Introduction

The importance of cholinergic activity in the brain to learning and memory function was first recognized more than 30 years ago, when relatively low doses of certain muscarinic acetylcholine-receptor antagonists (e.g., the belladonna alkaloids atropine and scopolamine) were found to induce transient cognitive deficits in young human volunteers that resembled those observed in elderly (unmedicated) subjects [1]. This work and a number of subsequent clinical studies indicated that antimuscarinics disrupt attention [2–4], the acquisition of new information, and the consolidation of memory [1,4,5]. Later studies found that scopolamine could alter certain features of the human electroencephalogram (e.g., delta, theta, alpha, and beta activity) in a fashion that mimics some of the changes observed in patients with Alzheimer’s disease (AD) (reviewed by Ebert and Kirch [6]).

In support of these cited pharmacological investigations, a considerable number of studies of the brains of elderly people and of AD patients have shown damage or abnormalities in forebrain cholinergic projections that are important to memory structures (e.g., cortex, hippocampus), and these results correlate well with the level of cognitive decline [7,8]. Interestingly, scopolamine appears to negatively affect cognitive performance to a greater extent in elderly subjects than in younger subjects [9–11], and it impairs subjects with AD more dramatically than nondemented elderly subjects [12]. Similarly, aged rodents display cognitive impairments in many learning and memory tasks [13], manifest cholinergic deficits [14–16], and are more sensitive to the disruptive effects of scopolamine than young rats [16]. Moreover, lesions in young animals that damage cholinergic input from the basal forebrain (e.g., nucleus basalis magnocellularis, medial septum/diagonal band) to the neocortex or hippocampus disrupt performance of a variety of memory-related tasks. These findings, particularly the early studies cited, led to the development of the so-called cholinergic hypothesis, which essentially states that a loss of cholinergic function in the central nervous system (CNS) contributes significantly to the cognitive decline associated with advanced age and AD (reviewed by Bartus [17]). Using this hypothesis as a guiding principle, scopolamine (and to a lesser extent other antimuscarinic agents) has been used extensively as an amnestic drug in animals to model the cognitive dysfunction associated with human dementia and Alzheimer’s disease. While a few studies have been conducted using scopolamine as an amnestic agent in nonhuman primates (e.g., Aigner and Mishkin [18] and Terry et al. [19]), the majority of studies have been conducted in rodents, particularly rats. In addition, scopolamine-reversal experiments in rodents have been used extensively as an initial screening method to identify therapeutic candidates for cognitive disorders such as AD.

Memory-Related Task Impairment in Rats by Scopolamine and Other Antimuscarinic Agents

Table 2.1 provides an overview (with a few representative references) of the wide variety of memory-related tasks that have been shown to be impaired by the non-selective antimuscarinic agent, scopolamine. Such tests encompass a wide range of behavioral procedures from classical conditioning (Pavlovian) tasks (e.g., inhibitory avoidance and fear conditioning), to spatial learning tasks (e.g., water maze and radial arm maze), to methods that assess prepulse inhibition of the auditory gating response. Antimuscarinics have also been shown to disrupt performance of more-complex operant (working-memory related) procedures such as delayed matching and delayed nonmatching tasks, time estimation procedures, and most recently, models of executive function (e.g., attentional set shifting) in rats.

