and Silvia R. Castanheira Pereira1
Laboratório de Neurociência Comportamental e Molecular – LaNeC, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Alcoholic dementia is a disorder characterized by multiple cognitive deficits that include memory impairment associated with one or more cognitive disturbances listed in the present text. First, we characterize the disorder and describe aspects of using nonhuman models for studying specific and particular patterns of behavioral failures and biological dysfunctions found in cases of chronic alcohol consumption. Some kinds of animal models are depicted. Although there is no experimental model that displays all aspects considered as criteria for the diagnosis of alcoholic dementia, an animal model that is considered to be the most satisfactory to study behavioral and neurobiological aspects of this disease is that in which both high/chronic ethanol exposure and thiamine deficiency variables could be controlled. In this chapter, we show that animal models that manipulate only a single recognized etiological factor are less effective to elucidate the multiple influences that lead to alcoholic dementia. We conclude that even considering that only particular aspects of this disease could be approached using experimental animals; these studies can shed light on the biological processes, causing specific and particular patterns of cognitive failure.
Key wordsAlcoholic dementiaMemory impairmentChronic ethanol exposureThiamine deficiency
1 Alcoholic Dementia
The first step when using animals to study a cognitive dysfunction is to characterize the disorder. The one we are presently concerned with is “alcoholic dementia.” Not everyone who drinks chronically develops dementia, and the major risk factors for disease development and the mechanisms by which this occurs have remained unclear. There are data indicating that abuse of alcohol alone does increase the risk of dementia, whereas the potential deleterious or beneficial effects of light to moderate drinking remain unclear (1–3). Alcohol abuse may contribute to cognitive impairment in several different ways. Acute use of alcohol (acute intoxication) impairs attention, memory, executive functions, and visuospatial skills (4–9), while chronic abuse causes neurocognitive deficits in memory, learning, visuospatial functions, psychomotor speed processing, executive functions, and decision-making and may lead to persistent amnesic disorder and alcoholic dementia (5, 10, 11). Among the several kinds of dementia, we cite substance-induced persisting dementia, which may be due to drug abuse, medication, or toxin exposure. A number of toxins have been reported to cause dementia, but the principal one in most societies is alcohol (ethanol). Alcoholic dementia is a disorder characterized by multiple cognitive deficits that include memory impairment associated with one or more cognitive disturbances listed in Table 1.
Criteria for alcohol-induced persisting dementia in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association (12))
A. The development of multiple cognitive deficits manifested by both
1. Memory impairment (impaired ability to learn new information or to recall previously learned information)
(a) One (or more) of the following cognitive disturbances: (a) aphasia (language disturbance)
(b) Apraxia (impaired ability to carry out motor activity despite intact motor function)
(c) Agnosia (failure to recognize or identify objects despite intact sensory function)
(d) Disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting)
B. The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level or functioning
C. The deficits do not occur exclusively during the course of a delirium and persists beyond the usual duration of alcohol intoxication or withdrawal (code: 291.2)
D. There is evidence from the history, physical examination, or laboratory findings that the deficits are etiologically related to the persisting effects of alcohol use (code: 291.2)
Cognitive impairment may range between severe dementia and subtle deficits, which may be reversible (at least in part) or permanent. Although chronic alcoholism is associated with cognitive impairments, there are still conflicting opinions about the pathogenesis of alcohol-related memory impairments (12). Much of this debate has revolved around the relative contributions of nutritional deficiency and alcohol to the neuropathological lesions (13, 14). One of the most important questions concerning alcoholic dementia is whether long-term alcohol use may have direct neurotoxic effects on the brain, leading to a characteristic dementia syndrome. Clinical and neuropsychological data point toward the existence of an alcoholic dementia without secondary complications. Improvements in neuroimaging technology, such as magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography have contributed significantly to unravel structural abnormalities in uncomplicated alcoholics (with no hepatic or thiamine deficiency problems) who are cognitively impaired (2, 15, 16). The existence of specific neurotoxic effects of alcohol on the central nervous system (CNS) has been approached in a number of studies (2, 17, 18).
