TL neuro

July 10, 2014

Cognitive deficits produced by chronic alcohol drinking

Filed under: Alcohol, CANTAB, Discrimination/Reversal Learning — mtaffe @ 11:24 am

A new paper from the laboratory is now in press in print:

M. Jerry Wright, Jr and Michael A Taffe, Chronic periadolescent alcohol consumption produces persistent cognitive deficits in rhesus macaques. 2014, Neuropharmacology, 86:78-87. DOI: 10.1016/j.neuropharm.2014.07.003 [Publisher]

Although human alcoholics exhibit lasting cognitive deficits, it can be difficult to definitively rule out pre-alcohol performance differences. For example, individuals with a family history of alcoholism are at increased risk for alcoholism and are also behaviorally impaired. Similarly, a 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. It has been shown that better cognitive function at the time of treatment predicts abstinence in alcoholics.

Wright-Cog2-Fig4discrimlearningAnimal models of controlled alcohol exposure permit balanced group assignment, thereby ruling out the effects of pre-existing differences. We have developed a model in which periadolescent male rhesus monkeys consume alcohol in short daily sessions, five days per week, for many months (see Additional Reading, below). This permits the longitudinal assessment of cognition and behavior throughout a course of chronic exposure to, and withdrawal from, alcohol. The group mean intake over the course of this study was 1.38 g of alcohol per kilogram bodyweight, which corresponds to just over 5 standard drinks consumed in an hour each day. The individual range was from 0.74 g/kg (3 standard drinks) to 1.93 g/kg (almost 8 standard drinks). Again, consumed over an hour. We interpret this as being consistent with binge drinking but note that many human alcoholics maintain high blood alcohol levels across most of the waking day.

In this new paper, a group of 5 monkeys consumed alcohol over the course of 10 months (200 sessions) and were then withdrawn from chronic alcohol. A parallel control group of 5 monkeys drank the Tang vehicle only. We show here a lasting deficit in the 24-hour retention of a learned discrimination when animals were. In this task, animals determine which of two different stimuli is associated with reward by trial-and-error responding. Once they made a criterion of 12 out of 15 correct responses, they were deemed to have learned the discrimination. We present data as the percentage of correct responses as well as the number of errors (square root transformed to normalize the variance in this figure) made prior to reaching criterion. Animals were evaluated on the same discrimination a day later and control subjects exhibited a performance savings (increased accuracy, reduced errors to criterion) which indicates some retention of what they had learned the day before. The chronic alcohol / 6-week withdrawn monkeys showed no such savings, as if they had no recollection of the prior day’s session.

This part of the study shows that lasting cognitive deficits are caused by chronic binge-level alcohol consumption over the course of 10 months. The treatment groups were matched on alcohol preference and behavioral capability prior to the assignment to chronic alcohol or vehicle conditions. Thus, we can rule out the role of pre-existing differences to a larger extent than is possible in human studies.

ADDITIONAL READING:
Crean et al. (2011): Chronic alcohol consumption impairs visuo-spatial associative memory in periadolescent rhesus monkeys.
Taffe et al. (2010): Long-lasting reduction in hippocampal neurogenesis by alcohol consumption in adolescent nonhuman primates.
Katner et al. (2007): Robust and Stable Drinking Behavior Following Long-Term Oral Alcohol Intake In Rhesus Macaques
Katner et al. (2004): Controlled and Behaviorally Relevant Levels of Oral Ethanol Intake in Rhesus Macaques Using a Flavorant-Fade Procedure
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This work was supported by USPHS / NIH grants R01 AA016807 and R01 DA035482; Dr. Wright was supported by training grant T32 AA007456.

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March 28, 2013

Cannabidiol attenuates memory deficits that are caused by Δ9-tetrahydrocannabinol

Filed under: Cannabidiol, Cannabis, CANTAB, vsPAL — mtaffe @ 1:30 pm

A prior post discussed an apparently protective effect of cannabidiol (CBD) against memory deficits in humans caused by smoking cannabis. The key feature of the design was that Morgan and colleagues examined the Δ9-tetrahydrocannabinol (THC) and CBD content of their subjects’ (self-provided cannabis). The authors then grouped subjects into those who had relatively high-CBD cannabis and relatively poor-CBD cannabis; THC content was roughly equivalent. The authors reported that delayed recall was impaired acutely by cannabis smoking…but only if the cannabis was low in CBD. The relatively higher CBD content cannabis did not impair the memory performance of those individuals who smoked it.

The major concern with the study is that the humans subjects self-selected themselves into the treatment groups. Higher-CBD cannabis is relatively rare in recreational markets. It is possible that cannabis users who have access to (or intentionally choose) this restricted sub-population of the available cannabis are different, in one or more ways, than those users who do not have access or prefer other types of cannabis. Since they obtained their own cannabis we cannot know if there were other factors, socio-economic, regional, use-profile, peer groups, etc that were associated with choosing one type of cannabis over another. We similarly cannot know if they differed in memory ability and indeed there was a nonsignificant trend for better baseline memory in the CBD-enriched cannabis subjects.

