Atropine and scopolamine are muscarinic receptor antagonists with amnestic properties that have been used for decades in experimental animals to induce impairment in their performance of a variety of tasks requiring intact working and reference memory [1–3]. As long as 30 years ago, scopolamine had been used in clinical research studies (e.g., see [4]). Scopolamine has also been used clinically (though less frequently than in past years) as an adjunct to surgical or obstetric procedures to induce sedation and post-procedural amnesia. Since the first reports of a central cholinergic deficit associated with Alzheimer’s disease, the connection had been made between the cognitive and memory deficits associated with this disease and the reversible amnestic effects induced by centrally acting muscarinic cholinergic antagonists. Indeed, blockade of central muscarinic receptors could induce a pattern of cognitive impairment even in young subjects reminiscent of that observed in the aged, or in individuals with Alzheimer’s disease. For many years, the amnestic action produced in animals by the administration of centrally acting muscarinic cholinergic antagonists, particularly scopolamine, has been a widely used model for the characterization of potential cognition-enhancing drugs [5]. For animal studies, however, pharmacological models of induced memory impairment have been suggested to be of limited value because they fail to replicate the pathological aspects and the progressive degenerative nature of Alzheimer’s disease [6]. Despite this limitation, scopolamine-induced memory impairment, particularly when coupled with a version of the inhibitory avoidance [7] task provides a relatively rapid phenotypic screening tool for drug discovery in the field of cognition enhancement. A criticism often leveled at what might be termed the scopolamine reversal test pertains to the lack of versatility in the model, since scopolamine’s actions are limited to the blockade of brain function mediated via cholinergic (muscarinic) receptors. In Alzheimer’s disease basal forebrain cholinergic neurons appear to be targeted primarily in early stages of the disease. However, other neurotransmitter systems can be affected [8,9]. Alzheimer’s disease attacks cholinergic neurons in specific brain regions where the disease process leads to the decreased expression of specific subtypes of muscarinic cholinergic receptors. Presynaptic M2 receptors (located on cholinergic basal forebrain projection neurons) are depleted more severely than postsynaptic M1 receptors [10]. Scopolamine, however, is relatively nonselective pharmacologically with respect to receptor subtypes, and the drug does not discriminate very much with respect to brain region. Scopolamine certainly would have little direct effect on non-cholinergic neuronal pathways, although cholinergic neurons have functional interactions with a wide variety of neurotransmitter systems that could be affected indirectly by the drug. Despite these limitations, the amnestic responses elicited by scopolamine in humans appear to mimic very closely the cognitive deficits associated with Alzheimer’s disease [5]. Another advantage of scopolamine reversal as a model system for Alzheimer’s disease is that the induced memory impairment is reversible, which lends itself well to screening methods in drug discovery. The utility of the scopolamine model has been partially validated by the ability of centrally acting cholinomimetic drugs to reverse the effects of scopolamine on memory task performance. Studies with the centrally acting cholinesterase inhibitor physostigmine demonstrated consistent but partial reversal of scopolamine-induced memory deficits [11,12]. More recent studies with the currently prescribed Alzheimer’s drugs rivastigmine, donepezil, and galantamine have reported similar scopolamine reversal properties in the rat [13–16]. However, cholinomimetic drugs are not the only pharmacological class to reverse scopolamine-induced memory deficits [17–19], attesting perhaps to the greater than expected versatility of the model. Although the scopolamine reversal model is in wide use in preclinical stages of drug development, some examples of the model have been applied to clinical studies in young or healthy aged subjects. Indeed, a diverse set of compounds with unrelated pharmacological properties have shown efficacy in reversing the amnestic and sedating actions of scopolamine in clinical trials (Table 17.1). In preclinical studies, perhaps the two most widely used rodent tasks for studying or screening cognition-enhancing drugs are the inhibitory avoidance and the water maze tasks. However, clinical versions of these tasks are not well established. Computer-presented operant tasks designed for assessing the cognitive deficits associated with Alzheimer’s disease are available such as the CogState™ product [27,28] and the CANTAB™ product [29,30]. Computer presented cognitive test procedures are becoming more prevalent in the clinical cognitive testing domain. Therefore, there would be some advantage to having available preclinical models that are more relevant than those often used for preclinical drug screening.
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Title:
Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache.
Posttraumatic headache (PTH) is one of the most common, debilitating and difficult symptoms to manage after a mild traumatic brain injury, or concussion. However, the mechanisms underlying PTH remain elusive, in part due to the lack of a clinically relevant animal model. Here, we characterized for the first time, headache and pain-related behaviours in a rat model of concussion evoked by a mild closed head injury (mCHI) - the major type of military and civilian related trauma associated with PTH - and tested responses to current and novel headache therapies.Concussion was induced in adult male rats using a weight-drop device. Characterization of headache and pain related behaviours included assessment of cutaneous tactile pain sensitivity, using von Frey monofilaments, and ongoing pain using the conditioned place preference or aversion (CPP/CPA) paradigms. Sensitivity to headache/migraine triggers was tested by exposing rats to low-dose glyceryl trinitrate (GTN). Treatments included acute systemic administration of sumatriptan and chronic systemic administration of a mouse anti-CGRP monoclonal antibody.Concussed rats developed cephalic tactile pain hypersensitivity that was resolved by two weeks post-injury and was ameliorated by treatment with sumatriptan or anti-CGRP monoclonal antibody. Sumatriptan also produced CPP seven days post mCHI, but not in sham animals. Following the resolution of the concussion-evoked cephalic hypersensitivity, administration of GTN produced a renewed and pronounced cephalic pain hypersensitivity that was inhibited by sumatriptan or anti-CGRP antibody treatment as well as a CGRP-dependent CPA. GTN had no effect in sham animals.Concussion leads to the development of headache and pain-related behaviours, in particular sustained enhanced responses to GTN, that are mediated through a CGRP-dependent mechanism. Treatment with anti-CGRP antibodies may be a useful approach to treat PTH.
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Title:
The Revival of Scopolamine Reversal for the Assessment of Cognition-Enhancing Drugs.