Year: 2017
Type: editorial
Abstract: 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 AUD- and 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) for normalizing these changes as a means to reverse critical behavioral features of AUDs linked to PFC dysfunction, such as loss of control over alcohol seeking. Beyond the molecular changes wrought by abused drugs, how do the effects of these drugs on brain regions such as the PFC and striatum manifest themselves at the microstructural level? Gipson and Olive (2016) consider one of the most widely studied structural correlates of drug effects, and for that matter, other environmental events [e.g. learning and ‘insults’ (e.g. stress) – dendritic spines]. They also offer an excellent overview of the major molecular players regulating spine dynamics and discuss how different types of dendritic spines are quantified and categorized, and the problems with the current means of doing so. One of these players is glutamate, the topic of two complementary reviewers by Hopf (2016) and Morisot and Ron (2016). Of the myriad receptors through which glutamate transmission is mediated, signaling through the N-methyl-d-aspartate (NMDA) receptor has received much attention as a key mediator of drug-induced adaptations in the glutamate system. As Hopf notes, this focus naturally builds from a vast literature documenting the NMDA receptor as a locus for synaptic and behavioral plasticity (e.g. learning), given that drugs of abuse potently affect these same processes. He expertly surveys what we currently understand as the effects of drug exposure on NMDA receptors (particularly those containing the GluN2B subunit) and the consequences of genetically or pharmacologically modulating them for behaviors relevant to AUDs and other SUDs. This discussion is extended by Morisot and Ron, who delve into the molecular pathways downstream of the GluN2B-containing NMDA receptor that act as plausible substrates for the deleterious behavioral effects of alcohol. For example, the authors contend that Fyn tyrosine kinase and mammalian target of rapamycin complex 1 are co-opted by chronic alcohol to modify NMDA receptor function in regions such as the dorsal striatum to generate alterations in alcohol seeking. They then posit the corollary question of whether targeting some of these NMDA receptor interacting molecules might reverse some of the adverse consequences of alcohol. Inhibitory gamma-aminobutyric acid (GABA)ergic neurotransmission is Yin to the excitatory glutamatergic Yang of brain signaling. Like glutamate and the NMDA receptor, the GABA system is highly sensitive to alcohol and other drugs of abuse, as discussed in a comprehensive review by Stephens et al. (2016). The authors introduce a preclinical literature that has aimed to dissect the relative functional roles of GABAA receptors with differing subunit compositions and relate this to work in humans that identifies a significant genetic association between various subunits (e.g. GABRA2 and GABRB1) and AUDs and other SUDs. Illustrating the strength of translational research in this field, the authors go on to expertly bring the discussion back to evidence from rodent quantitative trait loci, mutant and drug exposure studies that firmly place the GABAA receptor as a key orchestrator within neural circuitry of addiction and another possible target for new medications. What are the factors that will ultimately determine the success of new drugs brought to the clinic to treat AUDs and SUDs? Khoo et al. (2016) draw attention to the critical influence played by contextual information in modulating the likelihood of drug relapse. At the heart of this issue is a phenomenon in which drug seeking that is ostensibly lost after extinction readily ‘renews’ when probed in a context different from that where extinction took place. Drawing on elegant studies from their own group and others, Khoo et al. delineate the neural circuits known to underlie context-induced reinstatement and raise the prospect of one day leveraging this knowledge base to clinical practice (e.g. via deep brain stimulation). In the more immediate term, existing therapies, such as those that seek to help patients establish more adaptive patterns of thinking and behaving around drugs, remain the best hope for patients. Perry and Lawrence (2016) espouse the compelling case for the centrality of cognitive deficits (inflexibility, inattention and poor impulse control) in addictions and propose the use of pharmacological adjuncts to cognitive behavioral therapies to more effectively correct these deficits. They catalogue some of the drugs that have potential promise in this regard – from mGluR5 metabotropic glutamate receptor allosteric modulators to psychostimulants such as methylphenidate – and also the non-drug interventions including brain stimulation and even exercise. As a collective, these 12 articles offer an excellent introduction to drug addiction research for the general reader, as well as a timely update on the current state of the field for those working in this area. The authors have provided an outstanding resource for the journal's readers.
Source: Genes Brain & Behavior
DOI: 10.1111/gbb.12359
Author: Andrew Holmes
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2578724798