Trends in Neurosciences
Volume 32, Issue 10, October 2009, Pages 517-524
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Opinion
Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction

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Forebrain dopamine circuitry has traditionally been studied by two largely independent specialist groups: students of Parkinson's disease who study the nigrostriatal dopamine system that originates in the substantia nigra (SN), and students of motivation and addiction who study the role of the mesolimbic and mesocortical dopamine systems that originate in the ventral tegmental area (VTA). The anatomical evidence for independent nigrostriatal and mesolimbic dopamine systems has, however, long been obsolete. There is now compelling evidence that both nominal “systems” participate in reward function and addiction. Electrical stimulation of both SN and VTA is rewarding, blockade of glutamatergic or cholinergic input to either SN or VTA attenuates the habit-forming effects of intravenous cocaine, and dopamine in both nigrostriatal and mesocorticolimbic terminal fields participates in the defining property of rewarding events: the reinforcement of memory consolidation. Thus, the similarities between nigrostriatal and mesolimbic dopamine systems can be as important as their differences.

Introduction

The midbrain dopamine neurons that project to the forebrain were initially identified as a single continuous layer [1], arising from a single embryological cell group [2]. However, perhaps because the lateral and medial portions were largely restricted to established brain regions—the dorsal substantia nigra (SN) and the ventral tegmental area of Tsai (VTA)—the lateral and medial portions of this layer were given different labels (A9 and A10, respectively) and eventually became identified with two distinct nominal systems (a nigrostriatal system and a mesolimbic system [3]). The two nominal systems in turn became identified with different functions: the nigrostriatal system—known to degenerate in Parkinson's disease—with motor function, and the mesolimbic system—important for the habit-forming effects of cocaine and for approach behaviors—with motivation and reward function (Box 1). Although the simple dichotomy between a nigrostriatal motor system and a mesolimbic reward and motivational system has had long-lasting influence, it is a misleading dichotomy. The nigrostriatal and mesolimbic dopamine “systems” are not simply differentiated anatomically, and significant functional interactions between the two systems have been recently suggested 4, 5. Here, I discuss the anatomical complications and lines of functional evidence that the substantia nigra dopamine neurons, and not just those of the ventral tegmental area, play a significant role in reward and addiction.

Section snippets

Anatomical complications

As was noted previously [1], there is no clear boundary between the two nominal midbrain dopamine systems (Figure 1). Anterograde and retrograde tracing studies show that the SN and VTA dopamine cells have overlapping, not distinct, projection fields [6]. The discovery of dopamine terminals in prefrontal cortex—initially thought to arise uniquely from the VTA—prompted postulation of a third (mesocortical) or an expanded (mesocorticolimbic) system, but projections to the prefrontal cortex were

Brain stimulation reward

The discovery that rats and humans will learn to work for direct electrical stimulation of certain brain regions (termed “intracranial self-stimulation”), coupled with the observation that humans find such stimulation pleasurable, led to the mapping of reward-related circuitry throughout the brain (Box 2). Rats learn to work for stimulation of dozens of brain sites, many of which are presumably linked in series to form one or more reward-related circuits or subcircuits. The most unambiguous

Intravenous cocaine reward

Early studies of intravenous cocaine self-administration emphasized the ventral striatum (nucleus accumbens) as a substrate of cocaine reward. First, similar to the effects of systemic dopamine receptor blockade, dopamine-specific lesions of the ventral striatum were found to disrupt self-administration of intravenous cocaine and amphetamine. This, of course, did not rule out a similar role for the dorsal striatum; in neither case were dorsal striatal lesions tested for comparison. Small

Reward prediction

If the activation of dopaminergic neurons plays a significant role in reward function, these neurons should be responsive to the presentation of rewarding stimuli. This has been well established by electrophysiological studies; neurons presumed to be dopaminergic by their electrophysiological characteristics are excited by unexpected food rewards [39]. When, after many repeated trials, an animal learns that some distal environmental stimulus reliably predicts the presentation of reward,

Reinforcement and memory consolidation

Investigators interested in the elusive mechanism of the essential feature of reward function—reinforcement—have studied it at both the behavioral and the cellular level. The concept of reinforcement was first and most clearly articulated by Thorndike [as reviewed in 49], who initially described it as the “stamping-in” of associations and subsequently elaborated it as “the aftereffects of a connection upon it.” In his view of reinforcement as strengthening the connections between neurons that

Summary and concluding remarks

Although the present hypothesis is that nigrostriatal and mesolimbic dopamine systems play common roles in reward function, this is not to imply that they are specialized for reward function or that they play a necessary role in reward. Dopamine-deficient mice are still capable of rudimentary learning. Forebrain dopamine release is caused not only by reward stimuli but also by stress and aversive stimuli. Near-total depletions of the forebrain dopamine cause aphagia, adipsia and akinesia; thus,

Acknowledgements

Supported by funding from the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. I thank Yavin Shaham, Stefanie Geisler and Maria Flavia Barbano for constructive comments on an earlier draft of the paper.

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