Drug addictions: new insight into causes, comorbidity and potential treatments

Drug addictions are serious medical conditions that have genetic and neurobiological correlates that remain elusive, but which are a subject of intense investigation. This issue of G2BREVIEWS presents a dozen articles on the latest breakthroughs in drug addiction from some of the leaders in the field. One of the particularly problematic features of addictions is that they are very often comorbid with other disorders. Two reviews consider the striking epidemiological link between the incidence of alcohol-use disorders (AUDs) and disturbances in mood and affect. Holleran and Winder (2016) discuss current efforts to model changes in anxiety-like and depression-related behaviors in rodents with a history of either forced or voluntary ethanol consumption. They point to promising recent data showing that increases in depression-related indices can be observed in mice after even relatively mild ethanol exposure regimens, which can be ameliorated by clinically tractable pharmacological treatments such as ketamine. Gilpin and Weiner (2016) discuss possible neurobiological bases for the frequent co-occurrence of AUDs and posttraumatic stress disorder (PTSD). They discuss studies of human patients identifying potential neural abnormalities, including stress signaling pathways and corticolimbic and mesolimbic circuits, which represent plausible convergent pathophysiological substrates for PTSD and AUDs, and potential loci to target novel therapeutic approaches. The authors then survey the salient rodent literature that attempt to model escalations in alcohol drinking caused by exposure to stressors ranging from forced swimming to social isolation, highlighting what should be the main goals of future work. Human addictions are not limited to alcohol and other drugs of abuse; across species, strong preferences can develop to a wide variety of rewarding stimuli. Golden et al. (2016) describe a remarkable phenomenon of how a subset of sexually experienced CD-1 mice exhibit persistent preference for places in which they had previously been able to engage in aggression towards a submissive C57BL/6J intruder. They go on to discuss some of the possible neural mechanisms involved and set the stage for exploring these in future work by generating CD-1×C57BL/6J F1 hybrid transgenic Cre mice that will allow for genetic access to dopamine D1 and D2 receptors. The dopamine system represents a particularly interesting mechanism based on a compelling literature implicating D2 receptor abnormalities in substance-use disorders (SUDs) that is authoritatively reviewed in this issue by Dobbs et al. (2016). More specifically, they relay correlative evidence, from human, non-human primate and rodent subjects, that low striatal D2 receptor availability is a risk factor for psychostimulant addiction, and discuss findings from rodents that begin to establish a causal link between reduced D2 receptor function, altered intra-striatal neuronal connectivity and attendant shifts in behavioral responses to psychostimulants, as well as other AUDand SUD-relevant traits. The question about the role of striatum in addiction is also taken up by Gremel and Lovinger (2016). An issue emphasized by these authors is that both acute and chronic exposures to most drugs of abuse affect dopaminergic activity and associated plasticity not only in the nucleus accumbens, as has been historically emphasized, but also in the more dorsal compartment of the striatum. They bring into focus emerging evidence that drug-induced changes in the dorsal striatum promote processes (e.g. habitual reward seeking) that favor addiction-like patterns of behavior. Another major ‘regional player’ in SUDs and AUDs is the (medial) prefrontal cortex (PFC) – the focus of a review by Heilig et al. (2016). These authors give an excellent overview of this topic. Their main concern here, however, is the broad suite of lasting transcriptional, microRNA and epigenetic changes (the ‘PFC transcriptome’) that are produced by dependence-inducing exposure to alcohol and innovative strategies and molecular candidates (e.g. mGluR2 and BDNF )