The Protracted Mnemonic Response To Nicotine

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As more experience working with nicotine in primates developed, it was noted that, when animals were tested on the day following nicotine pretreatment (in the absence of further drug or vehicle treatment), significant enhancement of performance efficiency continued to be maintained.23 Performance levels returned to prenicotine levels on the following day (i.e., within 36 hours after injection). This protracted feature of nicotine's beneficial mnemonic actions was unexpected, particularly in view of the short plasma half-life of the drug in rhesus monkeys.24 Levin and colleagues10 reported similar findings in rats. In fact, they demonstrated that this protracted effect of nicotine was not dependent upon the presence of the drug at the time of behavioral training. The improvement in task efficiency measured on the day after nicotine administration generally occurred for trials associated with long delay intervals, as they had for the previous day's session. This pattern (of retention interval receiving the greatest improvement on the day of testing being the same retention interval receiving the greatest improvement upon testing 24 hours later) generally was maintained for other compounds evaluated under similar conditions. Table 8.1 presents the increase in DMTS task performance efficiency by macaques obtained from the best dose for eight nicotinic compounds of differing chemical structure and nicotinic receptor selectivity. Each of these compounds was administered by the intramuscular route, and DMTS testing was initiated within 30 min after drug injection. The animals were also tested without drug or vehicle treatment on the following day, approximately 24 h after drug administration. Each of these compounds was first administered as an increasing dose-response regimen, and each compound produced an inverted-U-type relationship between effect and dose. The exception was for a study with isoarecolone in which the highest dose tested represented the maximal response for the dose-response.25 Therefore, with the possible exception of isoarecolone, the individualized best dose determined for each animal represents the theoretical maximal potential level of improvement in task performance efficiency for each compound.

On the day of administration, the degree of task improvement ranged from about 9 to 19% of the sessions' 96 trials answered correctly, with SIB-1553A, ABT-418, and nicotine representing the compounds with the greatest level of apparent effectiveness (Table 8.1). ABT-089 and isoarecolone represented an intermediate level of improvement and the two GTS-21 analogs represented the lowest degree of effectiveness. The nicotinic receptor antagonist mecamylamine provided a level of mnemonic effectiveness equivalent to that of nicotine. The mechanism for the positive cognitive actions of low doses of mecamylamine is not completely understood26 (see below), but since the drug is classified as nicotinic it did enhance task performance,

TABLE 8.1

Rank Order of Eight Nicotinic Drugs in Their Ability to Improve DMTS Performance Efficiency by Macaques

Rank Order

TABLE 8.1

Rank Order of Eight Nicotinic Drugs in Their Ability to Improve DMTS Performance Efficiency by Macaques

Rank Order

Rank Order

Change in %

Delay Interval

Protracted

Change in %

Initial Effect

Trials Correct

(Initial Effect)

Effect

Trials Correct

SIB-1553A

18.5

Short

GTS-21

15.2

ABT-418

17.3

Long

4OH-GTS-21

11.6

Nicotine

15.1

Long

Nicotine

10.9

Mecamylamine8

14.2

Long

Mecamylamine

10.9

ABT-089

12.7

Long

ABT-089

7.1

Isoarecolone

11.0

Averageb

Isoarecolone

4.4 (n.s.)

4OH-GTS-21

9.3

Averageb

ABT-418

3.7 (n.s.)

GTS-21

9.1

Long

SIB-1553A

3.1 (n.s.)

The data represent average increases in DMTS performance efficiency derived from estimation of best dose. The best doses for each subject (N = 5-6) were obtained from dose-response data.

