Performance Deficits By Nicotinic Drugs

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Attention deficit hyperactivity disorder (ADHD) is among the most prevalent of childhood and adolescent disorders, accounting for up to 50% of clinic visits in these populations. The predominant characteristics of ADHD, inattention and dis-tractibility, are also among the symptoms associated with prenatal and early postnatal exposure to a variety of toxicants, as well as with a wide variety of neurologic and psychiatric disorders including AD, Parkinson's disease, Huntington's disease, Tourettes syndrome, and schizophrenia. The primary therapeutic agents utilized for ADHD and other disorders where distractibility and inattention are prominent features include methylphenidate, dextroamphetamine, mixed amphetamine isomers, and pemoline. While the efficacy of these agents has been demonstrated, they are also associated with a wide variety of adverse effects including insomnia, decreased

appetite and weight loss, irritability, elevated heart rate and blood pressure, etc.49 Furthermore, the most common pharmacologic agent used, methylphenidate, appears to lack efficacy in neurodegenerative conditions such as AD.50 A number of secondary treatments are available (e.g., antidepressants, clonidine, etc.); however, it is clear that a need for alternative therapeutic agents exists.

Nicotine has been shown in a number of studies to enhance arousal, visual attention, and perception and may ameliorate the deficits in vigilance and memory task performance induced by fatigue.5152 The drug also improves reaction time and shortens information processing time.53 Accordingly, it has been evaluated as a potential therapy for ADHD as well as for a variety of other cognitive disorders. Due to the social stigma associated with nicotine as well as its untoward physiological effects (e.g., elevated blood pressure and heart rate, gastrointestinal side effects, etc.) and undesirable pharmacokinetic profile, a search for structurally related compounds which do not exhibit these limitations has been underway for several years. Both nicotine and an isoxazole isostere of nicotine, ABT-418, have shown efficacy in small clinical trials in human adult ADHD patients.5455

For the purposes of novel drug development in this area, a new version of the DMTS task in monkeys was recently introduced which incorporates a task relevant distractor (DMTS-D task) that appears on a limited number of trials in order to evaluate test compounds for their ability to ameliorate distractibility.56 The task is conducted in a similar fashion to standard DMTS except that on 18 of the 96 trials a distractor stimulus consisting of a random array of flashing colored lights appears on the test panels and lasts for 3 seconds. Distractor lights are generated by the same 3 colored diodes as those used for sample and choice stimuli. The 3-second duration of the distractor was chosen based on observation that distractors of lesser duration were not effective in disrupting DMTS performance. The remaining trials are presented as standard DMTS trials distributed across all delay intervals. To reduce the extent to which habituation to the distractors may develop during repeated testing, DMTS-D sessions are conducted a maximum of 3 times per 2-week interval, with a minimum of 3 days of standard DMTS testing conducted in between. Furthermore, saline is administered in a random fashion (i.e., on days before and after test compound doses) to minimize any potential artifact of the order of drug administration.

The distractors most notably reduce performance associated with short delay intervals in young monkeys, an effect which is sensitive to methylphenidate associated improvement.56 The nicotinic agonists, nicotine, ABT-418, ABT-089,57 and SIB 1553A, an arylalkyl pyrrolidine58 have also been evaluated, with positive results. A comparison of the effects of these compounds in young-adult macaques performing the DMTS-D appears in Figure 8.2. Each of the compounds improved performance of the DMTS-D at one or more of the doses evaluated and, in fact, at least two of the compounds (i.e., ABT-089 and SIB 1553A) had a superior dose-effect profile when compared to methylphenidate (i.e., more doses were effective). SIB 1553A appeared to be a particularly effective agent as indicated by the fact that several (quite low) doses were effective. None of the nicotinic agents were associated with untoward effects at the doses tested.

