Opening New Vistas in Basic and Preclinical Addiction Research

A Retrospective View on the Hallmarks of Neurobiological Alcohol and Drug Abuse Research

What were the major achievements in the past in neurobiologically oriented alcohol and drug abuse research? This can only be answered by a very personal view. I would like to illustrate this in terms of the hallmarks of alcohol research. In 1940, Curt Paul Richter reported that laboratory rats voluntarily consume alcohol, although with high individual variability. This discovery marked the beginning of animal research in the study of alcohol. Furthermore, this observed variability in alcohol intake provided the basis for the generation of alcohol-preferring and nonpreferring rat and mouse lines, eight of which have been genetically selected since 1960. Thousands of studies on alcohol drinking in rodents have been conducted subsequently, permitting the deciphering of the genetic and neurochemical basis of alcohol reinforcement. Studies of alcohol self-administration in laboratory animals remain crucial to the development of medication in the field of alcohol research, and the predictive value of these models is demonstrated by the fact that all available pharmacotherapies (e.g., naltrexone and acamprosate) have been based on animal work of this nature. The same is true for any other drug of abuse—without appropriate animal models only little progress would have been made in the field of addiction research. In fact, most of the animal models (e.g., intravenous self-administration of heroin and cocaine) provide excellent face and construct validity.

In terms of construct validity, the discovery of the brain reinforcement system by James Olds in 1954 —one of the outstanding experimental psychologists of the last century—ultimately provided the key to understanding the neuroanatomical correlates underlying alcohol and drug reinforcement. Again, knowledge derived from animal work on the neuroanatomical and functional aspects of alcohol and drug reinforcement has been systematically translated to humans by means of neuroimaging techniques.

The foundation for understanding the neurochemical substrates of alcohol and drug reward was laid by the three research teams in 1973 responsible for identifying the first opioid receptors. In the hunt for the endogenous ligands, John Hughes and Hans Kosterlitz then identified the first opioids in the brain only 2 years later, and called them enkephalins. However, it took almost two decades until the molecular cloning of the first opioid receptors was achieved. These studies not only promoted opioid research in general, but also represented key discoveries for subsequent alcohol and drug abuse research. Similarly, the isolation of Δ ⁹ -tetrahydrocannabinol in 1964 by the group of Ralph Mechoulam marked the beginning of cannabinoid research. The brain targets of tetrahydrocannabinol remained unidentified until 1988, when a seminal paper by the group of Allyn Howlet identified a G-protein–coupled receptor as the target of natural cannabinoids. It was followed immediately by the molecular cloning of the cannabinoid receptor 1 ⁶⁰ and by the identification of the first endogenous ligand of the cannabinoid receptor, an arachidonic acid derivative termed anandamide. These key discoveries led to one of the most active fields of research in neurobiology. But the real surprise came from the discovery of the role of the endocannabinoid system in reward processes and in the neurobiology of addictive behavior. Both the endocannabinoids and the cannabinoid receptor appear to be crucial in opioid, alcohol, psychostimulant, and nicotine addiction and it can be foreseen that within the next 10 years we will have effective treatments on the market targeting various components of the endocannabinoid system.

In addition to endocannabinoids, endogenous opioid systems are thought to induce the pleasurable and rewarding effects of alcohol and other drugs of abuse, and thereby constitute ideal targets for treatment. The first description of opioid receptor blockade by means of naltrexone, and the resultant reduction of voluntary alcohol consumption in rats marked the starting point of the development of relapse medication in alcohol research. A decade later, the first reports on the clinical efficacy of naltrexone in alcohol-dependent individuals were published and a recent meta-analysis of 24 randomized controlled trials that included a total of 2861 subjects demonstrates that naltrexone decreased the relative risk of relapse compared to placebo by a significant 36%. A further milestone in medication development was the finding that a functional polymorphism of the μ-opioid receptor gene may predict response to naltrexone. Although this finding has been replicated recently, no final judgement on this pharmacogenetic discovery will be possible for several years. Nevertheless given that our century is dominated by the belief that personalized medicine will power further biomedical developments, the study of Oslin et al. has already marked this shift in paradigms. Despite the promise of pharmacogenetics to identify treatment responders, there have so far been very few success stories in all of medicine.

New Vistas in Neurobiological Alcohol and Drug Abuse Research

Addictive behavior is the result of cumulative responses to drug exposure, the genetic make-up of an individual, and the environmental perturbations over time. This very complex drug × gene × environment interaction, which has to be seen in a lifespan perspective, cannot be studied by a reductionistic approach. Instead, a systems-oriented perspective in which the interactions and dynamics of all endogenous and environmental factors involved are centrally integrated, will lead to further progress in alcohol and drug abuse research. My future perspective adheres to a systems biology approach such that the interaction of a drug with primary targets within the brain is fundamental to an understanding of the behavioral consequences. As a result of the interaction of a drug with these targets, alterations in gene expression and synaptic plasticity take place that either function as protective mechanisms or lead to long-lasting alteration in neuronal network activity. As a subsequent consequence, drug-seeking responses ensue that can finally lead via complex environmental interactions to an addictive behavior ( Fig. 74.1 ). This systems biology approach opens up new vistas in addiction research on the genetic (see Section “New Vistas on the Genetic Level”), molecular (see Section “New Vistas on the Molecular Level”), synaptic (see Section “New Vistas in Alcohol- and Drug-Induced Synaptic Plasticity”), neuronal network (see Section “New Vistas on Neuronal Network Activity”), and finally on the behavioral level (see Section “New Vistas on Studying Alcohol- and Drug-Related Behaviors”).

New Vistas on the Genetic Level