Wilksx, Lucy; (1991) Behavioural consequences in rodents of anticonvulsant drug administration: tolerance and withdrawal. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The experiments described in this thesis were designed to examine the effects of chronic drug treatment and drug withdrawal for three anticonvulsant drugs: lorazepam, sodium phenobarbital and phenytoin. The effects of chronic drug treatment on locomotor activity and head-dipping in the holeboard, seizure threshold, and aggressive behaviour were investigated. In addition, the extent to which tolerance and withdrawal developed following single doses of sodium phenobarbital, and the benzodiazepines lorazepam and oxazepam, was investigated and, in order to explore in more detail the pattern of behavioural effects of these drugs at various times after treatment, the effects of single doses across across time on a variety of behavioural measures were also explored. The results indicated that tolerance and withdrawal may develop to the effects of lorazepam and oxazepam in the holeboard after only a single dose. When the effects of single doses of these drugs across time were investigated, a number of changes in holeboard behaviours were observed several hours after drug treatment which were not observed at earlier time points. The changes across time observed in holeboard measures did not appear to follow the same pattern as the changes in seizure threshold or in vivo receptor binding. The extent to which tolerance and withdrawal developed to the effects of single doses of phenobarbital was not clear; however, enhancements in aggressive behaviour observed 8 to 12 hours after a single dose in rats differed in nature from those observed at the 1 and 6 hour time points and holeboard behaviours were enhanced 12 hours after phenobarbital and reduced at the 1 and 6 hour time points. These effects may represent single-dose withdrawal responses. The relationship between the development of tolerance and the appearance of withdrawal responses was examined for both acute and chronic drug effects. In both the acute and the chronic studies, the appearance of withdrawal responses did not appear to be associated with the development of tolerance. Although the results indicated that there were complex reasons for the poor relationship between tolerance and withdrawal they did not demonstrate a direct link between these two phenomena and may indicate that tolerance and withdrawal are separate phenomena.

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