We therefore conducted a controlled animal study in which the effects of CBD on a memory-impairing dose of THC could be assessed in the same subjects. This paper has recently been accepted for publication published.

Wright, M.J., Jr., Vandewater, S.A. and Taffe, M.A. Cannabidiol attenuates deficits of visuo-spatial associative memory induced by Δ9-tetrahydrocannabinol, Brit J Pharmacol, 2013 Dec;170(7):1365-73 [ PubMed ][ Publisher Link ]

PALFig-3stimGreyIn this task the animal first sees a given pattern in a single spatial location on the screen (“sample” phase of the trial). After touching it, there is a brief screen blank and then the pattern is presented in two or more positions (“choice” phase). Touching the pattern in the same location is a correct response. The difficulty of each trial is increased by presenting 2, 3 or 4 stimulus-location associations first and then querying all of them- in this case a successful trial completion requires touching the correct location for each stimulus that was presented. We’ve previously shown that THC degrades performance of this task in a manner that depends on both the trial difficulty (how many pattern-location associations have to be remembered) as well as the THC dose. This is interpreted as a relatively selective effect- in contrast a spatial memory task which does not depend on associating any pattern with the spatial location is impaired in a difficulty-independent manner.

CBD-THC-vsPALIn this figure we show the effect of multiple treatment conditions on the performance of the most difficult trials in which 4 stimulus-location associations have to be completed correctly. In this case, the animals are permitted up to 6 attempts to get each trial right. The data show that both 0.2 and 0.5 mg/kg doses of THC reduce the proportion of correctly completed trials. This effect is ameliorated if the THC is injected simultaneously with 0.5 mg/kg CBD. Since it was the same subjects, tested repeatedly, the effects of pre-existing differences in memory function can be ruled out.

Update:

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These studies were supported in part by P20 DA024194.

January 8, 2013

Two new reports describe alcohol and THC effects on cognitive function

The following two articles have been recently accepted for publication:

Wright, Jr, M.J., Vandewater, S.A., and Taffe, M.A. The influence of acute and chronic alcohol consumption on response time distribution in adolescent rhesus macaques. Neuropharmacology, 2013, in press [ Publisher Link ]

Wright, Jr, M.J., Vandewater, S.A., Parsons, L.H. and Taffe, M.A. Δ9tetrahydrocannabinol impairs reversal learning but not extra-dimensional shifts in rhesus macaques. Neuroscience, 2013, in press

February 29, 2012

Δ9-Tetrahydrocannabinol impairs visuo-spatial associative learning and spatial working memory

Filed under: Cannabis, CANTAB, Cognition, MDMA, SOSS, vsPAL — mtaffe @ 6:59 am

This paper has been accepted for publication:

Taffe, M.A. Δ9-Tetrahydrocannabinol impairs visuo-spatial associative learning and spatial working memory in rhesus macaques, J Psychopharmacol, October 2012 26: 1299-1306, first published on April 22, 2012 doi:10.1177/0269881112443743 [PubMed] [DOI]

In this paper we show that acute treatment with Δ9-THC interferes with the performance of two memory tasks in a manner that depends on both trial difficulty within the task and the dose administered. These results contrast with much prior literature using recognition memory or related tasks in which the effect of THC did not appear to be task specific, i.e., degrading performance in a difficulty-dependent manner. Our results are consistent with a prior observations using spatial delayed response tasks, further emphasizing a role for intact endocannabinoid function in spatial and/or working memory and learning.

Figure 3. The mean (N=4; ±SEM) percentage of trials correctly performed in the vsPAL task on the first attempt, and after a maximum of 6 attempts, are presented for baseline, vehicle and THC treatment conditions. The open symbols indicate significantly improved trial completion after repetition when compared with the initial attempt for a given treatment condition and trial type. Within a given trial-difficulty level, a significant difference from the vehicle and baseline conditions is indicated by #, from the vehicle condition (only) by &, and a difference from the 0.1 mg/kg condition by *.

August 4, 2011

CANTAB Self-Ordered Spatial Search Task: Strategy paper

Filed under: CANTAB, SOSS — mtaffe @ 11:40 am

This paper is now published [updated 9/2/2011]

Michael A. Taffe and William J. Taffe. Rhesus monkeys employ a procedural strategy to reduce working memory load in a self-ordered spatial search task. 2011, Br Res, 1413: 43-50. [DOI]

The object in this task is to select each box once and only once for a successful trial completion. A two second delay between each response and a manual distraction means that memory is required for successful completion. Subjects adopt a distance-minimizing response-path strategy that is correlated with successful trial completion. This correlation is observed between individuals and across months of training within individuals.

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