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Title: The effects of intra-dorsal raphe administration of strychnine on rat behaviour and its interactions with ethanol
Author: Greig, Scott James
Awarding Body: University of Dundee
Current Institution: University of Dundee
Date of Award: 2013
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Abstract:
Previous studies have identified a population of inhibitory strychnine-sensitive glycine receptors, which are expressed on the serotonergic neurons which originate from the dorsal raphe nucleus. In addition, the serotonergic neurons of the dorsal raphe nucleus, which mediate the release of the neurotransmitter serotonin, have been implicated as a component of the neurocircuitry which underpins the generation of an anxious state. Therefore, the receptor antagonist strychnine was administered into the dorsal raphe nucleus of Sprague-Dawley rats and behaviour was investigated in the open field, elevated plus-maze and locomotor activity box. The intracerebral microinjection of strychnine into the dorsal raphe nucleus had no effect on anxiety-like behaviours or locomotor activity in animals exposed to the open field. The elevated plus-maze methodology was validated, prior to the investigation of the strychnine-sensitive glycine receptors, by replicating the previously reported anxiolytic effects in response to the systemic administration of chlordiazepoxide. Animals were divided into two groups and either remained in the home cage or were repeatedly exposed (1 hr/daily) to an elevated open platform stressor over 10 days prior to testing in the elevated plus-maze. In the elevated plus-maze, the administration of strychnine into the dorsal raphe nucleus selectively reversed the increase in the percentage of the total time spent exploring the open runways of animals pre-exposed to the elevated open platform stressor. However, there was no effect of strychnine on the anxiety-like behaviours of animals which remained in the home cage prior to testing in the elevated plus-maze. In addition, the administration of strychnine into the dorsal raphe nucleus did not significantly influence the locomotor activity in either group. However, the administration of the endogenous agonist glycine into the dorsal raphe nucleus did not appear to elicit an anxiolytic-like effect. Therefore, the data suggest that the strychnine-sensitive glycine receptors of the dorsal raphe nucleus may play a role in the habituation to an inescapable stressor. Furthermore, previous studies have identified that the strychnine-sensitive glycine receptors expressed in the dorsal raphe nucleus are potentiated by low, physiologically relevant, concentrations of ethanol. Therefore, it was hypothesised that a component of the anxiolytic properties of ethanol may be mediated by the strychnine-sensitive glycine receptors of the dorsal raphe nucleus. However in response to the systemic administration of ethanol, the anxiolytic properties of ethanol in the elevated plus-maze appeared to be masked by the sedative component of the drug. Therefore, an alternative route of administering ethanol was investigated. The intracerebroventricular administration of ethanol appeared to elicit an anxiolytic-like effect, as measured by the elevated plus-maze, in the absence of an overt change in locomotor activity. Therefore, the effect of concurrent intracerebral administration of strychnine into the dorsal raphe nucleus and ethanol into the lateral ventricle was investigated in the elevated plus-maze and a locomotor activity box. Contrary to the original hypothesis, the administration of strychnine into the dorsal raphe nucleus did not reverse a component of the anxiolytic effects of the intracerebroventricular administration of ethanol in the elevated plus-maze. However, contrary to the previous studies in the elevated plus-maze, the administration of strychnine into the dorsal raphe nucleus reduced the locomotor activity of the animals administered the artificial cerebrospinal fluid vehicle, but not ethanol, into the lateral ventricle. In addition, the administration of strychnine into the dorsal raphe nucleus reduced the duration of the trial time spent exploring the central zone of the locomotor activity box suggesting an anxiogenic-like effect. In addition, the administration of ethanol into the dorsal raphe nucleus was investigated in the elevated plus-maze. However, the administration of ethanol into the dorsal raphe nucleus did not significantly influence either the indices of anxiety-like behaviours or the locomotor activity in the elevated plus-maze. However, this may have been due to the diffusion of ethanol from the target site. Collectively, the results of the present study suggest that the administration of strychnine into the dorsal raphe nucleus mediates the suppression of locomotor activity and an anxiogenic-like effect. However, these effects appear to depend upon the basal anxiety state of the animal. At present, the data do not support the hypothesis of an interaction between the strychnine-sensitive glycine receptors of the dorsal raphe nucleus and the anxiolytic properties of ethanol. However, potentially confounding variables associated with the methodology may have masked measurable behavioural in response to the administration of ethanol. Therefore, the interpretation of the results must be considered in the context of these limitations.
Supervisor: Not available Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.600755  DOI: Not available
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