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The pharmacology of executive functioning

part 2

research reports

Jack, Bergman; Louk, Vanderschuren; Ellenbroek, Bart; Paul, Willner

doi: 10.1097/FBP.0000000000000457
EDITORIAL

The first part of this Special Issue on the Pharmacology of Executive Functioning (Behavioural Pharmacology 29.7) comprised eight important review papers. This second part presents a range of original research reports in human and nonhuman subjects, focussed on impulsivity, processing capacity, predictability and decision making, that provide a compelling portrayal of the methodological virtuosity and scientific rigor that characterize this field of investigation.

The first paper by Rojas-Leguizamón et al. tackles the troublesome issue of how best to model Attention Deficit Hyperactivity Disorder in laboratory animals. The authors use a nicely designed timing task to closely analyze response inhibition in spontaneously hypertensive rats (SHR), which are often used for this purpose. Their data show that SHR rats may take longer to learn to inhibit responding than other strains but, once that is accounted for, the response to amphetamine does not differ – raising the question of homology between the SHR model and the clinical condition. The next report by Maguire and colleagues also concerns response inhibition in rodents, this time comparing the effects of morphine and amphetamine in an adjusting variant of the widely used Stop Signal Reaction Time task. The authors show that neither drug produced much effect on response inhibition at doses that increased (amphetamine) or decreased (morphine) premature responding. Of interest, daily morphine treatment accentuated its own motoric effects but diminished those of amphetamine, illustrating the difficulty in predicting how repeated drug exposure modifies drug sensitivity under behaviourally complex conditions.

The third report again takes up the question of concordance between preclinical methodology and the clinical conditions that are modelled. Here, Riedel et al. compare the performance of different mouse strains on a variant of the Barnes maze, and elegantly explore the relationship between cognitive load and the expression of learning deficits. Their data show that 129S2/SvHsd mice with a mutation of the DISC1 (disrupted-in schizophrenia) gene display a load-related learning deficit, supporting the utility of this mutant mouse as a model for cognition-related deficits in schizophrenia. Katz et al. continue the display of methodological elegance that characterizes the reports in this issue by examining variables that can govern the effects of psychotropic drugs on cognitive functioning. Using the well-established 5-Choice Reaction-Time procedure in mice, they show that the facilitative effects of psychomotor stimulant drugs are not further increased by the introduction of a presignal warning stimulus. However, these effects are markedly impaired by introducing some unpredictability in the timing of the signal presentation – clearly illustrating the deep interplay between the behavioural and pharmacological determinants of psychomotor stimulant activity. The next report by Lambert and colleagues takes us away from the animal models of cognition to a delightfully descriptive study of executive function in human subjects. These authors ask the simple question of whether males and female individuals differ in constructing Tinker Toys (Tinker Toy Test). Their data suggest that there was little sex-related difference (e.g. the number of pieces used in a construction did not vary) but that male individuals tended to score higher on a symmetry scale. In view of the awakened realization of the importance of examining the role of sex as a biological variable, this type of investigation – interrogating the role of sex in basic cognition-related processes – is as necessary as it is informative.

The remaining four reports in this Special Issue are focused on research that uses variants of choice procedures in which behaviour is maintained under concurrently available schedules of reinforcement. Under these experimental conditions, the allocation of behaviour, that is, ‘choice’, is considered to reflect a preference for one or the other option for reinforcement. This is a rich area of experimental investigation, and, in recent years, tremendous strides have been made in understanding the neural networking, as well as behavioural underpinnings of decision-making processes that are thought to be reflected in ‘choice’. This work has fortified our understanding of decision making as a dynamic neurobiological process that is continually informed by ongoing experience. From a behavioral perspective, ‘choice’ is closely governed by the individual’s reinforcement history, which has a direct impact on the subject’s response to immediate contextual contingencies.

The first of these four reports illustrates this principle of choice behaviour and how it can be constructively utilized in a clinical setting. Here, Hardy and colleagues engage human subjects with varying addiction histories in a task that involves enlarging one of two images that are concurrently presented. The results indicate that choosing to enlarge a drug-related image (people smoking or alcohol), rather than another reinforcement-related image, can be associated with addiction factors in the individual’s history (e.g. dependence severity). It is easy to see the potential value of this deceptively simple choice procedure as a clinical instrument, for example, for objectively measuring the ability of treatment programs to devalue such addiction-related images.

The last three reports in this issue take us back to studies in the animal laboratory. Moore et al. used rats to examine the relationship between impulsive behaviour, as defined by ‘choice’ in a delay discounting task, and binge-like eating in rats, also considered to be an ‘impulsive’ type of behaviour. Perhaps surprisingly, but consistent with a number of previous studies using different methodologies, there was no apparent relationship between the two types of ‘impulsive’ behaviours, which may illustrate how very different biological processes are unfortunately subsumed into the same behavioural category. The next paper by Ferland et al. also concerns maladjusted behaviour, in this case, in relation to understanding decision-making processes in gambling behaviour. As in the study by Katz and colleagues mentioned above, these authors explore the effect of uncertainty on otherwise predictable performance but, here, under complex choice conditions. In a choice between a certain but lower-value reward or a less certain but higher-value reward, most rats respond to a reduction in the value of the riskier option by shifting behaviour toward the less risky option. However, a subgroup did not shift their behaviour when presented with ‘losses disguised as wins’, and this lack of effect could be reproduced by inactivating the basolateral amygdala. Although a great deal of work remains to be carried out to support the idea that this brain region might be involved in compulsive gambling behaviour, this study is an excellent example of how sophisticated behavioural and neurobiological techniques can be powerfully combined into an enticing line of investigation.

The final report in this Special Issue takes us yet further along the path of sophisticated choice procedures to understand the neurobiological control of decision-making processes. Blaes et al. establish a discounting procedure in which responding for the larger reward is risky because, on a probabilistic basis, it is punished. Using selective ligands as pharmacological tools, the authors show that dopamine D2, but not other monoaminergic, mechanisms likely mediate the response to risk in this scenario. The introduction of variable punishment into the experimental conditions is a unique aspect of this fascinating study. This report nicely presages what surely will be increasingly sophisticated laboratory approaches to understanding complex behaviour, that is, cognitive functioning, and thus is a fitting way to conclude this Special Issue.

Jack Bergman

Louk Vanderschuren

Bart Ellenbroek

Paul Willner

November 2018

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