To reduce subjective bias and standardize DSM-IV criteria (see Table 1) for alcohol-induced persisting dementia, Oslin et al. (19) proposed some criteria to improve the validity and reliability of the diagnosis of “Alcohol-related dementia” (ARD) (13). These authors reported that individuals with ARD are less cognitively impaired than patients with Alzheimer’s disease and that both their cognitive and functional status frequently stabilizes. They consider ARD to differ from alcohol-induced dementia (DSM-IV) in that the presence of language impairment (aphasia) is less likely in ARD. This absence of aphasia in ARD is of clinical importance for the potential differentiation of the latter from Alzheimer’s disease, frontotemporal dementia, and vascular dementia (20).
Brain neuropathological lesions observed in demented alcoholic patients are more extensive in patients who have additional vitamin B1 (thiamine) deficiency, i.e., Wernicke–Korsakoff Syndrome (WKS). In alcoholics, several factors may contribute to thiamine deficiency and to dysfunctions of the thiamine-dependent or -metabolizing enzymes: (i) nutritional thiamine deficiency due to poor eating habits often seen in alcoholics; (ii) impairment of thiamine absorption from the intestine (21); (iii) changes in thiamine-metabolizing enzyme activity in the brain, e.g., a significant decrease in thiamine pyrophosphokinase activity caused by excessive alcohol consumption (22); (iv) changes in activity of thiamine-dependent enzymes that participate in the metabolic pathway (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase) (23).
The most characteristic symptoms of WKS are anterograde amnesia (i.e., the inability to learn and form new memories), retrograde amnesia (i.e., the loss of memories formed prior to the onset of WKS), and impairment of several cognitive processes (24). According to latter publication, these cognitive and memory deficits are accompanied by characteristic pathological damage to several brain structures. In these cases, alcohol may have a direct neurotoxic effect on cortical neurons, but much of the damage may be secondary to diencephalic pathology caused by thiamine deficiency, including loss of nerve cells in the thalamus, cell death and hemorrhages in the mammillary bodies, and enlargement of the third ventricle.
Results of a necropsy study by Harper (25) showed that 80% of 131 patients with WKS were not diagnosed as such during life. This is in accordance with some authors who have cast doubt on the existence of primary alcoholic dementia as a neuropathological entity and suggest that the majority of cases of alcoholic dementia are in fact WKS (26).
Wernicke’s encephalopathy is a neuropsychiatric condition that can lead to dementia and occurs as a result of thiamine deficiency. It has been described as an acute neurological disorder characterized clinically by oculomotor abnormalities, cerebellar dysfunction, and altered mental state, and characterized pathologically by hemorrhagic lesions in the wall of the third and fourth ventricles (27). Korsakoff’s syndrome is characterized by profound amnesia, disorientation, and frequent confabulation and is defined as a disproportionate impairment in memory, relative to other features of cognitive function, resulting from nutritional (thiamine) deficiency (28). Although the typical Korsakoff’s syndrome presents as a pure amnesic state without significant intellectual decline, some patients are reported to show remarkable and overall dementia. Scanning studies have shown that patients with Korsakoff’s syndrome have a more widespread cerebral and subcortical atrophy than alcoholic patients without amnesia (29). Because Korsakoff’s syndrome often follows or accompanies Wernicke’s encephalopathy, with the typical clinical pattern emerging when the acute global confusional state of the latter resolves, and both appear to share common pathological substrates, a number of researchers describe this continuum as WKS (26 28 30). The widely held view is that the cognitive deficits of varying types and severities found in alcoholics arise as a result of a coexisting thiamine deficiency syndrome (14). According to these authors, the fact that the degree of vulnerability of patients with Wernicke’s encephalopathy to Korsakoff’s syndrome appears to vary according to the history of alcoholism goes against the widely cited conclusion of Victor et al. (31) that Wernicke’s encephalopathy and Korsakoff’s syndrome are the acute and chronic phase of the same thiamine deficiency syndrome. Relating to the fact that alcohol consumption plays a relevant role in this syndrome, Martin et al. (32) consider that the most devastating neurological disorder caused by thiamine deficiency is WKS, which is seen most commonly in alcoholics. In short, clinical pathological issues regarding the so-called “alcoholic dementia” remain under debate. Although clinical observation favors the diagnosis of primary alcohol dementia, caused by direct alcohol neurotoxicity, further confirmation from the neuropathological and biochemical perspectives is required. Moriyama et al. (13) concluded that repeated episodes of subclinical WKS may partially account for the chronic state of primary alcoholic dementia, thus supporting the notion that primary alcoholic dementia exists in continuum with chronic and subclinical types of WKS. However, the role of thiamine deficiency remains undetermined in chronic “uncomplicated” alcoholism, but postmortem study indicates that Wernicke’s encephalopathy is underdiagnosed in life (16 32 33). He et al. (34) consider that these unsolved possibilities can be addressed with larger in vivo and postmortem animal studies that manipulate thiamine levels in the context of bouts of high alcohol exposure aimed at paralleling human alcoholism. Uncomplicated alcoholics likely sustain repeated bouts of less profound nutritional deficiency, which may contribute to their milder in vivo neuroradiological findings when compared with those marking WKS (14). McIntosh and Chick (35) state that improvements in imaging technology and the continuous progresses in brain neurochemistry knowledge have started to unravel the association between alcohol, thiamine, and memory. It has been proposed that most organic brain syndromes in alcoholic patients are variants of the WKS, and that there is no need to consider a separate category of “alcoholic dementia.”
