic and behavioural responses of Maudsley non-reactive and Maudsley reactive inbred rats on exposure to an aversive novel environment.

The present experiments compared the noradrenaline and behavioural responses of inbred Maudsley reactive (MR) and non-reactive (MNRA) rats when they are exposed to the light or dark arena of a light/dark shuttle-box. Behavioural scores confirmed that both strains of rats perceived the light arena to be more aversive than the dark one. Using in vivo microdialysis, exposure to the light, but not the dark, arena was found to increase noradrenaline efflux in both the frontal cortex and the hypothalamus of MNRA and MR rats. However, whereas the increase in the frontal cortex of both strains and the hypothalamus of MR rats was transient, the hypothalamic response in MNRA rats was maintained throughout exposure to the test zone. Strain differences in activity/visit and time/visit were evident but it was not possible to discern whether this could be attributed to the strain difference in the hypothalamic noradrenaline response. Nevertheless, it remains possible that, by comparison with MR rats, the prolonged noradrenaline response in the hypothalamus of MNRA rats could contribute to their well-documented, greater resistance to aversive environmental stimuli.

A microdialysis study of the noradrenergic response in rat frontal cortex and hypothalamus to a conditioned cue for aversive, naturalistic environmental stimuli.

RATIONALE: Extracellular noradrenaline concentration in the rat forebrain is increased by aversive environmental stimuli. This study investigated whether conditioned cues for such stimuli have the same effect. METHODS: After training rats to associate a tone (conditioned cue) with transfer from a neutral zone to a brightly lit zone of a light/dark shuttle-box (unconditioned stimulus), microdialysis probes were implanted into the frontal cortex and hypothalamus under halothane anaesthesia. Changes in extracellular noradrenaline concentration were then monitored on exposure to the tone alone. Parallel experiments monitored rats' behaviour in the light arena. RESULTS: A single exposure to the light arena increased extracellular noradrenaline in the frontal cortex and the hypothalamus but neither a single, nor repeated, exposure to the tone alone had any effect. After conditioning trials, the tone alone increased extracellular noradrenaline in the frontal cortex but not the hypothalamus, whilst the tone+transfer to the light arena resulted in a prolonged increase in extracellular noradrenaline in both brain regions. The time that rats spent within the light arena was also prolonged. CONCLUSIONS: Noradrenergic neurones in the frontal cortex, but not the hypothalamus, respond to conditioned cues for aversive environmental stimuli. However, prolongation of the noradrenergic response in both brain regions could contribute to the behavioural adaptation to such unconditioned stimuli.

Modulation of sibutramine-induced increases in extracellular noradrenaline concentration in rat frontal cortex and hypothalamus by alpha2-adrenoceptors.

1. The effects of sibutramine (0.25 - 10 mg kg-1 i.p.) on extracellular noradrenaline concentration in the frontal cortex and hypothalamus of freely-moving rats were investigated using microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of sibutramine in these brain areas was also determined. 2. Sibutramine induced an increase in extracellular noradrenaline concentration, the magnitude of which paralleled dose, in both brain areas. In the cortex, this increase was gradual and sustained, whereas in the hypothalamus it was more rapid and of shorter duration. 3. In both the cortex and hypothalamus, pretreatment of rats with the alpha2-adrenoceptor antagonist RX821002 (3 mg kg-1 i.p.) potentiated increases in the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i. p.), by 7 and 10 fold respectively. RX821002 also reduced the latency of sibutramine to reach its maximum effect in the cortex, but not in the hypothalamus. 4. Infusion of RX821002 (1 microM) via the probe increased the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i.p.) in both brain areas. In the hypothalamus, the effects of RX821002 on the accumulation of noradrenaline induced by sibutramine were 2 fold greater than those in the cortex. 5. These findings support evidence that sibutramine inhibits the reuptake of noradrenaline in vivo, but that the accumulation of extracellular noradrenaline is limited by noradrenergic activation of presynaptic alpha2-adrenoceptors. Furthermore, the data suggest that terminal alpha2-adrenoceptors in the hypothalamus exert a greater inhibitory effect over the control of extracellular noradrenaline accumulation than do those in the cortex.

Effect of novel environmental stimuli on rat behaviour and central noradrenaline function measured by in vivo microdialysis.

