M rill Ii

ABT- 418 Optimal Doses Young Monkeys

IS 10

Zero Delays 3 Short Delays Medium Delays Long Delays

10 min 24 Hr

N = g Aged Monkeys

FIGURE 8.3 Comparisons in accuracy for each delay interval of the DMTS task by young adult and aged monkeys 10 min and 24 h following the IM administration of nicotine and ABT-418. Data represented are the mean change in percentage correct + SEM. (96 trials/session) for performances associated with the individualized optimal doses of each compound. * = significantly different from saline associated baseline (P<0.05, repeated measures ANOVA).

the clinic. For example, male/female differences have been noted regarding nicotine withdrawal in smokers,67 smoking cessation,68 nicotine reinforcement,69 body weight loss,70 and the hemodynamic response to stress.71 In these examples, the differential responsiveness attributed to sex often was manifest as an altered sensitivity to nicotine by females — reflected in a differential dose-response relationship. During early studies of the effect of nicotine and its analogs in aged macaques, the first impression was of no sex difference in response to nicotine. However, in a recent head-to-head comparison of the effect of nicotine in aged male and female rhesus monkeys,72 the most pertinent finding was the marked difference between males and females in the profile of their responses to nicotine. Aged male monkeys showed improvement at lower doses of nicotine, and exhibited much less variance in the response compared with the females; this, despite the fact that response to the averaged (of all four delay intervals) best dose was similar for both sexes (Figure 8.4). It is not known whether these differences in response to nicotine are related to estrogen deprivation in the females, or whether they occur in younger animals. It is also not known whether the response to other potential AD drugs will exhibit these apparent sex-related differences. From an optimistic viewpoint, there is every reason to consider that, with proper dose titration, the nicotinic class of cognitive enhancing agents now under development will prove as useful in females as in males.

DOSE-RESPONSE

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