2 Animal Models of Alcoholic Dementia
2.1 General Aspects on Using Nonhuman Models
Animal models may have either face validity (i.e., they mimic some aspect of the human condition) or predictive validity (i.e., results obtained with the animal model are predictive of actions of alcohol or of treatment efficacy in humans) (36). Basic research into the etiology of neurological disorders is often initiated in animal models. Nevertheless, most animal models are limited by the fact that animal models do not produce the plethora of behaviors that humans express. Many researchers study the relationships between cognitive and biological processes through comparative methods, using patients with cognitive impairments, mainly amnesic patients (37–39). However, the research techniques used in these studies are limited by ethical and/or practical considerations, and hence, the use of animal models is essential to obtain, in parallel with human experiments, the desired precision of manipulation and accuracy of measurement. As a first step to approach the questions regarding the biological basis of cognition, some laboratories have used simpler systems to study biological changes associated with learning. Using experimental models to study different aspects of cognitive deficits, researchers have obtained evidence that some behavioral modifications are associated with molecular neurobiological changes (40–42). Moreover, mammalian animal memory tasks analogous to human memory tests have been developed, and both yield results that support correspondence in mnemonic function (43, 44). The results obtained from experimental models may provide a starting point for an understanding of the relationship between organic and psychological phenomena and shed light on the hypothesis that each aspect of behavior is mediated by specific neural mechanisms in the brain. Considering that the basic biological substrate of mental processes by which a subject perceives, acts, learns, and remembers might be similar in different species, simpler systems (e.g., the rodent CNS) are useful models to understand some of the basic principles of interaction between mind and brain. As psychoactive drug effects develop gradually and can persist for a long time after cessation of chronic drug administration, this approach is useful to study the steps of a neurodegenerative process associated with cognitive performance impairment as in alcoholic dementia. In this case, we can follow each stage of the process at both the cognitive and biological level.
2.2 Animal Models of Alcoholism
Animal models have been developed to study various aspects of alcohol use and dependence, including alcohol-seeking behavior, alcohol-related organ damage, tolerance to alcohol, and physical dependence on alcohol. Additionally, because animal models can be genetically manipulated, they are valuable for research on the genetic determinants of alcoholism. Although no animal model replicates all aspects of this disorder, they can offer some advantages. For instance, they make it possible to dissect different components of the disorder. In this aspect, animal models can be useful to understand molecular mechanisms that play a relevant role in that disease and to study the correlations between specific behavioral deficits and neurobiological dysfunctions.
Factors potentially contributing to the behavioral performance of animals in different kinds of models for alcohol abuse include the species of choice, age of the animals, duration of alcohol treatment and abstinence, method of alcohol administration, and the model’s face and predictive validity (45–47). It is unlikely that an animal model will be developed that completely mimics all the characteristic effects of acute or chronic alcohol ingestion in man. Thus, to describe some kinds of animal models that have been used to study aspects of chronic alcoholism and to subsequently highlight the relations between these and the criteria stated in DMS-IV for alcoholic dementia, the following paragraphs are divided into two main topics: (i) a short description of the types of animal models for studying chronic alcoholism and (ii) an animal model that is considered the most satisfactory to study some aspects of alcoholic dementia.
