Associate editor: D. Lovinger
The role of mesolimbic dopamine in the development and maintenance of ethanol reinforcement

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Abstract

The neurobiological processes by which ethanol seeking and consumption are established and maintained are thought to involve areas of the brain that mediate motivated behavior, such as the mesolimbic dopamine system. The mesolimbic dopamine system is comprised of cells that originate in the ventral tegmental area (VTA) and project to several forebrain regions, including a prominent terminal area, the nucleus accumbens (NAcc). The NAcc has been subdivided into core and shell subregions. Both areas receive converging excitatory input from the cortex and amygdala and dopamine input from the VTA, with the accumbal medium spiny neuron situated to integrate the signals. Although forced ethanol administration enhances dopamine activity in the NAcc, conclusions regarding the role of mesolimbic dopamine in ethanol reinforcement cannot be made from these experiments. Behavioral experiments consistently show that pharmacological manipulations of the dopamine transmission in the NAcc alter responding for ethanol, although ethanol reinforcement is maintained after lesions of the accumbal dopamine system. Additionally, extracellular dopamine increases in the NAcc during operant self-administration of ethanol, which is consistent with a role of dopamine in ethanol reinforcement. Behavioral studies that distinguish appetitive responding from ethanol consumption show that dopamine is important in ethanol-seeking behavior, whereas neurochemical studies suggest that accumbal dopamine is also important during ethanol consumption before pharmacological effects occur. Cellular studies suggest that ethanol alters synaptic plasticity in the mesolimbic system, possibly through dopaminergic mechanisms, and this may underlie the development of ethanol reinforcement. Thus, anatomical, pharmacological, neurochemical, cellular, and behavioral studies are more clearly defining the role of mesolimbic dopamine in ethanol reinforcement.

Introduction

Alcoholism is a chronic, relapsing disease that is characterized by the presence of a specific group of behaviors (McLellan et al., 2000, Koob, 2003, Watkins et al., 2003). Given that this disorder is behavioral in nature, it follows that the etiology of this highly destructive syndrome involves brain dysfunction. Hence, the search for neural substrates that mediate this drastic behavior has been a primary focus in modern alcoholism and drug abuse research. In particular, the brain systems that govern motivation are thought to be disrupted in a specific way such that the individual loses control over consumption of ethanol. The loss of control over drug seeking and drug taking is a hallmark of addiction to a variety of drugs of abuse, and there are likely to be similarities and overlapping mechanisms in how the brain has been affected in alcoholism compared with other addicting drugs such as cocaine and heroin. The effect of any drug on brain function is ultimately due to the molecular interactions between the drug and target molecules that reside on neurons or other cells that influence neuronal function. However, the molecular and cellular effects of drugs are eventually integrated into actions on neuronal circuits that make up systems that are responsible for overt behaviors. Thus, an understanding of how ethanol produces the disease of alcoholism requires knowledge of how ethanol affects particular molecular, cellular, and system level functions. This review will focus on one particular system in the brain that is thought to play an important role in the overwhelming compulsion to seek and consume ethanol—the mesolimbic dopamine system. At the outset, it should be stated emphatically that focusing this review on the mesolimbic dopamine system is not meant to imply that this system is the only or the most important system that contributes to ethanol reinforcement. Compelling evidence is available for the role of other neurotransmitter systems (Roberts et al., 1996, Thiele et al., 1998, Melendez et al., 2003). However, new evidence continues to implicate the mesolimbic dopamine system as a key player in the development of ethanol reinforcement.