TABLE 2.1

Behavioral Studies Indicating Amnestic Effects of Antimuscarinic Agents in Rats

Similar to scopolamine, the nonselective muscarinic antagonist atropine, as well as several drugs with selectivity at muscarinic-receptor subtypes, disrupts performance of several of the same behavioral procedures (see Table 2.1). For example, the M₁-selective antagonist pirenzepine impairs learning of rats in such hippocampal-dependent tasks as delayed nonmatching to position [20] and delayed matching to position [21] as well as working memory in tests such as the radial arm maze [22], spatial memory in the water maze [23,24], and T-maze representational memory [25]. The passive-avoidance test is impaired by either systemic [26] or central injections [27,28] of pirenzepine, administered before the acquisition session. In the previously cited Andrews study [21], the effects of pirenzepine were interpreted as more specific for spatial short-term memory than scopolamine, since delay-dependent disruption of performance was noted with the former but not the latter compound. In fact, scopolamine induced a delay-independent disruption of all task parameters, including motivation and motor performance. Since the M₂-receptor antagonist AFDX 116 had no effect on receptors are not task performance in the same study, the authors suggested that M₂ responsible for the disruptive effects of muscarinic antagonists on spatial short-term memory. Regarding other selective muscarinic antagonists, Roldán et al. [29] showed that systemic administration of the M₁ antagonists biperidine and trihexyphenidyl impaired the consolidation of the passive-avoidance response in a dose-dependent manner. Trihexyphenidyl and benztropine (another M₁ antagonist) produced significant dose-dependent decreases in prepulse inhibition in a fashion similar to that of scopolamine [30], while the M₁-selective antagonist dicyclomine [31] impaired passive-avoidance learning as well as contextual fear conditioning in rats [32].

The Nature of the Effects of Antimuscarinics on Memory Performance (Potential Limitations)

While few would argue that muscarinic antagonists have negative effects on memory-related task performance, the specifics of such behavioral effects have been debated for years (see reviews in the literature [33–37]). Many investigators have interpreted the negative behavioral actions as impairment of learning (or state-dependent learning), working memory, short-term memory, encoding/consolidation, or retrieval. Conversely, others propose that the behavioral effects of antimuscarinic agents are not specific to learning and memory, since muscarinic receptors are also involved in the regulation of attention and arousal [4,6,36,38]. The effects of atropine in a nonspatial (visual discrimination) swimming task led Whishaw and Petrie [39] to conclude that cholinergic systems are involved in the selection of the movements or strategies that are prerequisite for learning, as opposed to learning and memory per se. Such (so-called) nonmnemonic effects were also deduced from the delay-independent performance deficits observed in several delayed-response tasks [40–43] as well as by deficits in both motor function and motivation [44]. The negative effects of scopolamine on the accuracy of short retention intervals in a delayed nonmatching-to-position task led Han et al. [45] to suggest that antimuscarinic agents produce general deficits in reference or procedural memory. Finally, some investigators completely reject any mnemonic explanations for the actions of antimuscarinic agents and argue that they primarily alter stimulus sensitivity, sensory discrimination, vision, perseveration, or habituation, etc. (reviewed by Collerton [46]).

The fact that a wide variety of noncholinergic agents have been observed to antagonize the behavioral effects of scopolamine further supports some of the arguments presented above (i.e., that the scopolamine amnesia model is not selective for memory function or even for the cholinergic system). For example, the nootropic agent piracetam has been observed to antagonize scopolamine in a passive-avoidance task [47] and in a delayed match-to-position task [48]. Estrogen replacement in ovariectomized rats significantly reduced deficits in the performance of a delayed matching-to-position (T-maze), with the deficits being produced by intrahippocampal, but not systemic, scopolamine administration [49]. A TRH (thyrotropin releasing hormone) analog, NS-3(CG3703), ameliorated scopolamine-induced impairments in a delayed nonmatching-to-sample task using a T-maze as well as a radial arm maze procedure [50]. The ethanolic extract of Indian Hypericum perforatum (an herbal agent) reversed scopolamine deficits in passive avoidance [51], while the seed oil of Celastrus paniculatus (another Indian herbal agent) prevented scopolamine-related deficits in water-maze performance in rats [52]. Furthermore, a number of serotonin-receptor ligands (e.g., 5-HT₃, 5HT_1A, 5HT₄, 5-HT₆) [53–56] reverse scopolamine deficits in several memory-related tasks, as do drugs from a number of additional classes (e.g., amphetamine, fluoxetine, and strychnine, as reviewed by Blokland [36]).

