Animal models of dementia

Abstract

The major use of animal models for dementia i s in the development of new therapeutic drugs. In contrast to other areas in psychopharmacology, where the predictive validity of animal models can be established by examining their response to known therapeutic agents, the search for antidementia drug5 is hampered by the absence of recognized clinically effective reference compounds. Research scientists are therefore obliged to validate their models in terms of their similarity to the clinical condition. A second problem is the therapeutic target. Although antidementia drugs are intended to improve cognition in a general sense, the foremost therapeutic targets are the deficits in memory and attention associated with aging. The aging animal would appear to represent the best available model providing it can be shown that the cognitive deficits observed are similar to those observed in old age in humans. A logical consequence of this approach is to validate other experimental models in terms of their resemblance to naturally occurring age-related impairments.To illustrate these points, this paper reviews data obtained in aging animals in various behavioral models and the effects of drugs thereon. Comparisons are made between drug effects in aged animals with those observed in experimental models in young animals in which cognitive deficits are induced by anticholinergic drug treatment or lesions to cholinergic-rich brain regions. It is concluded that aging induces cognitive deficits mainly associated with short-term memory but that other aspects of cognition, namely attention and information processing speed, also decline with age. Putative antidementia drugs, particularly those facilitating cholinergic transmission, appear frequently to have more marked effects in experimental deficit models than in aged animals themselves. D 1995 WII~Y-LISS, inc

The Serotonin1AReceptor Partial Agonist S15535 [4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine] Enhances Cholinergic Transmission and Cognitive Function in Rodents: A Combined Neurochemical and Behavioral Analysis

“…Hippocampal cholinergic pathways play a major role in spatial memory and, correspondingly, performance in the water-maze is severely disrupted by scopolamine (Porsolt et al, 1995). The reversal of its effects by S15535 resembles findings of a previous study with MDL73005, which likewise acts as an agonist and antagonist at pre-and postsynaptic 5-HT 1A receptors, respectively, although its D 2 antagonist properties complicate interpretation of its actions (Bertrand et al, 2001).…”

“…Procognitive actions of S15535 were lost at higher doses, perhaps reflecting the onset of postsynaptic 5-HT 1A receptor activation (see above). A biphasic dose-response curve also was seen in a related procedure of operant, working memory, an operant DNMTS task in aged rats, in which the influence of drugs upon memory (response accuracy) and attention (latency to respond) can be differentiated (Porsolt et al, 1995). Interestingly, S15535 preferentially improved the compromised attentional function displayed by aged rats.…”

“…"Delayed nonmatching to position" models of short-term, spatial working memory, in which rats choose between spatially separated, retractable levers, are dependent upon the operation of cholinergic mechanisms in the hippocampus and FCX (McAlonan et al, 1995;Herremans et al, 1996). Although it has been questioned whether mnemonic (compared with motor) factors underlie the perturbation of performance in this model provoked by activation of hippocampal 5-HT 1A receptors, stimulation of 5-HT 1A autoreceptors specifically improves cognitive function (Cole et al, 1994;Porsolt et al, 1995;Stanhope et al, 1995;Warburton et al, 1997;Pache et al, 2003). Accordingly, S15535 enhanced performance of mice in the present spatial DNMTS (place) variant of this paradigm at autoreceptor-activating doses that exert little influence upon motor function (Millan et al, 1994(Millan et al, , 1997a.…”

“…They were housed in groups of five or six. The method used follows that described by Porsolt et al (1995). The Morris water-maze consisted of a circular water tank (150 cm in diameter) filled with water (27°C) and with an escape platform (15 cm in diameter) located 18 cm from the perimeter, always in the same position 2 cm beneath the surface of the water.…”

“…Young controls were 2 months old (mean weight 264 g) at the beginning of the experiment. As described previously (Porsolt et al, 1995), the experiments were conducted in standard, soundproof operant chambers for rats (30 ϫ 25 ϫ 30 cm; Coulbourn Instruments, Lehigh Valley, PA) fitted with a white house light, one or two retractable levers, and a food pellet (45-mg) dispenser. In the one-lever configuration, the lever was located centrally above the food tray.…”