The data represent average increases in DMTS performance efficiency derived from estimation of best dose. The best doses for each subject (N = 5-6) were obtained from dose-response data.

a Mecamylamine, a nicotinic receptor antagonist, also exhibits positive mnemonic actions at low doses (see text).

b Task performance improvement was not specific to a particular delay interval; the average for the effect across all four delay intervals is presented. (n.s.) not significant and was included for purposes of comparison. Table 8.1 also lists the rank order of the same 8 compounds in their ability to improve DMTS task performance efficiency 24 h after drug administration (also see Figures 8.1 and 8.3). Individual data were derived from those presented in the table for the initial effect, i.e., the data from the sessions run 24 h after drug administration were compared to vehicle levels of task performance in the same manner as were the initial (same-day) sessions. Although nicotine, mecamylamine, ABT-089, and isoarecolone maintained the same relative order in terms of mnemonic effectiveness as they had for their initial effects, SIB-1553A and ABT-418, essentially exchanged places in the ranking order with the two analogs of GTS-21. In fact, SIB-1553A and ABT-418, which were the most effective compounds in the initial sessions, evoked no significant level of task improvement during the 24-h sessions. Perhaps even more surprisingly, for GTS-21 analogs, the degree of task improvement measured during 24-h sessions was, on average, greater than that for the initial sessions.

The mechanism underlying the protracted positive mnemonic actions produced by nicotine has not been determined; however, certain points may be relevant. For example, compounds listed in Table 8.1 exhibit rather short plasma half-lives, and it is unlikely that significant compound remains in the brain or circulation 24 h after administration. These drugs also do not give rise to more active or long-lived metabolites. In fact, the active metabolite of GTS-21, 4OH-GTS-21,27 produced responses almost indistinguishable from those produced by the parent compound. Another observation that may seem heretical is that the agonist properties of these compounds may not be required for eliciting a positive mnemonic response. The antagonist mecamylamine produced a profile of enhanced task performance efficiency virtually identical to that for nicotine; mecamylamine is only ten-fold less potent than nicotine in this regard.26 Moreover, the anabaseine analog GTS-21, which appears to offer some selectivity for the a7 subtype,28 has been characterized as a weak (12% of the nicotine effect) partial agonist in a functional assay using expressed human a7 receptors.29 In fact, GTS-21 exhibited no functional agonism (ion flux) in cell systems expressing predominantly a402 and ganglionic (a3) nicotinic receptors despite very good in vitro binding potency (e.g., Ki = 20 nM for a402 receptors).29 However, GTS-21 blocked the ion flux response to nicotine with an IC50 of 2.5 ||M. Memory and cognition are not the only physiological substrates for mecamy-lamine's actions, however. Low concentrations (10 to 100 nM) of the antagonist also produce the nicotine-like action of enhancing the expression of cell surface NGF receptors on differentiated PC-12 cells.3031 This response was not mimicked by the a402-preferring dihydro-0-erythroidine (DHBE) (unpublished data). This antagonist differs in two important ways from mecamylamine: it is not lipid soluble and it is a competitive antagonist for the agonist recognition site. Mecamylamine is a lipid-soluble, noncompetitive, nicotinc channel blocking agent.

Which, if any, of these properties contributes to either the initial or the protracted phases of nicotinic-mediated positive cognitive effects in animals and humans is unknown. In terms of the protracted effect, one additional lead may be derived from Table 8.1. Since the analogs of GTS-21 are a7-preferring agents, and since both ABT-418 and SIB-1553A are compounds that prefer subtypes other than a7, it may be reasonable to implicate the a7 subtype in mediating the expression of the protracted mnemonic action produced by nicotinic drugs. Isoarecolone also evoked no significant protracted improvement in task performance. Although the subtype binding characteristics of isoarecolone have not been ascertained, the compound exhibits several characteristics in behavioral assays that are unlike nicotine's. For example, the drug does not substitute for nicotine in the nicotine discrimination task in rats.25 As such, it appears that chemical synthetic approaches to dissociate nicotine from its toxicity (cardiovascular, gastrointestinal, addictive, etc.) by creating more subtype selective agents also may have limited the ability of these newer drugs to evoke the protracted positive mnemonic response. However, it is not yet clear whether this ability is a necessary property for a useful memory-enhancing agent.

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