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Department of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
Alcohol consumption is an integral part of daily life in many societies. The benefits associated with the production, sale, and use of alcoholic beverages come at an enormous cost to these societies. The World Health Organization ranks alcohol as one of the primary causes of the global burden of disease in industrialized countries. Alcohol-related diseases, especially alcoholism, are the result of cumulative responses to alcohol exposure, the genetic make-up of an individual, and the environmental perturbations over time. This complex gene x environment interaction, which has to be seen in a life-span perspective, leads to a large heterogeneity among alcohol-dependent patients, in terms of both the symptom dimensions and the severity of this disorder. Therefore, a reductionistic approach is not very practical if a better understanding of the pathological processes leading to an addictive behavior is to be achieved. 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 research. This review adheres to a systems biology perspective such that the interaction of alcohol with primary and secondary targets within the brain is described in relation to the behavioral consequences. As a result of the interaction of alcohol with these targets, alterations in gene expression and synaptic plasticity take place that lead to long-lasting alteration in neuronal network activity. As a subsequent consequence, alcohol-seeking responses ensue that can finally lead via complex environmental interactions to an addictive behavior.
2 Note that the term dependence is avoided in this review. Addiction is a pathological behavioral syndrome that has to be strictly separated from physical dependence. Transient neuroadaptive processes underlie physical dependence to alcohol, whereas persistent changes within specific neuronal systems underlie addictive behavior. To avoid any confusion between clinicians, psychologists, and preclinicians, the term dependence should refer to a state of physical dependence.
3 For historical reasons, blood alcohol concentrations are calculated as g/kg blood plasma given in percent. Since the specific weight of plasma is 1.23, a BAL of 500 mg/dl corresponds to 4.06
.
4 For reference, a low intoxicating BAL of 50 mg/dl is equivalent to an ethanol concentration of 10.6 mM.
5 N265M: the in vivo action of general anesthetics is strongly attenuated by this point mutation (227).
6 Various alcohol-preferring and nonpreferring rat lines have been developed within the last 50 yr. Depending on the line, preferring rats consume 5–9 g·kg–1·day–1 ethanol, whereas the nonpreferring lines consume less than 1 g·kg–1·day–1. These lines are very powerful animal models in the study of the neurochemical substrates of alcohol reinforcement. A comprehensive overview of the different lines has recently been reported (31, 83, 93, 382, 354, 454).
7 In addition, a functional cross-talk between the endocannabinoid and opioid systems has been found in the mutual modulation of drug/alcohol reinforcement and reward processes (143, 401).
8 Differences in gene expression can arise from cis-regulatory changes that affect transcription initiation, transcription rate, and/or transcript stability in an allele-specific manner, or from trans-regulatory changes that modify the activity or expression of factors that interact with cis-regulatory sequences.
9 Type II people tend to become alcohol dependent at an early age and have a high family risk of alcoholism, more severe symptoms, and a negative perspective of life (59).
10 A four-bottle paradigm has the advantage of overcoming initial preference problems. Rats usually prefer lower concentrated alcohol solutions (<6%) over higher concentrated alcohol solutions. Following a period of taste adaptation, a shift towards preference for higher concentrated alcohol solutions is observed. Furthermore, individual sensitivities and preferences to alcohol solutions are usually observed. The free choice presentation of various concentrated alcohol solutions bypasses the problem of individual preferences; in this model a rat is allowed to drink what it likes most. Indeed, in a four-bottle paradigm, high alcohol intake and preference in common stock rats are observed during the acquisition of alcohol drinking behavior in male (444) as well as in female rats (147). In conclusion, a four-bottle paradigm results in a higher daily alcohol intake and preference compared with a two-bottle choice paradigm with a fixed alcohol concentration of 10% which has been used in most of the studies on alcohol drinking behavior in the rat performed to date.
11 Overall, female rats in our studies consume greater amounts of alcohol than male rats (147). This is in accordance with previous studies reporting that there is a sex difference in ethanol ingestion (7, 258) and that female rats consume significantly greater amounts of alcohol. Such a sex difference is also seen in other species such as mice and monkeys (25, 362). At first glance, this appears to be in stark contrast to observations in humans, since epidemiological and clinical studies demonstrate that women consume less alcohol than men. However, we have recently reported that if alcohol intake in humans were to be calculated on a g/kg basis instead of the number of drinks consumed, consumption in females would be much the same or even more compared with that in males (239). Contrasting sex differences in humans and animals are mainly related to social barriers in different populations and to an artifact in calculating exact alcohol intake. The reasons for sex differences in alcohol consumption are still poorly understood. However, it is obvious that intrinsic sex differences in brain organization and the actions of circulating gonadal steroids may contribute to the enhanced voluntary alcohol intake observed in female animals (7).
12 In the large-scale study COMBINE (11), over 1,300 patients were treated with either naltrexone or placebo. While half the patients received a low-dose standard supportive therapy (Medical Management), the other half received a more intensive psychotherapy, i.e., cognitive-behavioral intervention (CBI). All groups showed a substantial reduction in drinking. During treatment, those patients receiving naltrexone plus medical management, CBI plus medical management and placebo, or both naltrexone and CBI plus medical management had a higher percentage of abstinent days than the group receiving placebo and medical management only, which is indicative of a significant naltrexone x behavioral intervention interaction.
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