A CALL FOR SYSTEMS APPROACHES IN ADDICTION RESEARCH

Authors


In his review about neurobiology and addiction, Harold Kalant comes to an important conclusion: ‘It is inherently impossible to explain addiction by pursuing only the analytical study of drug interactions with the nervous system at ever finer levels of molecular structure and function’[1]. Instead of the classical reductive scientific approach in addiction research, he proposes to take a systems approach for achieving a better understanding of addictive behaviour. Thus, only by studying the interaction of drug effects with the different system levels, i.e. from the genetic to the molecular level, from the synaptic to the neuronal network level, and finally from the behavioural level to its interactions with the environment, will we be able to detangle the multi-dimensional puzzle of addictive behaviour [2,3]. Harold Kalant is most probably right in his conclusion. However, before I deconstruct the classical reductive approach I would like to offer my appreciation to the fascinating research field of neurobiology. Neurobiology is the greatest playground for curious scientists, and the methodological progresses in this field are breathtaking. I would like to give just one example of how advanced neuroscience can be: only recently, optogenetic tools have been introduced to brain research. Optogenetics is an emerging field, combining optical and genetic techniques to probe neural circuits within freely moving laboratory animals, at the millisecond-timescale needed to understand brain information processing [4]. This technique is based on a group of light-sensitive ion channels called channelrhodopsins that can be integrated by genetic engineering into the neuronal cell membrane. By a laser-diode-coupled optical fibre targeting a specific neuronal population of interest, a brief light pulse can then activate those neurones. The Deisseroth laboratory from Stanford University has now applied this fascinating technique to stimulate the reward system and to induce conditioned place preference [5,6]. They introduced the light-sensitive proteins to different parts of the reward system. The animals then underwent a conditioned place preference study [7]. Instead of presenting a drug reward or any other reward, they applied pulses of light to either the ventral tegmental area or the nucleus accumbens via an optical fibre. Thus, whenever the mice moved into the designated location of the conditioning box, the light activated the light-sensitive proteins and switched on the biochemical signalling pathways which would normally be initiated when the animals are given a drug. Remarkably, the optical stimulation was sufficient to replace a drug reward, and as a result the mice spent more time the following day in the location at which the stimulation had been delivered than in other parts of the conditioning box [5,6]. From a technical viewpoint these studies are outstanding, but what have we learned from these studies? Not more, as we have already known from the classical studies by James Olds in the early 1950s. Following electrical stimulation of several brain sites he could also induce a conditioned place preference and thereby discovered the reward system [8]. Hence, in line with the conclusion from Harold Kalant, optogenetic studies are a much finer analysis of the molecular structure and function of the reward system than the initial studies by James Olds, but will not help us to understand why, in some individuals, repeated drug administration leads to an allostatic decrease in reward function [9], and thereby induces a compulsive drug-taking behaviour. Instead, a systems approach might be more helpful to understand the switch to compulsive drug use: a molecular oscillator model has been described where levels of oscillations are changed by repetitive drug administration, leading to set-point adjustments that may underlie allostatic shifts in drug reinforcement processes [2,10]. Although systems approaches in addiction research are still in its infancy, they might eventually be useful for a better understanding of the addicted brain.

Declaration of interest

None.

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