2.3 Some Animal Models for Studying Aspects of Chronic Alcoholism
The attention of researchers has been mostly directed to the following alcohol-associated phenomena: alcohol dependence, tolerance, withdrawal symptoms/signals, craving and relapse, alcohol-induced hepatic damage, and ethanol-reinforced-self-intoxication, each of which has been demonstrated in both man and animals. Many studies using animal models to approach behavioral aspects and biological mechanisms which are involved in these phenomena have been carried out (36). As mentioned before, the different effects of alcohol consumption depend on several factors, such as route and timing of alcohol administration (e.g., binge/intoxication or chronic consumption), strain, sex, and age of the animal. Many models have been validated in pharmacological studies and have provided some insight into the neurochemical and cellular changes underlying alcohol dependence, tolerance, and addictive behaviors. These topics are deeply approached in some extensive reviews describing different aspects of alcohol abuse (48–50). Models of relapse behavior have a high degree of predictive validity (51).
One of the main procedures used as a model of alcohol dependence to study many aspects of addictive behaviors is submitting rats to a prolonged exposure to alcohol vapor (52–54). This type of manipulation produces persistently increased alcohol intake in genetically nonselected rats. In addition, exposure to repeated cycles of intoxication and withdrawal, which mimics the course of the clinical condition, is extremely effective for inducing increased alcohol drinking (55, 56). Additionally, like intragastric administration, the dose of ethanol given to the animals can be controlled when exposure to alcohol vapor is used (57, 58).
Besides intragastric administration and exposure to alcohol vapor, prolonged oral administration of ethanol through either aqueous solutions (different concentrations have been used) or liquid diet is often used to study the chronic effects of the drug on brain and behavior (59–62). Using these administration routes, some authors have demonstrated that chronic alcohol consumption can induce cognitive deficits and neurobiological dysfunction (59, 63–65). It is important to emphasize that, unlike administration through vapor, in which the animal is forced to receive the ethanol treatment, when using oral administration the experimenter can give ethanol as the sole source of fluid (forced consumption) or give the animal the opportunity to choose between two solutions, with or without drug. In the latter case, the animal has voluntary access to ethanol.
According to Spanagel (48), when designing an animal model that covers several aspects of alcohol dependence and alcohol-related disease, a necessary precondition is that the laboratory animal has voluntary access to alcohol for a long time (at least for several months). The large variability in alcohol preference among individual animals and strains has allowed researchers to selectively breed rats for differential alcohol preference, generating pairs of animal strains that are characterized by particularly low or high alcohol consumption levels. For instance, two pairs of lines were generated in Finland and Sardinia. The Finnish model – called Alko Alcohol and Alko Nonalcohol rats – comprises two strains of albino rats that were selectively bred from 1963 onwards based on their preference or rejection of a 10% alcohol solution versus water (66, 67). The Sardinian alcohol-preferring rat line has also been selectively bred for high alcohol preference and consumption for over 20 years (68). Other important alcohol-preferring rat lines are the Indiana University alcohol preferring and the high-alcohol-drinking lines (69). Another model to study alcohol preference is that of knockout mice that can be used to assess the involvement of a particular gene in alcohol drinking behavior (70, 71).
In a review on animal models of alcohol abuse, Tabakoff and Hoffman (36) state that operant alcohol self-administration has not only been used to assess the reinforcing effect of alcohol but also to model the craving for alcohol experienced by abstinent alcoholics. When animals have been drinking alcohol regularly and are then subjected to a period of forced abstinence from alcohol, they show a reliable increase in alcohol intake when alcohol is again made available (i.e., the alcohol deprivation effect). Whether this apparently enhanced motivation to ingest alcohol is an accurate model of craving in humans is not clear. However, this model does have significant predictive validity; the drugs now used to reduce craving and relapse in humans (72, 73) can also block the increased responding associated with the alcohol deprivation effect in animal models (74). According to its aims, research addressing chronic ethanol treatment and alcohol self-administration with nonhuman models can be divided into: (i) demonstration that alcohol self-administration could be established; (ii) verification that ethanol self-administration can not only be induced but also maintained; (iii) establishment of a useful model for investigating potential pharmacotherapies; (iv) addressing consequences and risk factors for excessive alcohol drinking associated or not to a secondary cause (e.g., thiamine deficiency). Considering the latter, brain degeneration is among the numerous possible consequences of ethanol abuse, which can be related to a severe cognitive impairment. The relative contributions of a direct effect of alcohol and thiamine deficiency to biological and behavioral dysfunctions are still obscure. In this case, the use of animal models is useful because the neurochemical and molecular biological data can be determined and also its correlation to the specific behavioral aspects assessed.
