Chronic periadolescent alcohol consumption produces persistent cognitive deficits in rhesus macaques
Introduction
Chronic heavy alcohol use in humans has been associated with differences in neuroanatomy and brain physiology as well as deficits of perception, learning and memory (Oscar-Berman et al., 1997, George et al., 2001, Agartz et al., 2003, Harper et al., 2003, Pfefferbaum et al., 2009, Spreckelmeyer et al., 2011). While cognitive function is generally thought to improve in adult humans after extended abstinence from alcohol (Rosenbloom et al., 2004, Fein et al., 2006, Kopera et al., 2012), some cognitive deficits appear to persist after the cessation of alcohol consumption [see (Fein et al., 1990) for review] and the extent of any recovery may be related to age, length of abstinence and whether periods of abstinence were interrupted by alcohol consumption (Rourke and Grant, 1999, Munro et al., 2000, Zinn et al., 2004). A recent examination of a very large sample of 18–22 year-old men indicated that those who drank alcohol on a daily basis had the lowest IQ of any group examined (Müller et al., 2013). However, such findings could be confounded by a number of factors including pre-existing cognitive differences in those who end up drinking daily and the effect of cognition on willingness or ability to cease drinking. For example, better cognitive function at the time of treatment predicts abstinence in alcoholics (Abbott and Gregson, 1981, Parsons, 1994, Wehr and Bauer, 1999).
While the association of lower cognitive function with chronic alcohol exposure in humans is documented, it is difficult to exclude the contribution of other factors. There is evidence that poor pre-morbid cognitive function is a predictor of illicit drug use and alcohol abuse (Moriyama et al., 2006). In addition, individuals with alcoholic family members perform worse than control subjects on tests of verbal IQ, visuospatial perception, attention, memory, executive function and electrophysiological indices of cognitive function (Begleiter et al., 1984, Hill et al., 1990, Whipple et al., 1991, Polich et al., 1994, Harden and Pihl, 1995, Ozkaragoz et al., 1997) in the absence of chronic drinking.
The complexity of establishing causality between alcohol drinking and cognitive function can be circumvented by controlled studies in animal models. Due to their anatomical and physiological similarities to humans, relative alcohol preference and wide behavioral repertoires, monkey models provide a high level of validity for the cognitive impact of alcohol in humans (Tabakoff and Hoffman, 2000, Grant and Bennett, 2003). For instance, the role of the frontal cortex in working memory is well-established (Courtney et al., 1998a, Courtney et al., 1998b, Koch et al., 2005, Curtis, 2006). In monkeys (and other animal models), the working memory deficits that results from lesions to the frontal cortex (Collins et al., 1998) are similar to the deficits in adult humans that consume alcohol chronically (Townshend and Duka, 2005, Kopera et al., 2012). The extended period of adolescence in rhesus macaques (Lewis, 1997, Schwandt et al., 2010) makes them an excellent model for human developmental psychopharmacology and we have recently shown that repeated consumption of alcohol alters several cognitive functions in periadolescent monkeys (Crean et al., 2011). Deficits in pattern-spatial associative memory that were identified were likely a result of changes in hippocampal neurodegeneration and neurogenesis (Taffe et al., 2010). Because the monkeys were matched on alcohol preference and general cognitive ability prior to exposure, those data support the conclusion that deficits in human alcoholics are produced by the alcohol consumption itself.
