The earliest studies that sought to examine the ability of nicotine to enhance cognitive performance were performed in rodents, and many of these experiments were predicated on the known alerting or nootropic effect of certain CNS stimulant drugs. We entered this area in 19881 and chose to study the potential cognitive-enhancing actions of nicotine in nonhuman primates with the premise that nicotine's actions involved more complex mechanisms than a nonspecific sharpening of attention or arousal. Interest was based largely on two findings. In studying the effects of nicotine in humans 2 years earlier, Wesnes and Warburton2 concluded that nicotine facilitates state-dependent learning and does not affect associative processes. Secondly, the strong relationship between the ability of the centrally acting nicotinic receptor antagonist mecamylamine to impair performance of the retention trial of an inhibitory avoidance task in rats, and its ability to inhibit the biosynthesis of acetylcholine in cortical and limbic structures was impressive.3 These findings, along with earlier and concurrent work showing that nicotine enhances the release of brain acetylcholine motivated continuing study of the effect of nicotine on a complex memory task in monkeys. In the first study, five young adult macaques were well trained in the performance of a computer-assisted delayed matching-to-sample (DMTS) task.1 The subjects were tested individually in a sound-attenuated chamber (subsequent to this initial study, subjects were, as they are now, routinely tested within their home cages). It was during this study that each animal was normalized for his performance in the task so that delay intervals were adjusted on an individual basis to provide for a standard level of performance efficiency (forgetting curve). A near-zero-second delay also was imposed to ascertain task motivation and any nonmnemonic effect of drug administration. This normalization approach is currently recommended for most delayed response tasks.4 This first study also demonstrated that mecamylamine was indeed amnestic in the primate subjects, and that pretreatment with low doses of mecamylamine (that did not affect task performance) completely blocked the task-enhancing effect of nicotine. A curious finding was that the lowest dose of mecamy-lamine (0.25 mg/kg) seemed to enhance task performance efficiency slightly. This unexpected effect of mecamylamine is discussed in more detail later.
The first study with nicotine also provided additional aspects of the drug's pharmacology not previously known. For example, the doses of nicotine used to enhance memory in our subjects were very low, ranging from 1 to 20 |g/kg, i.m. This range appeared to be much lower than those used in rodent studies for memory enhancement. Although plasma levels of nicotine were not measured, it is unlikely that they would have exceeded 100 nM. However, this concentration represents the threshold range used to achieve significant neurotransmitter release (e.g., Wilkie et al. and Reuben and Clarke56). This apparent discrepancy in the potency of nicotine for the two processes does not necessarily rule out a role for evoked transmitter release in nicotine's positive mnemonic actions. For example, it is possible that small, but important levels of transmitter release might occur below the sensitivity of most biochemical measures. In support of this possibility, Wesnes and colleagues78 reported that the muscarinic antagonist scopolamine blocked the effect of nicotine on information processing. They initially interpreted this finding to indicate that the effect of nicotine on encoding was pharmacologically nonspecific. This finding has essentially been replicated in monkeys,9 and the preferred interpretation of the blocking effect of scopolamine is that it indicates nicotine does indeed enhance the release of acetylcholine, which in turn activates muscarinic receptors as a component of nicotine's beneficial effects on cognition. Part of this enthusiasm for the concept also is derived from similar experiments in rodents, along with Levin and colleagues' interesting findings of synergism in the amnestic actions of combined central nicotinic and muscarinic receptor blockade.10 Moreover, some years ago, it was noted that the hypertensive response to central injection of nicotine was blocked by pre-treatment with central injection of atropine. The cardiovascular response to central injection of nicotine also was blocked by prior depletion of brain acetylcholine with hemicholinium-3, again suggesting that nicotine's central cardiovascular response was mediated through release of endogenous acetylcholine.11 Thus, there appears to be a common mechanistic feature mediating these two rather disparate (memory and blood pressure) pharmacological actions of nicotine. It is interesting to note that the reverse experiment was not successful; that is, nicotine failed to reverse scopolamine-induced impairment of a visual recognition memory task in monkeys.12
Again returning to the initial study with nicotine in monkeys, one other feature of nicotine's actions is exemplified in those experiments. This is the very narrow range of potential therapeutic action of nicotine. Generally, responsiveness is relegated to one or two doses in a series of less than two log units. This is not a feature specific to nicotine; indeed, it is the case for most drugs in various pharmacological classes that have been demonstrated to improve cognitive performance in behavioral tasks. The highly individualized response to memory-enhancing drugs led Bartus13 to suggest that the effectiveness of a drug could mainly be determined by performing a dose-response series, and then selecting the individualized optimum dose or "best dose." Bartus used this approach to help identify nonresponders and it has also been used as a means of comparison of drug effectiveness.14 However, the question remains as to the mechanism(s) contributing to the inverted-U-dose-response relationship. For nicotine, it has been suggested that this effect is related to nicotine's ability to produce a desensitization type of receptor blockade at higher doses. Alternatively, higher doses of nicotine may be associated with side effects that could interfere with task motivation. The observation that drugs from other pharmacological classes exhibit a similar dose-response relationship profile1518 speaks against the depolarization hypothesis, although it cannot be completely ruled out (e.g., blockade of nicotinic receptors does result in an amnestic response). However, in the initial study with mecamylamine,1 the quaternary nicotinic antagonist hexame-thonium was used to control the potential peripheral actions (mainly ganglionic blockade) of mecamylamine on subjects performing the DMTS task. When monkeys were pretreated with hexamethonium, the nicotine-induced improvement in average DMTS efficiency was enhanced across all delays (although the effect was not statistically significant). Thus, it may be possible to widen the therapeutic window of certain agents like nicotine by preventing peripheral side effects with low levels of peripheral nicotinic receptor blockade.
