Davis, Sarah; (1993) Factors affecting behaviour and changes in monoamines induced by novel stimuli in rodents. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Although stress causes neurochemical changes in central noradrenergic and serotonergic neurones, how these changes relate to the response and behavioural adaptation to stress is poorly understood. One prominent theory has suggested that cortical [beta]-adrenoceptor down-regulation underlies resistance to stress. This theory is based on studies of the effects of noxious stimuli such as immobilization. Whether this relationship holds for non-noxious stimuli such as novelty as well, or whether different types of stimuli have different neurochemical effects has been little considered. This project addresses this important question and has compared noxious and non-noxious stress. Both the short- (0-3 h) and long-term (7 days) effects of swim stress and novelty on indices of central noradrenergic and serotonergic function were evaluated, and behaviours induced by these forms of stress measured. Parallels between stress-induced neurochemical and behavioural changes were further evaluated by investigating the effects of treatments known to alter stress-induced behavioural responses. To achieve this, the effects of repeated stress (once-daily saline injection) or administration of a monoamine reuptake inhibitor (sibutramine) on the neurochemical effects of novelty or swim stress were examined. Neither short-term effects of novelty or swim stress, nor long-term effects of swim stress involved changes in indices of noradrenergic function (e.g. cortical noradrenaline levels, [beta]-adrenoceptor binding), regardless of animals' pretreatment. However, a positive correlation between [beta]-adrenoceptor density and behavioural indices of resistance to novelty was seen, as has been previously described; this was the opposite to the correlation reported in the literature for noxious stressors. The data also suggested differences in estimates of [beta]-adrenoceptor density in mouse cortex when different radioligands ([3H]-CGP 12177, [3H]-dihydroalprenolol) were used. However, an investigation of the displacement of [3H]-dihydroalprenolol by 5-HT receptor ligands indicated that this was not due to binding of this radioligand to 5-HT1B 5-HT1C or 5-HT2 receptors in mouse cortex; binding of [3H]-DHA to 5-HT1A receptors could not be ruled out. Cortical 5-HT2 receptor binding was unchanged immediately after a 6 min swim. However, long-term effects of the swim included increases in both 5-HT2 receptor density and 5-HT synthesis. These changes, which were attenuated by repeated stress pretreatment (once-daily saline injection), were still evident in sibutramine-pretreated animals. In contrast to the different effects of these pretreatments on neurochemical effects of the swim, both repeated stress and sibutramine had similar effects on certain behavioural changes induced by swim stress (immobility) and novelty (locomotor activity). It is concluded that (i) the nature of the correlation between [beta]-adrenoceptor density and resistance to stress depends on the form of stress studied (ii) differences between the binding of [3H]-dihydroalprenolol and [3H]-CGP 12177 might be due to binding of the former radioligand to 5-HT1A receptors in mouse cortex (iii) a single exposure to swim stress has long-lasting effects on central 5-HT2 receptors (iv) repeated saline injection can alter both neurochemical and behavioural responses to acute stress These data have evident implications for studies of the long-term effects of stress, for instance post-traumatic stress disorder. Furthermore, although vehicle injection is used as a control for studies of the effects of injected drugs, the marked effects of this procedure suggest that vehicle injection alone is an inadequate control for such studies.

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