Obviously, these effects do not add credence to the idea of using antimuscarinics to model AD, which is clearly characterized by deficits in cholinergic activity, learning, working memory, and executive function. However, in contrast to the aforementioned delayed-response tasks, there are several rat studies in which scopolamine was found to have delay-dependent effects (e.g., spatial alternation, delayed matching, and delayed nonmatching-to-sample tasks) that were interpreted as deficits in working-memory performance [57–59]. Interestingly, a recent study indicated that scopolamine (but not methylscopolamine) impaired both affective (reversal learning) and attentional set-shifting components in the rat, thus implicating muscarinic receptors in the CNS control of executive function [60]. Furthermore, the effects of antimuscarinics on attention (often discussed as nonmnemonic) are not necessarily a limitation to using antimuscarinics to model certain aspects of dementia, since attentional deficits are a common feature of the condition. Finally, the criticisms regarding the so-called reversal effects of noncholinergic agents cannot be considered altogether convincing until rigorous pharmacological investigations of each of the aforementioned compounds are completed. It is clear that several representative agents from the classes listed (e.g., estrogen, 5-HT ligands, and herbal extracts) indeed have direct or indirect effects on the cholinergic system (see the literature [52, 61–63]).

Other Limitations and Criticisms of the Use of Antimuscarinics as Amnestic Agents

The use of antimuscarinic agents to model human dementia and the conclusions drawn from such studies have been criticized for a number of additional reasons (see Fibiger [34]). The most formidable challenge appears to arise from the limitations of using a unitary theoretical construct (i.e., central muscarinic-receptor blockade) to model memory-related dysfunction, considering the fact that cholinergic neurons (or their projections) and, in particular, muscarinic receptors are found in virtually every region of the CNS. Accordingly, the disruption of memory-related task performance by antimuscarinic agents could arise from a multitude of pharmacological actions. Such effects could also contribute to the inconsistent results that have often been observed across several types of memory-related tasks, as discussed previously. In light of the diverse brain lesions observed in conditions such as AD and the inherent complexities involved in learning and memory processing, single-transmitter hypotheses of dementia have been described as “worse than naïve” by some [33]. Thus, while the “face validity” of scopolamine amnesia models can be argued from the perspective that pronounced cholinergic dysfunction in the brain is a common feature of dementia, “construct validity” may be less convincing, since scopolamine impairments are acute, systemic, and (thought to be) primarily postsynaptic, whereas the pathology of dementia is characterized as chronic, brain-specific, and — in the context of cholinergic projections — primarily presynaptic (reviewed by Steckler [64]). Furthermore, “predictive validity” also appears to be limited, given that numerous investigational compounds have been observed to have the ability to reverse or attenuate scopolamine-related deficits in memory-related tasks, whereas few have been successful in clinical trials (see Sarter et al. [35]).

Somewhat less tenable criticisms are the so-called absence of dose-effect analyses in much of the published work and the failure of many investigators to use methylated (i.e., charged) forms of agents such as scopolamine and atropine to control for the effects of peripheral muscarinic blockade (reviewed by Fibiger [34]). While it is common for investigators to use a single dose of scopolamine in memory studies (in particular, the studies in which potential therapeutic agents are screened for their ability to prevent or reverse the amnestic effects of antimuscarinics), there are now a multitude of published studies across a number of behavioral paradigms in which dose-effect analyses have been conducted. As a result, it seems unnecessary for every investigator who performs a study with scopolamine to reestablish dose-effect curves, particularly in well-established learning and memory paradigms. Figure 2.1 through Figure 2.4 provide representative data from work in our laboratory, where dose-dependent effects of scopolamine (or clear dose-related trends) were observed in (three of the four) behavioral tasks ranging from spatial learning to auditory gating tasks to working-memory tasks. It should be noted that we did not detect delay-dependent impairments in performance of our delayed-response task (the Delayed Stimulus Discrimination task) [61,65].

FIGURE 2.1

Dose-related effects of scopolamine on performance of rats in a water-maze test. Scopolamine hydrobromide (0.1 or 0.3 mg/kg) or saline was administered subcutaneously 30 min before testing. N = 10 to 12 rats per group. A: Results of hidden-platform test (more...)

FIGURE 2.2

Dose-related effects of scopolamine on performance of rats in a step-through latency test. Scopolamine hydrobromide (0.4 or 1.0 mg/kg) or saline was administered subcutaneously 30 min before testing in a passive (inhibitory avoidance) task utilizing a (more...)

FIGURE 2.3

Dose-related effects of scopolamine on performance of rats in a test of prepulse inhibition of the auditory gating response. Scopolamine hydrobromide (0.01, 0.033, 0.10, or 0.33 mg/kg) or saline was administered subcutaneously 40 min before testing. (more...)

