Review
The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse?

https://doi.org/10.1016/j.neubiorev.2005.04.016Get rights and content

Abstract

In this review we will critically assess the hypothesis that the reinforcing effect of virtually all drugs of abuse is primarily dependent on activation of the mesolimbic dopamine system. The focus is on five classes of abused drugs: psychostimulants, opiates, ethanol, cannabinoids and nicotine. For each of these drug classes, the pharmacological and physiological mechanisms underlying the direct or indirect influence on mesolimbic dopamine transmission will be reviewed. Next, we evaluate behavioral pharmacological experiments that specifically assess the influence of activation of the mesolimbic dopamine system on drug reinforcement, with particular emphasis on animal experiments using drug self-administration paradigms. There is overwhelming evidence that all five classes of abused drugs increase dopamine transmission in limbic regions of the brain through interactions with a variety of transporters, ionotropic receptors and metabotropic receptors. Behavioral pharmacological experiments indicate that increased dopamine transmission is clearly both necessary and sufficient to promote psychostimulant reinforcement. For the other four classes of abused substances, self-administration experiments suggest that although increasing mesolimbic dopamine transmission plays an important role in the reinforcing effects of opiates, ethanol, cannabinoids and nicotine, there are also dopamine-independent processes that contribute significantly to the reinforcing effects of these compounds.

Introduction

Drug addiction is a chronically relapsing disorder characterized by compulsion to use one or more drugs of abuse, the inability to control drug intake and continued drug use despite negative consequences (Leshner, 1997, Deroche-Gamonet et al., 2004). Although many factors contribute to drug addiction, drugs of abuse function as reinforcers, which by definition causes repetition of drug taking, a necessary precondition for the neuronal adaptations that constitute addiction. The complex changes in the brain that underlie addiction are just now beginning to be understood and there are many excellent review articles addressing this topic (Koob, 2000, Hyman and Malenka, 2001, Nestler, 2002, Wolf, 2002, Kalivas, 2004, Kauer, 2004, Kelley, 2004, Volkow et al., 2004, Wise, 2004). Here, we focus on the reinforcing effects of five major classes of abused drugs (psychostimulants, opiates, ethanol, cannabinoids and nicotine), which we argue are at least partly due to increased dopamine transmission in limbic regions of the brain. Although these classes of drugs of abuse have different primary sites and mechanisms of action, a greater appreciation of the similarities among the effects of different abused drugs will help to focus research on genetic/physiological predispositions for drug abuse and the development of potential treatment interventions for individuals at high risk of addiction.

Drugs of abuse produce their reinforcing effects through actions in the limbic component of the basal ganglia, a circuit of nuclei that is responsible for the influence of motivational, emotional, contextual and affective and information on behavior (see Fig. 1). Limbic nuclei including the amygdala, hippocampus and medial prefrontal cortex (mPFC) send major glutamatergic projections to the nucleus accumbens, which is subdivided in to limbic and motor subregions known as the shell and core, respectively (Heimer et al., 1997). The nucleus accumbens has two main outputs, which are GABAergic projections to the ventral pallidum and ventral tegmental area (VTA)/substantia nigra. Both the ventral pallidum and VTA send GABAergic efferents to the medial dorsal thalamus. Glutamatergic projections from the medial dorsal thalamus to the mPFC close this limbic circuit (for reviews see Alexander et al., 1990, Pierce and Kalivas, 1997, Kalivas and Nakamura, 1999, Groenewegen and Uylings, 2000, Zahm, 2000, Heimer, 2003). Dopaminergic neurons in the VTA innervate the nucleus accumbens, amygdala, hippocampus, mPFC and ventral pallidum, and changes in dopaminergic transmission play a critical role in modulating the flow of information through the limbic circuit comprising these interconnected nuclei (Napier and Maslowski-Cobuzzi, 1994, Carr et al., 1999, Kalivas and Nakamura, 1999, Wise, 2002, Jay, 2003, Sesack et al., 2003).