The studies in this current investigation sought to further determine the extent of cognitive deficits produced in male rhesus macaques that consumed alcohol chronically, five days per week, during the periadolescent epoch. We focus on the adolescent age range because evidence shows that over 90% of adult alcoholics started drinking before the age of 21 (SAMHSA, 2011) and 20% of US high-school seniors have consumed 5 or more standard drinks in one session within the 2 week interval prior to survey (Johnston et al., 2012a, Johnston et al., 2012b). Likewise, the study was conducted in males because in US 12th grade students, male rates for past-30-day alcohol use, past 2-week heavy drinking and daily alcohol use exceed the female rates (Johnston et al., 2012a, Johnston et al., 2012b). Thus we decided to focus on modeling the sex that is of greatest risk in the human target condition. It is also the case that the human brain exhibits significant changes in structure and function during adolescence (Huttenlocher, 1979, Huttenlocher et al., 1982, De Bellis et al., 2000, De Bellis et al., 2001, De Bellis et al., 2005). It is hypothesized that interference in the development of the prefrontal cortex (Pfefferbaum et al., 1994, Giedd et al., 1999, Thompson et al., 2000, Durston et al., 2001, Paus et al., 2001) may underlie impairments in visuospatial skills, attention and executive function which are observed in recently detoxified adolescents (Tapert and Brown, 1999, Brown et al., 2000). The focus of this study was therefore on behavioral domains that are associated with intact frontal cortical function including spatial working memory, retention of discrimination learning and performance of a response-time task. The alcohol exposure model for this study was selected to meet the binge criteria of 5 standard drinks in a single ∼hour long interval (see Crean et al., 2011; for discussion) in an attempt to model after school-day consumption. The behavioral assessment model used a computerized, touch-screen battery (Cambridge Neuropsychological Test Automated Battery; CANTAB) that has been designed with parallel versions suitable for human and nonhuman primate assessment (Weed et al., 1999). Studies using CANTAB measures in humans have identified deficits of reaction time, spatial working memory, spatial memory span and attentional set shifting in abstinent, previously alcohol dependent adults (Kopera et al., 2012). Female, but not male, binge drinkers were found to be impaired, relative to non-binge drinkers, on spatial working memory assessed with CANTAB (Townshend and Duka, 2005). Children with pre-natal alcohol exposure have been found impaired on reaction time, spatial working memory and spatial memory span (Rasmussen et al., 2011). The use of parallel behavioral assessment tools in monkeys in the present study greatly enhances the translational comparison of the findings.
Section snippets
Subjects
These experiments were conducted using ten male rhesus macaques (Macaca mulatta; Primate Products, Inc., Immokalee, FL, USA); prior studies in these animals have been reported by Wright and colleagues (Wright et al., 2013a, Wright et al., 2013d). At the onset of the present studies, the median age of the monkeys was 58 months (range = 50–59 months) and 7 of the 10 monkeys were born within 60 days of each other. Animals were obtained as a single cohort with identical weaning and group housing
Alcohol consumption and blood–alcohol levels
As reported previously, mean individual daily alcohol consumption ranged from 0.74 g/kg ( ± 0.04 SEM) to 1.93 g/kg ( ± 0.04 SEM) with an overall group mean intake of 1.38 g/kg ( ± 0.02 SEM) for the entire chronic exposure interval. Consumption patterns were generally consistent within each monkey (Wright et al., 2013d) and blood-alcohol levels (BAL) were reliably related to the dose consumed (Wright et al., 2013d). In Fig. 2, the BALs previously reported are identified by treatment group: the
Discussion
These data demonstrate that as little as 6 months of chronic, binge-level alcohol consumption (120 drinking sessions) produces working memory deficits as assessed with the Self-Ordered Spatial Search (SOSS) task in periadolescent rhesus macaques. It was further determined that 24-hr retention of a visual discrimination task was impaired after 6–8 weeks of discontinuation from drinking subsequent to 10 months of chronic alcohol. The study also found that the accuracy and response time in a
Author contributions
M.J.W., Jr. and M.A.T. designed the overall study, components of which were implemented and refined by M.J.W., Jr. under the supervision of M.A.T. Analysis of the data and creation of figures was conducted by M.J.W., Jr. with input from M.A.T. and drafting of the manuscript was by M.J.W., Jr. and M.A.T. Both authors have approved the manuscript.
Acknowledgments
The authors would like to acknowledge the expert technical contributions of Sophia A. Vandewater and Maury Cole. This work was supported by USPHS grants AA016807 and DA035482; Dr. Wright was supported by training grant AA007456. This is publication #25004 from The Scripps Research Institute.
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