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Novel techniques for the study of drugs and behaviour

doi: 10.1097/FBP.0000000000000367

Special Issues are a particular feature of Behavioural Pharmacology: every year since Volume 1 in 1990 has seen the publication of at least one Special Issue. The aim of this Special Issue on ‘Novel Techniques for the Study of Drugs and Behaviour’ was to provide a showcase for recent technical advances in areas such as gene editing, optogenetics, neuroimaging and others that provide novel opportunities for neuroscience. It will not disappoint: all these techniques and more are represented, in three reviews and six empirical papers. Just as happened when genetically modified animals appeared on the scene 25 years ago, these techniques, collectively, are likely to radically change the way in which behavioural pharmacologists work.

The first review paper, by Zelena and colleagues, provides a methodological treatise on optogenetics, a technique in which genes for light-sensitive proteins are introduced into the brain and light signals are used to control the activity of the cells in which the genes are expressed. Optogenetics was awarded the title of ‘Method of the Year’ by Nature Neuroscience in 2010. At that time this was a new technique, with fewer than a hundred publications overall, but it has exploded in popularity and now sees some 5–600 publications a year. The review by Zelena and colleagues summarizes the technical considerations governing the choice of vector (typically an adeno-associated virus) and light-sensitive channel, the pattern, intensity and timing of the stimulation protocol, and, where genetically modified animals are used, the choice of mutant strain. We anticipate that this review will come to be seen as essential reading for anyone using or planning to use optogenetic techniques.

The second review paper, by Maltbie and colleagues, considers the use of functional MRI studies to understand the pharmacology of ketamine, which has long been used as a pharmacological model for schizophrenia, but more recently has emerged as a potential treatment for treatment-resistant depression and suicidal ideation. The review focuses on a systems-level approach showing that ketamine produces robust and consistent effects at the whole-brain level that are conserved across humans and nonhuman primates. The authors argue, based on functional MRI evidence, that the therapeutic potential of ketamine may be derived from a strengthening of executive control circuitry, making it an intriguing candidate for the treatment of drug abuse in addition to its other therapeutic applications.

A third review, by Kangas and Bergman, presents an overview of touchscreen technology in the study of cognition-related behaviour. Touchscreen technology was introduced for human experimentation some 25 years ago and later extended to nonhuman primates and rodents. A recent development, reviewed here, is the availability of flexible experimental designs under the control of the experimenter. The authors provide a primer on the construction of a touch-sensitive experimental chamber, and present data from a proof-of-concept study examining cross-species continuity in performance of a repeated acquisition task across a diverse assortment of animals (rats, marmosets, squirrel monkeys, rhesus macaques). The results illustrate how contemporary touchscreen methodology can be tailored to desired experimental goals and adapted to provide formal similarity in cognitive tasks across species, with high translational potential.

The first two empirical papers present studies using gene-editing techniques. Woloszynowska-Fraser and colleagues used a Cre-recombinase-dependent adeno-associated virus to block neural transmission specifically in parvalbumin-positive GABAergic neurons of the limbic and infralimbic prefrontal circuitry. These cells are critical for the control of network activity, particularly the gamma-frequency oscillations that are prominent during working memory, and are thought to be dysfunctional in schizophrenia. The modified animals presented with increased anxiety and impaired working memory, as well as a lack of behaviourally relevant modulation of gamma oscillations, comparable to endophenotypes of schizophrenia. The second paper, by Bates and colleagues used DREADDS (designer receptors exclusively activated by designer drugs) to artificially increase or decrease the activity of peripheral dorsal root ganglia sensory neurons expressing the G-protein coupled receptor MRGPRB4. These neurons have been shown to specifically detect the sensation of massage-like stroking resulting from social grooming, which is an important affiliative social behaviour in the rodent. Blockade of this neural activity in socially housed animals increased morphine withdrawal signs, therefore, demonstrating a protective effect of social grooming on the development of morphine dependence.

The next two empirical papers explore the potential of novel techniques for recording brain activity. Shnitko and colleagues used fast-scan cyclic voltammetry to study maternal behaviour in rats, specifically, the role of dopamine transients in the nucleus accumbens in the early postpartum period. The results showed that dopamine release was larger, and clearance faster, in postpartum than in virgin females; that this effect was blocked by gestational exposure to cocaine; and that the effect of cocaine may be mediated by a difference in pup-produced olfactory stimuli between naive and cocaine-exposed infants. In the second paper, Nirogi and colleagues report on an innovative study in which they monitored cortical and hippocampal electroencephalogram (EEG) telemetrically in rats simultaneously performing behavioural tasks. In two experiments, they examined the effects of scopolamine and donepezil during performance of a novel object recognition task, and the effect of amphetamine on behaviour in an open field. Although not finding perfect behaviour-EEG correlations, they were able to identify a number of EEG characteristics that were closely related to the behavioural changes.

The final two papers report studies using novel modes of drug administration. 6-Hydroxy-dopamine (6-OHDA) has long been used to model Parkinson’s disease, typically using unilateral intracranial injection to rats and using circling behaviour to evaluate drug effects. However, in marmosets, a primate model potentially of a greater translational value, unilateral 6-OHDA administration does not cause drug-elicited circling. Therefore, Ando and colleagues examined whether administering 6-OHDA bilaterally to marmosets might be more viable. The effects of methamphetamine and L-dopa were as predicted, supporting the potential value of this novel primate model. In the final paper, Noroozi and colleagues present a study of the therapeutic potential of the natural product curcumin, extracted from the ginger plant, on opiate addiction, using a morphine self-administration model. The novel feature of this study is that curcumin was encapsulated in dendrosomal nanoparticles for more sustained and efficient drug delivery. Their results showed that dendrosomal nanocurcumin substantially suppressed morphine intake without, however, reversing morphine-induced damage to the CA1 area of the hippocampus.

These papers span a range of exciting and innovative techniques, ranging from neural manipulation to neuroimaging, genetic modification to automated analysis of behaviour. In addition, they address a diversity of themes, including schizophrenia, cognition, addiction and neurodegeneration, as well as some papers that deal primarily with important technical issues. The Special Issue succeeds in its objective of showcasing the breadth and scope of methodological advances; we hope that the papers selected for inclusion will be widely read and widely cited.

Undoubtedly, technical developments such as those presented here improve our ability to conduct research in behavioural pharmacology and in behavioural neuroscience more generally. The questions that can be addressed, the flexibility in experimental design and the fine-grained analysis of changes in behaviour and brain all move our understanding forward. As always, however, good science advances not simply by using powerful techniques but by employing them in research that is thoughtful and rigorous in its design and conduct. The value of such remarkable improvements in our research toolbox depends ultimately upon our ability to harness them to open up and develop exciting and fruitful lines of behavioural pharmacology research.

Paul Willner

Jack Bergman

Louk Vanderschuren

Bart Ellenbroek

October 2017

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