Translating the neuroscience of alcoholism into clinical treatments: from blocking the buzz to curing the blues

Abstract

Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential.

Figure 1

As the addictive process evolves, the motivational mechanisms that drive alcohol seeking and relapse to excessive alcohol use shift. Initially, alcohol use is largely driven by pleasurable, positively reinforcing alcohol effects. As the alcohol addicted brain develops progressive neuroadaptations, there is a shift toward mechanisms that mediate relief from a negative emotional state that is experienced in the absence of drug. The relative weight of the respective category of motivational mechanisms will depend both on how far into this process an individual is, but also on individual susceptibility factors such as genetic makeup and stress exposure. Depending on these factors, personalized medicine approaches to alcoholism treatment will have to target different mechanisms. While the focus of the present review is on treatments targeting μ-opioid, CRH1 and NK1 receptors, other mechanisms within the respective category are also listed in the figure.