As mentioned earlier, chronic alcohol consumption can lead to Korsakoff’s syndrome, a memory deficiency attributed to diencephalic damage and/or to medial temporal or cortical dysfunction. A good number of animal models of Korsakoff’s syndrome involve thiamine-deficient diet manipulation. Two kinds of treatments are described for inducing thiamine deficiency in laboratory animal models: (i) to submit them to a thiamine-deficient diet or (ii) to associate the thiamine-deficient diet treatment with pyrithiamine (an inhibitor of the kinase responsible for thiamine phosphorylation). Both types of treatment can be combined with chronic ethanol administration resulting in the development of multiple cognitive deficits.
Diencephalic dysfunctions have been described in thiamine-deficient animals (75). Neurochemical alterations along with the white matter loss that occurs in key fiber tracts from the diencephalon after thiamine deficiency (76) suggest that this vitamin deficiency likely causes system-level dysfunction, which probably underlies the deficits in learning and memory documented in this animal model. Moreover, animals treated with pyrithiamine associated with a thiamine-deficient diet showed severe neurological signs in relatively short periods of time (77). Morphological lesions in diencephalic regions, similar to those found in humans with WKS, have been observed in animals treated with pyrithiamine (78). Clinical signs include ataxia, lethargy, anorexia, seizures, and impaired righting reflexes and ultimately death after a 20-day treatment (77).
Pfefferbaum et al. (79) found that the brain regions clearly affected by thiamine deficiency in alcohol-preferring rats consuming high concentration of alcohol were the thalamus, mammillary nuclei, inferior colliculi, lateral and fourth ventricles, and hippocampus. Dixon and Harper (80) stated that the enduring macrostructural and neurochemical abnormalities involving critical nodes of the Papez circuit carry liabilities for development of amnesia and incomplete recovery of nonmnemonic cognitive and motor functions subserved by the affected neural systems.
2.4 The Most Satisfactory Animal Model to Study Aspects of Alcoholic Dementia
As explained earlier, there have been a large number of studies in which chronic ethanol is given to animals; however, relatively few have been specifically designed to provide information about the mechanisms underlying alcoholic dementia. There is no animal model that displays all aspects considered as criteria for the diagnosis of alcoholic dementia in DMS-IV. Moreover, even considering the use of an animal model to study only some aspects of this disease, the central question concerning the relative contribution of both alcohol- and thiamine-deficiency-related neurotoxicity to bring about a characteristic dementia syndrome should be taken into account. This is an essential concern because, as mentioned earlier, the role of thiamine deficiency remains undetermined in chronic “uncomplicated” alcoholism (32, 81). In addition to this, the widely held view is that the cognitive deficits of varying types and severities found in alcoholics arise as a result of a coexisting thiamine deficiency syndrome (14). Thus, the possibility of manipulating these two independent variables in a nonhuman model, namely high ethanol exposure and thiamine deficiency, might be crucial to address these unsolved questions and also contribute to our understanding of molecular and behavioral aspects of alcoholic dementia. Besides, the control of these variables also allows obtaining evidence about the etiology of the multiple persistent cognitive deficits.
Following, the DMS-IV criteria for alcoholic dementia are used to describe a rationale for the viability of using a model of chronic ethanol consumption associated to thiamine deficiency (a kind of WKS model) to study aspects of this dementia. These descriptions exemplify, both at the behavioral and biological levels, the effects of excessive alcohol drinking associated or not to severe or subclinical episodes of thiamine deficiency, which are related to some of the clinical signs that make up, according to DMS-IV criteria, an alcoholic dementia picture.
Next, the DMS-IV criteria are presented along with the exemplifications of data obtained using the WKS animal model and its aspects of face validity are pointed out. According to DMS-IV, the development of multiple cognitive deficits manifested by two clinical signs has to be considered for the diagnosis of alcoholic dementia: (i) memory impairment and (ii) one (or more) of the following cognitive disturbances: aphasia (language disturbance); apraxia (impaired ability to carry out motor activity despite intact motor function); agnosia (failure to recognize or identify objects despite intact sensory function); disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting). Except for aphasia, all the other clinical signs can be assessed in nonhuman models. Despite the existence of contradictory data, several pieces of evidence in the literature show memory impairments in nonhuman models similar to those displayed by patients with diagnosis of WKS (caused by the association of chronic alcohol consumption and thiamine deficiency). However, only in few of these studies, further experiments were carried out to assess other cognitive disturbances (e.g., apraxia, agnosia, and executive dysfunction).