One of the major common effects of most drugs of abuse, including ethanol, is an enhancement of activity in the mesolimbic dopamine system, which leads to an increase in extracellular dopamine concentrations in target areas (Imperato & Di Chiara, 1986, Weiss et al., 1993, Doyon et al., 2003b). This is significant because the mesolimbic dopamine system is thought to be a critical substrate for the control of motivated and goal-directed behavior (Horvitz, 2000). Therefore, action of drugs of abuse on the mesolimbic dopamine system may be a common pathway that contributes to the compulsive drug-seeking and drug-taking behavior of drug addiction. Although it is clear that most addictive drugs produce an increase in mesolimbic dopamine release (Wise & Rompre, 1989), the precise mechanisms that lead to an increase in extracellular dopamine vary according to the molecular targets upon which each specific drug acts. For drugs like heroin, cocaine, and amphetamine, the molecular targets that mediate the enhancement of dopamine activity are well established, and the overall mechanisms by which these drugs alter extracellular dopamine concentrations are understood (Johnson & North, 1992, Giros et al., 1996). However, the exact molecular and cellular mechanisms through which ethanol alters the mesolimbic dopamine system are still not entirely clear. Furthermore, the precise role that dopamine plays in goal-directed behavior in general is still debated (Di Chiara, 1999, Horvitz, 2000, Schultz, 2000, Robinson & Berridge, 2001, Joseph et al., 2003, Salamone et al., 2003). This clearly limits our understanding of how ethanol-induced changes in mesolimbic dopamine lead to changes in a complex behavior such as compulsive ethanol ingestion. Moreover, the specific mechanisms that mediate the switch from controlled ethanol consumption to uncontrolled and compulsive ethanol ingestion that is seen in alcoholism are unknown. Presumably, this switch involves changes in gene expression, which lead to long lasting changes in neural pathways and systems that impact the motivation to seek and consume ethanol. Recent work suggests that ethanol promotes mechanisms that are known to alter synaptic communication between neurons in the mesolimbic dopamine system, and these mechanisms may contribute to the long lasting changes in ethanol-seeking behavior that occur in alcoholism (Maldve et al., 2002).

The overall viewpoint of the present review is that initiation of molecular and cellular events by ethanol leads to long lasting changes in the mesolimbic dopamine system. In turn, these changes in the mesolimbic system lead to enhancement of ethanol seeking and consumption. Initially, current views of how mesolimbic dopamine activity influences motivated and goal-directed behavior in general will be addressed. This will be followed by a critical discussion of various models of ethanol-seeking and -consuming behavior. The integration of these behavioral models with concomitant measures of neurochemical activity in behaving animals will then be addressed. Finally, the data will be interpreted in the context of how mesolimbic dopamine may participate in the initial stages of plasticity in the brain systems that mediate ethanol seeking and consuming behavior.

Section snippets

Anatomy of the mesolimbic dopamine system

The anatomy of the mesolimbic dopamine system has been studied intensively over the last few decades, and much progress has been made in defining the various cells that comprise the system and their connectivity with other brain areas. However, it is also still clear that much work remains to be done to understand the complexity of this system. The following brief description is limited in scope and focused on the major cellular elements. More detailed descriptions of the anatomy of this

Behavioral pharmacology of ethanol reinforcement with operant procedures

A rigorous assessment of the role of mesolimbic dopamine in ethanol reinforcement requires a behavioral model in which reinforcement can be reliably measured. Reinforcement is defined operationally as an increase in the probability or frequency of a particular behavior (the operant) upon presentation of a given stimulus or response (Skinner, 1938). In general, reinforcement can be considered as positive or negative. Positive reinforcement refers to an increase in the probability of a behavior

Approaches for relating extracellular dopamine activity to behavior

The behavioral pharmacology approach has been very informative for elucidating dopaminergic mechanisms that underlie ethanol reinforcement. However, there are serious limitations to the interpretation of pharmacological studies. Systemic administration of drugs does not allow conclusions to be made regarding central actions or sites of action within the central nervous system. Microinjection studies help to narrow down the site of action, but diffusion of the drug away from the intended target

Ethanol-induced plasticity in the mesolimbic system

Both environmental and genetic factors are known to influence ethanol drinking behavior (Crabbe et al., 1999), and presumably, the reinforcing effects of ethanol. The fact that an animal that has never been exposed to ethanol will eventually perform work to acquire ethanol in pharmacologically relevant doses shows that exposure to ethanol itself is an important environmental variable that is necessary for the development of reinforcement. Hence, repeated ethanol exposure produces

Summary and conclusions

The neurobiological mechanisms that underlie the propensity to drink ethanol, and the loss of control over ethanol drinking, are not understood in detail. However, a variety of experimental approaches are providing important clues to these processes. The focus of this review has been on mesolimbic dopamine, but it should be restated that this system does not work in isolation. Clearly, other brain areas and neurochemical systems interact with dopamine, or directly mediate various aspects of

Acknowledgments

The authors thank the technicians, graduate, and undergraduate students who have provided outstanding technical assistance in carrying out the studies from our laboratory. Discussions with Dr. Richard Morrisett are also acknowledged. Financial support was provided by NIAAA (AA11852, AA13486, AA07471), the Texas Commission on Alcohol and Drug Abuse, and The Waggoner Center on Alcohol and Addiction Research.

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