Effect of GABA A receptor modulators on PCP induced impairment of pre-

In this section the results showing the ability of NS.A, α5IA-II and alprazolam to alleviate acute PCP induced impairment in pre-pulse inhibition are presented.

5.2.2.1.Effect of NS.A on PCP impaired pre-pulse inhibition

When animals were given NS.A per se (0.3, 1, 3 mg/kg) pre-pulse inhibition impairment were induced at pre-pulse 4, 8 and 16 in a slightly dose dependent manner (see figure 5.11). For pre-pulse 24 no difference in pre-pulse inhibition was observed between the doses. NS.A did not affect the pre-pulse inhibition impairment of the PCP treated animals (2.5 mg/kg) for any of the pre-pulses.

These observations are supported by the statistical findings. The

‘pre-treatment’-’pre-pulse’ interaction was significant when NS.A was administered per se with a p-value less than 0.0001 and table 5.20 shows that NS.A per se significantly impair pre-pulse inhibition for pre-pre-pulse 4, 8 and 16. When NS.A was administered together with PCP none of the ‘pre-treatment’-related terms were significant and it is concluded that NS.A did not affect PCP impaired pre-pulse inhibition.

Figure 5.11. Pre-pulse inhibition. Prior to the experiment the rats have been pre-treated with either vehicle or NS.A (0.3, 1 or 3 mg/kg) and in addition treated with vehicle or PCP (2.5 mg/kg) (a) The percentage inhibition compared to naive startle response caused by the different pre-pulses 4, 8, 16 and 24 dB above background noise (b) The effect of the different pre-pulses on startle response.

Table 5.20. The p-values from the t-test comparison of the individual levels to a reference level for animals administered NS.A and vehicle in pre-pulse inhibition experiment.

p-value

Pre-treatment(0.3mg/kg):Pre-pulse(pp4) 0.0002

Pre-treatment(1mg/kg):Pre-pulse(pp4) 0.0013

Pre-treatment(3mg/kg):Pre-pulse(pp4) 0.0002

Pre-treatment(0.3mg/kg):Pre-pulse(pp8) <0.0001

Pre-treatment(1mg/kg):Pre-pulse(pp8) <0.0001

Pre-treatment(3mg/kg):Pre-pulse(pp8) <0.0001

Pre-treatment(0.3mg/kg):Pre-pulse(pp16) <0.0001

Pre-treatment(1mg/kg):Pre-pulse(pp16) 0.0001

Pre-treatment(3mg/kg):Pre-pulse(pp16) <0.0001

5.2.2.2.Effect of α5IA-II on PCP impaired pre-pulse inhibition

For animals administered α5IA-II per se (1, 3, 10 mg/kg) pre-pulse inhibition was not affected noticeably. A tendency of increased pre-pulse inhibition is seen for the 10 mg/kg dose mainly for all of the pre-pulses. In addition it should be noticed that unusual low startle response behaviour is seen for the animals administered 10 mg/kg (figure 5.12), and that this high dose in the fear conditioning experiments also caused a different behaviour compared to the other dose groups.

For the PCP treated animals the 10 mg/kg dose group is distinct from the other groups at pre-pulse 4 and 8. Unexpectedly, the remaining groups show an impaired pre-

Figure 5.12. Pre-pulse inhibition. Prior to the experiment the rats have been pre-treated with either vehicle or α5IA-II (1, 3 or 10 mg/kg) and in addition treated with vehicle or PCP (2.5 mg/kg) (a) The percentage inhibition compared to naive startle response caused by the different pre-pulses 4, 8, 16 and 24 dB above background noise (b) The effect of the different pre-pulses on startle response.

Table 5.21. The p-values from the t-test comparison of the individual levels to a reference level for animals administered α5IA-II and vehicle in pre-pulse inhibition experiment.

p-value

Pre-treatment(10mg/kg) 0.0469

Pre-treatment(10mg/kg):Pre-pulse(pp16) 0.0056

Pre-treatment(1mg/kg):Pre-pulse(pp24) 0.0305

Pre-treatment(10mg/kg):Pre-pulse(pp24) <0.0001

pulse inhibition compared to the pulse-alone meaning that the animals startle more when a small pre-pulse is present. For pre-pulse 24 no difference is seen in the pre-pulse inhibition between the groups.

The observed behaviour of the α5IA-II per se treated animals is verified statistically. ‘Pre-treatment’ and the ‘pre-treatment’-’pre-pulse’ interaction were significant with p-values 0.0046 and 0.0002, respectively, and from the results of the subsequent t-test listed in table 5.21, it is concluded that 10 mg/kg of α5IA-II increases pre-pulse inhibition at all pre-pulses. The significant difference between 1 mg/kg and the vehicle at pre-pulse 24 does not seem to be of biologically relevance when the graph is assessed. The obtained significance might be due to the small variance seen for these groups.

For the PCP treated animals no ‘pre-treatment’-related terms were significant and the described observations were thus not detected in the statistical analysis.

Figure 5.13. Pre-pulse inhibition. Prior to the experiment the rats have been pre-treated with either vehicle or alprazolam (0.4, 1.33 or 4 mg/kg) and in addition treated with vehicle or PCP (2.5 mg/kg) (a) The percentage inhibition compared to naive startle response caused by the different pre-pulses 4, 8, 16 and 24 dB above background noise (b) The effect of the different pre-pulses on startle response.

Table 5.22. The p-values from the t-test comparison of the individual levels to a reference level for animals administered alprazolam and vehicle in pre-pulse inhibition experiment.

p-value

Pre-treatment(4mg/kg):Pre-pulse(pp4) 0.0028

Pre-treatment(4mg/kg):Pre-pulse(pp8) 0.0121

Pre-treatment(0.4mg/kg):Pre-pulse(pp16) 0.0048

Pre-treatment(4mg/kg):Pre-pulse(pp16) <0.0001

Pre-treatment(0.4mg/kg):Pre-pulse(pp24) <0.0001

5.2.2.3.Effect of alprazolam on PCP impaired pre-pulse inhibition

The animals administered 4 mg/kg alprazolam per se induced impairment in pre-pulse inhibition for pulse 4, 8 and 16 and the startle response was even increased for pre-pulse 4 compared to pre-pulse-alone (see figure 5.13). The remaining doses were similar to the vehicle. Alprazolam did not influence the PCP induced impairment for any of the pre-pulses.

In the analysis of alprazolam administered per se the ‘pre-treatment’-‘pre-pulse’

interaction was significant with p < 0.0001. The p-values seen in table 5.22 support that alprazolam administered at 4 mg/kg impair pre-pulse inhibition when administered per se. Furthermore, the dose 0.4 mg/kg proved to be significant but this was not considered to be of biological importance.

When alprazolam was administered together with PCP no dose-related terms were significant which is consistent with the observed.