RATIONALE: Although physically aversive stimuli induce functional changes in central noradrenergic neurones, little is known about the noradrenergic response to environmentally aversive stimuli. OBJECTIVES: The first aim was to characterise environmental features that are perceived as stressful by rats. The second was to investigate whether changes in the concentration of extracellular noradrenaline are induced by these environmental features. METHODS: A light/dark shuttle-box was used to test rats' behavioural response to a range of stimuli (novelty, bright light, and the presence of an unfamiliar rat), either before or after microdialysis probe implantation. Changes in the concentration of extracellular noradrenaline in the frontal cortex and hypothalamus in vivo were then evaluated on exposure to these same test conditions. RESULTS: Naive rats spent less time in a brightly-lit test arena than a dark one. However, the behavioural response to the light arena was attenuated by the presence of an unfamiliar rat. Probe implantation intensified the response to the light arena but did not affect behaviour in the dark arena. In the microdialysis studies, there was no change in the concentration of extracellular noradrenaline on transfer of rats to the dark arena but there was an increase in both the frontal cortex (+45%) and hypothalamus (+75%) on exposure to the light arena. A similar increase was induced in both brain regions when the light arena contained an unfamiliar rat. CONCLUSIONS: Implantation of a microdialysis probe modifies the behavioural responses to certain environmental stimuli. Regardless of this, the extent to which rats perceive a novel environment as aversive is not the only determinant of the noradrenergic response to such stimuli. However, differences in stimulus controllability in the microdialysis and the behavioural experiments could influence the apparent intensity of the stress.

Incremental changes in extracellular noradrenaline availability in the frontal cortex induced by naturalistic environmental stimuli: a microdialysis study in the freely moving rat.

Changes in levels of extracellular noradrenaline (NA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindole-3-acetic acid (5-HIAA) in the frontal cortex, induced by exposure of unrestrained, conscious rats to novel environments, were compared using in vivo microdialysis. NA efflux increased when rats were transferred to a novel cage, but this was not significant when compared with either basal efflux or with changes after equivalent handling in their home cage. Increasing the intensity of illumination of the novel cage by fivefold significantly increased NA efflux with respect to basal efflux but not handled controls. However, a sustained and significant increase in NA efflux (cf. basal efflux or handled controls) was found when an unfamiliar conspecific was also present in the novel cage. In all cases, basal efflux was restored within 1 h of returning rats to their home cage. Neither handling nor environmental stimuli described above affected DOPAC efflux. 5-HIAA efflux was increased (cf. basal) in the presence of an unfamiliar conspecific, but this increase was no greater than that in handled rats. It is concluded that different naturalistic stimuli cause incremental changes in the levels of extracellular NA in the frontal cortex; these changes affect both phasic and tonic components of the response.

Preoperative rehearsal of active coping imagery influences subjective and hormonal responses to abdominal surgery.

Existing evidence suggests that preoperative psychological preparation that is designed to reduce anxiety may sensitize cortisol and adrenaline responses to surgery. In a controlled trial of abdominal surgery patients, we therefore tested the effects of a preoperative preparation that used guided imagery, not to reduce anxiety, but to increase patients' feelings of being able to cope with surgical stress; 26 imagery patients were compared with 25 controls who received, instead, background information about the hospital. State-anxiety was similar in each group, but imagery patients experienced less postoperative pain than did the controls, were less distressed by it, felt that they coped with it better, and requested less analgesia. Hormone levels measured in peripheral venous blood did not differ on the afternoon of admission, before preparation. Cortisol levels were, however, lower in imagery patients than in controls immediately before and after surgery. Noradrenaline levels were greater on these occasions in imagery patients than controls. The results are interpreted in relation to two theories. One states that preoperative "worry" reduces surgical stress. The other concerns the influence of active and passive coping on endocrine responses to stress.

Comparison of the effects of repeated electroconvulsive shock on alpha 2- and beta-adrenoceptors in different regions of rat brain.

The effects of ten, once-daily electroconvulsive shocks on alpha 2 and beta-adrenoceptor binding were investigated in the rat cortex, hippocampus, hypothalamus and cerebellum. [3H]Clonidine and [3H]dihydroalprenolol were used as radioligands for alpha 2 and beta-adrenoceptors respectively. Twenty-four hours after the last shock, the density of beta-adrenoceptors was reduced in the cortex and hippocampus, but not in the hypothalamus or cerebellum. There was no change in the apparent affinity of the beta-receptors in any of the regions studied. Alpha 2-adrenoceptor density was reduced in all the regions studied (cortex, hippocampus, hypothalamus) with, again, no change in their apparent affinity. It is concluded that the effects of electro-convulsive shock on alpha 2 and beta-adrenoceptors show regional variation; possible reasons for this variation are discussed.