FIGURE 2.4

Dose-related effects of scopolamine on performance of rats in a delayed stimulus discrimination task (DSDT). Scopolamine hydrobromide (5, 10, 25, and 50 μg/kg) or saline was administered subcutaneously 30 min before testing. N = 8 rats per group. (more...)

The use of methylated (i.e., charged or quaternary amine) forms of antimuscarinic agents as controls is also well documented in the literature. Several studies using scopolamine methylbromide as a control reported that there was no effect of this analog on task performance, while other studies found that tertiary anticholinergic drugs ranged from 20 to 36 times more effective than quaternary analogs at impairing memory-related task performance. It should also be noted, however, that many of these studies involved spatial learning tasks and that significant effects of quaternary anticholinergics have been observed in a number of studies using food-motivated, delayed-response tasks (for a review, see Evans-Martin et al. [65]). Several plausible explanations for an effect of quaternary cholinergic antagonists on such behaviors have been presented. For example, scopolamine may reduce the motivation for food consumption by reducing salivary secretions, by altering the taste of the reward, or by altering gastrointestinal function. These effects have been suggested in studies of the scopolamine salts and conditioned taste aversion [66]. In humans, muscarinic antagonists induce other peripheral effects such as blurred vision (by impairing accommodation [67]), a factor that (if also present in rodents) could certainly impact the performance of tasks that require the discrimination of visual cues (e.g., water maze). We have, in fact, observed some impairment of the visible-platform task in the Morris water maze in previous experiments in our laboratory [68].

Quaternary anticholinergics have been shown to inhibit the production of epinephrine by the adrenal medulla, which in turn decreases the release of glucose from the liver [69,70]. This may decrease the entry of glucose into the brain and thus the subsequent synthesis of acetylcholine or other important neurotransmitters. In support of this hypothesis, the effects of scopolamine on passive avoidance and spontaneous alternation have been shown to be attenuated or reversed by glucose or epinephrine [71]. Finally, there is credible evidence that behaviorally significant concentrations of quaternary anticholinergics penetrate the brain despite their polarized state in vivo [21].

Scopolamine-Reversal Studies and Drug Discovery

Notwithstanding the criticisms described in the preceding section, the scopolamine-reversal paradigm has retained popularity in drug discovery programs for the past 10 to 15 years for screening potential antidementia (or cognition-enhancing) compounds. It is likely that one of the reasons for the continued popularity of the model is that it can be set up relatively cheaply using rodents to perform tasks such as passive avoidance and the Morris maze, which makes the model amenable to high-throughput screening approaches. While the predictive validity of the model for drug development purposes has been challenged, it should be noted that all of the commonly prescribed antidementia compounds have been observed to attenuate scopolamine-induced deficits in attention, learning, and memory in rodents. For example, rivastigmine attenuated scopolamine-related deficits in a dose-dependent fashion in an operant delayed nonmatching-to-position (working memory) task in rats [59] and improved deficits in both reference and working-memory versions of a water-maze task [72]. Galantamine attenuated scopolamine-induced deficits in passive-avoidance tasks [73,74] as well as in T-maze and Morris water-maze tasks [75]. Donepezil (E2020) attenuated scopolamine-related impairments in a delayed match-to-position task, a five-choice serial-reaction time (sustained attention) task [76], and an eight-arm radial arm maze task [77]. Finally, recent data implicating CNS muscarinic receptors in the control of executive function is likely to further increase the enthusiasm related to this model [60].

Conclusions

For more than three decades, antimuscarinic agents — particularly scopolamine —have been used to investigate the role of the CNS cholinergic system in learning and memory processes in the mammalian brain and to screen potential treatments for dementia. For a variety of reasons (peripheral actions, nonmnemonic effects, lack of construct and predictive validity, reversal by noncholinergic agents), the scopolamine amnesia model has been criticized, although convincing arguments have also been presented to support the model. The popularity of the scopolamine amnesia model is likely to continue, especially in drug discovery programs for dementia-related therapeutics, in light of recent data implicating CNS muscarinic receptors in the control of executive function [60].

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