Differentiated Neurotransmitter Responses In The Brain

Although conclusive evidence has accumulated showing bidirectional communication between the immune system and the brain, the underlying neurochemical mechanisms have been hardly characterized. Until now, most studies have assessed concentrations of neurotransmitters and their metabolites in brain tissue samples as an index of turnover. Unfortunately, such studies provide only limited information on the extracellular (effective) concentrations of neurotransmitters and the time resolution of changes. Therefore, we have used an in vivo microdialysis technique in rats, which allows simultaneous assessment of various neurotransmitters and metabolites, as well as continuous monitoring of neurotransmitters over extended time periods (hours and days). In addition, we have developed a method to measure corticosterone levels in dialysates, providing an index of HPA axis activity. Because the extracellular space of the brain is devoid of corticosterone binding globulin, dialysate concentrations of corticosterone represent the free (biological active) fraction of this glucocorticoid. To elucidate the functional significance of inflammation-induced neurotransmission changes, in vivo microdialysis was combined with simultaneous measurement of body temperature and locomotor activity using a biotelemetry method. Moreover, behavioural activity (locomotion, rearing, grooming, eating, drinking, resting) was monitored by visual observation of the animals, and HPA axis activity was determined by the, already mentioned, measurement of corticosterone in dialysates (Figure 1).

Because peripheral inflammation induces, apart from immune, neuroendocrine,

In vivo microdlalyils combined with physiological and behavioural meaaursmants

In vivo microdlalyils combined with physiological and behavioural meaaursmants

Figure 1. Schcmatic overview of in vivo microdialysis combined with the measurement of other physiological and behavioural parameters. Microdialysates are collected for the determination of extracellular levels of 5-HT and NA, and their metabolites by a HPLC method, and free corticosterone by a radioimmunoassay (RIA). Body temperature, heart rate, and locomotion can be assessed by means of Hotel erne try (using an i.p. implanted transmitter and a receiver underneath the cage). Visual observation of the animals is used to determine the cffects of various treatments on specific aspects of behaviour.

Figure 1. Schcmatic overview of in vivo microdialysis combined with the measurement of other physiological and behavioural parameters. Microdialysates are collected for the determination of extracellular levels of 5-HT and NA, and their metabolites by a HPLC method, and free corticosterone by a radioimmunoassay (RIA). Body temperature, heart rate, and locomotion can be assessed by means of Hotel erne try (using an i.p. implanted transmitter and a receiver underneath the cage). Visual observation of the animals is used to determine the cffects of various treatments on specific aspects of behaviour.

and autonomic responses, also changes in behaviour (i.e., vigilance state and affect), we were interested in putative neurotransmitter alterations in higher limbic brain structures. Hence, experiments were focused on the hippocampus, which plays a key role in behavioural responses to stress. To be able to demonstrate regionally distinct patterns of neurotransmitter activation in the brain during inflammation, we compared responses in the hippocampus with those in the preoptic area, a brain structure known to be involved in autonomic (body temperature) and endocrine regulation. The results of our studies on the effects of i.p. administration of bacterial endotoxin on 5-HT and NA, two major neurotransmitter systems in both the hippocampus and the preoptic area, are described in the following sections and compared with data available from the literature. Moreover, the possible role of brain cytokines in these effects will be discussed,

3.1. Serotonin

3.1.1. Serotonin and the Hippocampus

3.1.1.1. Peripheral immune stimulation and hippocampal serotonergic neurotransmission, Stimulation of the immune system by i.p. administration of LPS (30-300 j.Lg/kg body weight) induced a dose-dependent increase in hippocampal extracellular levels of 5-HT (maximum between 200-250% of baseline) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA; maximum about 150% of baseline) (Linthorst, Flachskamm, Miiljer-Preuss. Holsboer, & Reul, 1995b; Linthorst, Flachskamm, Hols-boer, & Reul, 1996) (Figure 2A,B). The doses of LPS used in this and our subsequent studies (100|Ag/kg body weight) induced fever and a clear reduction in behavioural

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