FIGURE 8.2 Dose-effect relationship for several nicotinic receptor agonists compared to methylphenidate. Short-delay distractor trial performances (i.e., mean percentage correct + SEM) during interference sessions by young adult monkeys, 10 min following IM administration of test compound are presented. * Indicates a significant (p<0.05, repeated measures ANOVA) difference between the test compound and the saline-associated performance. Medium- and long-delay trials were not significantly affected by the distractor or the compounds illustrated. BL = saline baseline for standard DMTS performance; SAL = saline baseline performance associated with 3-sec distractor trials. N = 8 for each test compound, with the exception of SIB-1553A, N = 5.

FIGURE 8.2 Dose-effect relationship for several nicotinic receptor agonists compared to methylphenidate. Short-delay distractor trial performances (i.e., mean percentage correct + SEM) during interference sessions by young adult monkeys, 10 min following IM administration of test compound are presented. * Indicates a significant (p<0.05, repeated measures ANOVA) difference between the test compound and the saline-associated performance. Medium- and long-delay trials were not significantly affected by the distractor or the compounds illustrated. BL = saline baseline for standard DMTS performance; SAL = saline baseline performance associated with 3-sec distractor trials. N = 8 for each test compound, with the exception of SIB-1553A, N = 5.

8.5 EFFECT OF NICOTINE IN YOUNG AND AGED MONKEYS

One particularly notable and reproducible finding encountered over the years is improvement in DMTS task performance by both young adult and aged monkeys administered nicotine, as well as a variety of drugs with nicotinic properties. Enhanced DMTS performance in older monkeys is certainly relevant for the therapeutics of neurodegenerative conditions such as AD, Parkinson's disease, dementia with Lewy bodies and other age-related conditions in which subtypes of nicotinic receptors may be deficient. Aged monkeys (particularly aged rhesus) have been characterized as one of the most useful animal models for the CNS and behavioral abnormalities that occur in aged humans and AD patients. This assertion is based on observations that they begin to encounter learning and memory deficits during the second decade of life, with more substantial deficits apparent by the mid- to late 20s. With age, nonhuman primates have been shown to develop abnormal neurites, amyloid deposition, altered levels of neurotransmitters, and reductions in synaptic densities and pyramidal neurons with age. They also express the apoenzyme E isoform that is analogous to the human apoE4 isoform implicated as a risk factor in AD.59 60 Furthermore, improvements in DMTS performance by nicotine may be especially relevant since this working memory task engages many of the same neuronal substrates in monkeys as in humans (e.g., prefrontal cortex, hippocampus, etc.). A modified version of the DMTS paradigm has been used to study cognitive ability and impairment in AD patients, and delay dependent deficits in DMTS performance have been documented in both aged humans and those with AD.6162

Evaluation and comparison of nicotine and other nicotinic receptor agonists in both young adult and aged monkeys trained to perform the DMTS task has shown several age-related differences in response profile. For example, the improvement in task efficiency elicited by nicotinic drugs (particularly nicotine and ABT-418) appears to be more delay-specific in younger animals as compared with aged animals. As indicated in Figure 8.3, in young animals both compounds enhanced accuracy of DMTS performance, most notably for trials associated with the longest delays, whereas in older animals, enhanced performance appeared across several delays. The lack of a delay-specific response to nicotinic drugs in aged subjects may reflect the (generally) shorter durations required for each retention interval in aged animals, thus compressing the delay intervals relative to those used in young monkeys. Alternatively, aged monkeys are more prone to become distracted than are younger subjects, and it is more difficult to reverse the distractor-induced performance deficit with drug therapy in these animals relative to their younger cohorts.56 It is possible that the longer delay intervals offer more opportunity for distraction than do short delay intervals, thereby having a more profound role in the process of forgetting. If this were the case, nicotine would be less effective in reversing distraction-mediated reductions in task accuracy that might occur in aged subjects.

As discussed earlier, an important component of the ability of nicotine to improve DMTS performance efficiency is its protracted effect on task performance. This nicotinic property was evident in both younger and older subjects performing the task. As indicated in Figure 8.3 (and in the previous discussion), ABT-418 did not exhibit this property even after stimulating quite robust improvements on the day of administration.

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