Although a significant body of evidence in rodents largely supported these findings in monkeys, there was very little similar work in nonhuman primates from other labs with which to compare the early results. Rupniak and coworkers12 examined a wide range of doses of nicotine in young rhesus monkeys trained to perform a visual recognition memory task. In their study the lowest dose of nicotine tested (1 |g/kg) improved the group's task performance by about 16% of baseline levels. The authors admit, however, that the effect would have been more dramatic had they considered each subject's most effective dose. Hironaka and colleagues19 reported that nicotine improved the performance efficiency of four young adult rhesus monkeys trained to perform a version of the DMTS task. In their case, the reward consisted of a sweetened drink (banana-flavored reinforcement pellets can be used). There were other differences between the two paradigms: in the Hironaka report the subjects were not as well trained (30 to 63 sessions), and the animals performed 4 fixed-retention intervals of up to only 8 seconds in duration. Also, these animals performed the task in special test chambers (although it was not clear whether the subjects were restrained in a chair) and nicotine was administered by the subcutaneous route. Although this group reported that nicotine did enhance task performance in their subjects, there were some differences with respect to those described for the experiments above: for example, the Hironaka group observed significant task improvement with a rather high dose of nicotine (500 |g/kg). In contrast, in the experiments described earlier, the descending limb of the dose-response relationship occurred with doses as low as 20 |g/kg. Part of this discrepancy could be due to the differences in the respective routes of administration. The majority of task improvement observed by the Hironaka group was relegated to trials associated with short delay interval; these authors concluded that nicotine's actions might not be specific to memory function, but instead the drug might improve attention or ease of response. This possibility was supported by a later study in rhesus monkeys in which levels of arousal and orientation to peripheral targets were measured.20 Low doses of nicotine (3 to 12 |g/kg) reduced mean reaction times to onset of the target. The other studies with nicotine in a primate behavioral model of attention, on the other hand, support the ability of nicotine to enhance attention (see below); however, it is more than likely that effects attributed to low doses of nicotine also have relevance to other aspects of memory such as consolidation and recall. Perhaps the lower level of DMTS training by the subjects in the Hironaka study allowed nicotine to enhance attention selectively to the task, or perhaps to enhance aspects of reference memory over working memory.
Hudzik and Wenger21 examined the effect of nicotine on squirrel monkeys trained to perform a titrating (incrementing or decrementing retention intervals depending upon the previous trial's outcome) DMTS task. The dose range they used was rather high (10 to 1000 |g/kg), and they observed no statistically significant effect of the drug on titrating DMTS performance. However, on average, the group did exhibit improvement in terms of achieving longer durations of maximal and average retention intervals for sessions following administration of the lowest dose of nicotine, although, again, marked individual variability precluded statistical significance.
More recently, Schneider and his colleagues22 studied the effects of SIB-1508Y in a model of chronic low-dose MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine) in 4 cynomolgus macaques. The model was designed to permit Parkinsonian-like cognitive deficits to emerge, without confounding effects on motor function. SIB-1508Y, a new centrally acting nicotinic receptor agonist, had been characterized as a drug with striatal dopamine and hippocampal acetylcholine release properties. This combination of neuronal targets could prove useful for treating both motor and cognitive symptoms associated with Parkinson's disease. In the study, the authors used a small test battery (which included a version of DMTS task) to better ascertain the drug's potential actions on cognitive function. The chronic MPTP regimen resulted in a shift from mnemonic to nonmnemonic (delay-independent responding) strategies in the delayed response tasks. Treatment with SIB-1508Y (0.5 to 2.5 mg/kg, i.m.) significantly improved task performance and tended to resolve the MPTP-induced change in mnemonic strategy. In this case, performance for trials associated with Short delay intervals was improved to levels above those for longer delay intervals, in effect reconstituting a delay-dependent (mnemonic) approach to the task. A similar ability of nicotine to improve shorter delay interval-associated performance in aged subjects, who tend to have flatter delay-performance curves than younger subjects, (see below) has been noted. Curiously, in the Schneider study, nicotine administration (100 to 500 |g/kg) to two subjects failed to improve delayed response performance significantly. Again, this dose-range is considerably higher than that found to be effective in either young monkeys or in age-impaired subjects (see below).
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