Effect of α5IA-II per se evaluated by omitting the unconditioned stimulus

Figure 5.1.b and figure 5.2.a both show that 1 mg/kg α5IA-II treated animals during the tone-shock period at the conditioning day have an elevated movement level compared to the vehicle, whereas the movement level of the 10 mg/kg α5IA-II treated animals were lower than vehicle treated animals. The elevated movement level of the 1 mg/kg α 5IA-II animals was significant. Thus, it was speculated if the acute drug effect seen on the conditioning day during the tone-shock period could affect the test day results independent of the shock effect. Consequently an experiment with an experimental protocol identical to the traditional fear conditioning was performed, but with omission of the foot-shock on training day. The graphs in figure 5.8 summarises the effects of

5.1.11.2.Behaviour of α5IA-II rats on test day without previous unconditioned stimulus In figure 5.8.a no noticeable alteration is seen in the movement level in any of the

groups during or after the tone compared to the period before the tone (see appendix 5.9). The different α5IA-II groups might have a slightly increased movement level compared to the vehicle group before the tone.

This was not confirmed in the statistical analysis, since neither the ‘treatment’

nor the ‘treatment’-‘time’ interaction was significant (table 5.17). Thus, it is concluded that the behaviour of the α5IA-II groups did not differ from the vehicle group on test day.

5.1.11.3.Behaviour of α5IA-II rats on re-test day without previous unconditioned stimulus

No noticeable alteration was seen in the movement level of either the vehicle group or the α5IA-II groups in the period after the tone compared to the behaviour before the tone (figure 5.8.b). During the tone a minor tendencies of freezing may be seen for both of the groups.

Since no significance regarding the ‘treatment’-related terms was seen on test day it is not expected that the terms in question are significant on re-test day and as seen in table 5.18 this proved to be the case.

It is summarised that the acute drug effects observed at the conditioning day were not present on test day or re-test day. It is thus concluded that differences in movement level on test or re-test day caused by α5IA-II are dependent of the conditioned stimuli given on conditioning day and associated to learning processes.

Table 5.17. The p-values from the analysis of α5IA-II treated rats on test day in traditional fear conditioning experiment with no previous conditioned stimuli.

p-value

Table 5.18. The p-values from the analysis of α5IA-II treated rats on re-test day in traditional fear conditioning experiment with no previous conditioned stimuli.

p-value

5.2. Pre-pulse inhibition

In this section the effects of NS.A, α5IA-II and alprazolam on impaired pre-pulse inhibition will be discussed. The results are presented in the same manner as for the experiments with fear conditioning, with both observational trends in the graphs described followed by statistical analysis and final interpretation. As mentioned in section ‘4.2.5. Interpretational aspects of pre-pulse inhibition experiment‘ the term of interest is the ‘pre-treatment’-‘pre-pulse’ interaction and the significance level will be reported for each experiment. ‘Treatment’ is not of primary interest and the p-value is only reported if any departure from the expected is seen. In the present studies, impairment in pre-pulse inhibition was defined as reduction in startle response of the rats when there prior to the startle eliciting acoustic pulse has been presented a pre-pulse at either 4, 8, 16 or 24 dB above background noise.

Initially a study of pre-pulse inhibition impairment properties of PCP was executed, where PCP was administered to the rats at different doses and with different treatment times. This was done in order to determine the optimal dose and pre-treatment time for PCP induced pre-pulse inhibition impairment. Hereafter the effects of NS.A, α5IA-II and alprazolam on PCP induced impaired pre-pulse inhibition and the effects of the GABAA receptor modulators per se were tested in pre-pulse inhibition experiments. The effects of NS.A were also tested in amphetamine induced impaired pre-pulse inhibition.

In order to analyse the data a model was developed as described in section ’4.2 Analysis of pre-pulse inhibition experiments’. For all experiments with administration of ‘pre-treatment’ and ‘treatment’ the three way interaction

‘pre-treatment’-‘treatment’-‘pre-pulse’ was significant and the groups administeded different ‘treatment’ doses was found to have a different progression in regard to the pre-pulse size. Separate models were made for the two groups to facilitate the interpretation. Interaction plots (see section ‘4.2.5. Interpretational aspects of pre-pulse inhibition experiment’) derived from the full statistical model are shown for each NS.A, α5IA-II and alprazolam experiments.

These are presented in order to elucidate the compounds’ effects on pre-pulse inhibition per se, on impaired pre-pulse inhibition, the influence of the different pre-pulse levels and the interaction between these factors.

Additionally a study of pre-pulse inhibition impairment properties of methylphenidate was performed in mice and rats, respectively. The results obtained from this study are presented in appendix 5.10.