The notion that brain dopamine systems play a critical role in drug reinforcement is not new. In fact, the dopamine hypothesis of drug reinforcement dates to the late 1970s (Fibiger, 1978, Wise, 1978). Although a number of caveats have been applied to this hypothesis over the years, an overwhelming body of evidence indicates that dopamine contributes at least partially to the reinforcing effects of many abused drugs (Wise and Bozarth, 1987, Wise, 2004). In the following sections we will review the role of dopamine in the reinforcing effects of five major classes of abused drugs: psychostimulants, opiates, ethanol, cannabinoids and nicotine. There are thousands of research articles focusing on the issue of dopamine and drug reinforcement; therefore, our review will not be comprehensive. The focus of this review is on animal studies utilizing drug self-administration, which is the most homologous model of human drug taking. In self-administration studies, animals are trained to emit an operant response (lever press, nose poke, wheel turn, etc.) in order to obtain a drug reinforcer (typically administered intravenously, but also in preparations that can be eaten, smoked, etc.). In some instances, critical hypotheses have been addressed only using paradigms that assess various effects of abused drugs, such as conditioning to environmental cues (studied with conditioned place preference), subjective effects (drug discrimination), intra-cranial self-stimulation or behavioral hyperactivity, in which case evidence from these paradigms will be presented.

Section snippets

Evidence of abuse in humans

Currently, the most widely abused psychostimulants are cocaine, methamphetamine, and so-called club drugs such as (±)3,4-methylenedioxymethamphetamine (MDMA). In 2002, the number of U.S. citizens over the age of 12 who used cocaine, methamphetamine or MDMA during the previous month was estimated to be 2 million, 597,000 and 676,000, respectively (SAMHSA, 2003). Notably, there has been a particularly dramatic increase in MDMA use in recent years, with new users increasing from 168,000 in 1992 to

Evidence of abuse in humans

The abuse of opiates (morphine-like drugs) remains a significant public health problem. Indeed, since the mid-1990s, the use of heroin increased among both youths and young adults (SAMHSA, 2003). In 2002, there were an estimated 4.4 million regular users of opiates for non-medical purposes in the U.S. and the number of new heroin users reached levels not seen since the late 1970s (SAMHSA, 2003). Although heroin (diacetyl morphine) is the most widely abused opiate, in recent years abuse of

Evidence of abuse in humans

Ethanol is by far the most widely used drug in the world today. In the U.S. the use of ethanol is greater than all other drugs of abuse (including tobacco) combined (SAMHSA, 2003), which undoubtedly is due to the fact that ethanol use is not regulated among adults in this country. Although most ethanol users can be characterized as casual drinkers, the abuse rate of ethanol is substantial. It is estimated that 7.9% of the U.S. population age 12 or older is in need of treatment for alcoholism,

Evidence of abuse in humans

Marijuana, which is derived from the hemp plant Cannabis sativa, is the most commonly used illicit drug (SAMHSA, 2003). In 2002, it was estimated that 14.6 million Americans (or 6.2% of the U.S. population) had used marijuana at least once in the month prior to being surveyed. Approximately one third of these were heavy users, reporting marijuana intake on twenty or more days during the previous month. A similar number (4.29 million) of U.S. citizens were characterized as marijuana abusers (

Evidence of abuse in humans

It is estimated that 71.5 million Americans (or approximately 30% of the U.S. population over age 12) are regular consumers of a tobacco product, including cigarettes, cigars, pipes and smokeless tobacco (SAMHSA, 2003). The risk of addiction, defined as the percentage of people ultimately characterized as addicts among those that have ever tried a specific drug, is particularly high for tobacco relative to all other abused substances (O'Brien, 2001). Although this high addiction risk may be

Summary/conclusions

There is clear evidence that psychostimulants, opiates, ethanol, cannabinoids and nicotine increase dopamine transmission in limbic nuclei, and the nucleus accumbens in particular. Psychostimulants such as amphetamine and cocaine increase extracellular dopamine levels in limbic nuclei by interacting with the dopamine transporter (DAT). Opiates stimulate μ opioid receptors on GABAergic interneurons in the VTA, which disinhinits dopaminergic neuronal activity resulting in increased dopamine

Acknowledgements

The authors thank Ruth Reeves and Sharon Anderson for their input on earlier versions of this manuscript. We also thank Brian Inderwies for assistance creating the figures. The authors were supported by grants from the U.S. National Institutes of Health (RO1 DA15214, RCP; Brown University Center of Biomedical Research Excellence Grant P20 RR1578, VK).

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