Ciccia and Langlais (78) found learning and memory deficits in thiamine-deficient animals, whether or not submitted to chronic ethanol exposure, and verified that neurological symptoms were most associated with thiamine deficiency. These cognitive deficits appear to be caused by a synergistic interaction between chronic ethanol and thiamine deficiency. The authors also verified that ethanol alone affected short-term memory but did not alter long-term memory. Our group also showed that thiamine deficiency, whether or not associated to chronic ethanol treatment, induced a spatial learning and memory deficit. A significant interaction between the effects of chronic ethanol and thiamine deficiency was found (82). Furthermore, a thiamine deficiency episode induced a decrease in behavioral extinction (83). Some aspects of the observed cognitive deficits (memory and extinction) (82, 83) are correlated to neocortical and hippocampal cholinergic parameter changes. Recent lesion studies with rodents have suggested that the prefrontal cortex contributes to the temporal ordering of spatial and nonspatial events, to the level of attentional selection, as well as to the organization and planning of responses (84–86). Carvalho et al. (87) showed that, although the prefrontal cortex is considered by some authors as a nonvulnerable area to lesions caused by thiamine deficiency, this vitamin deficiency does cause neurochemical dysfunction in that region. In addition, cortical cholinergic projections are thought to play a fundamental role in cortical processing and to affect attentional and memory processes, including extinction (88, 89).
Considering that cholinergic neurotransmission in the basal forebrain plays a key role in attention, learning, and memory processes (90–92) and its dysfunction seems to be involved in the pathophysiology of dementias (93, 94), the biological data discussed here focus on this neurochemical system. Discussing all neurochemical systems that play a relevant role in the aforementioned cognitive processes would be beyond the scope of the present chapter.
Arendt et al. (95) reported extensive cholinergic cell loss in the nucleus basalis of Meynert (NbM) (origin of major cortical cholinergic projections) of patients with Korsakoff’s disease, but not in chronic alcoholics without dementia. There is increasing evidence implicating cholinergic mechanisms in the neuropsychological deficits seen in chronic alcoholics. Other authors have also described the involvement of the cholinergic system in Korsakoff’s disease (96, 97). Cholinergic dysfunction has been consistently linked to cognitive deficits in different neurodegenerative diseases, leading to the “cholinergic hypothesis,” which states that a loss of cholinergic function in the CNS contributes to the cognitive decline associated with aging and dementia (98). A loss of neurons in the NbM complex is reflected by a decrease in the activity of choline acetyltransferase in cortex and hippocampus (95, 99), which are the target areas of these cholinergic neurons (100, 101).
Arendt et al. (102) suggested that rats chronically treated with ethanol represent a suitable animal model to test the cholinergic hypothesis of memory dysfunction, as well as to develop strategies for an amelioration of the impairment in memory and cognitive function in dementia disorders associated with degeneration of the NbM, such as alcoholic dementia and Alzheimer’s disease. Floyd et al. (103) showed results indicating a neurotoxic effect of prolonged intake of ethanol on the basal forebrain cholinergic projection system, which may cause impairment of cholinergic innervation of target areas of the basal nucleus complex. Hodges et al. (59) verified that chronic alcohol (20% v/v in drinking water for 28 weeks) impaired acquisition of radial maze spatial and associative tasks by increasing both within-trial working and long-term reference memory errors. Alcohol-treated rats showed improvements in radial maze performance after treatment with cholinergic agonists (arecoline and nicotine) and disruption with antagonists (scopolamine and mecamylamine) at low doses, which did not affect controls. Transplants of cholinergic-rich basal forebrain and ventral mesencephalon fetal neural tissue in cortex and hippocampus of alcohol-treated rats improved radial maze performance to the control level. These results suggest that damage to the forebrain cholinergic projection system played an important part in the radial maze deficits displayed by alcohol-treated rats, since these animals were sensitive to cholinergic drug challenge and cholinergic-rich transplants, which restored cognitive function.< div class='tao-gold-member'>