Trends in Neurosciences
OpinionRoles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction
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.
References (94)
- et al.
What is the amygdala?
Trends Neurosci.
(1998) - et al.
Pimozide and amphetamine have opposing effects on the reward summation function
Pharmacol. Biochem. Behav.
(1984) A map of the rat mesencephalon for electrical self-stimulation
Brain Res.
(1972)- et al.
Intracranial self-stimulation in relation to the ascending dopaminergic systems of the midbrain: a moveable electrode mapping study
Brain Res.
(1980) Intracranial self-stimulation: mapping against the lateral boundaries of the dopaminergic cells of the substantia nigra
Brain Res.
(1981)Brain stimulation reward and dopamine terminal fields. II. Septal and cortical projections
Brain Res.
(1984)- et al.
Brain stimulation reward and dopamine terminal fields. I. Caudate- putamen, nucleus accumbens and amygdala
Brain Res.
(1984) D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat
Pharmacol. Biochem. Behav.
(1993)- et al.
Dopaminergic antagonism within the nucleus accumbens or the amygdala produces differential effects on intravenous cocaine self-administration under fixed and progressive ratio schedules of reinforcement
Brain Res.
(1993) Midbrain dopaminergic neurons in the mouse that contain calbindin-D28k exhibit reduced vulnerability to MPTP-induced neurodegeneration
Neurodegeneration
(1996)
Effect of noxious tail pinch on the discharge rate of mesocortical and mesolimbic dopamine neurons: selective activation of the mesocortical system
Brain Res.
Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system
Neuron
Contingent and non-contingent actions of sucrose and saccharin reinforcers: effects on taste preference and memory
Physiol. Behav.
Post-trial reinforcing hypothalamic stimulation can facilitate avoidance learning
Neurosci. Lett.
Memory facilitation by self-stimulation reinforcement mediated by nigrostriatal bundle
Physiol. Behav.
Dopaminergic antagonists prevent long-term maintenance of posttetanic LTP in the CA1 region of rat hippocampal slices
Brain Res.
The effect of dopaminergic D1 receptor blockade during tetanization on the expression of long-term potentiation in the rat CA1 region in vitro
Neurosci. Lett.
Different molecular cascades in different sites of the brain control memory consolidation
Trends Neurosci.
Synaptic plasticity in the basal ganglia
Behav. Brain Res.
Reward or reinforcement: what's the difference?
Neurosci. Biobehav. Rev.
Parsing reward
Trends Neurosci.
Mesolimbocortical and nigrostriatal dopamine responses to salient non-rewards
Neuroscieince
Evidence for the existence of monoamine-containing neurons in the central nervous system
Acta Physiol. Scand.
Late prenatal ontogeny of central monoamine neurons in the rat: flourescence histochemical observations
Z. Anat. Entwicklungsgesch.
Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum
J. Neurosci.
Neural systems of reinforcement for drug addiction: from actions to habits to compulsion
Nat. Neurosci.
Substantia nigra
Topographic organization of ascending dopaminergic projections
Ann. N. Y. Acad. Sci.
The neostriatal mosaic: II. Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems
J. Neurosci.
The corticotropin releasing factor binding protein (CRF-BP) within the ventral tegmental area is expressed in a subset of dopaminergic neurons
J. Comp. Neurol.
The basal ganglia
Brain dopamine and reward
Ann. Rev. Psychol.
Dopamine, learning and motivation
Nat. Rev. Neurosci.
The cells and axons mediating medial forebrain bundle reward
Brainstem pathways of reward
J. Comp. Physiol. Psychol.
Changes in morphine self-administration and morphine dependence after lesions of the caudate nucleus in rats
Psychopharmacologia
Self-administration of cocaine on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pretreatment
Psychopharmacology (Berl.)
Effects of the dopamine D-1 antagonist SCH 23390 microinjected into the accumbens, amygdala or striatum on cocaine self-administration in the rat
Brain Res.
Involvement of the dorsal striatum in cue-controlled cocaine seeking
J. Neurosci.
Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats
J. Neurosci.
Blockade of D1 dopamine receptors in the ventral tegmental area decreases cocaine reward: possible role for dendritically released dopamine
J. Neurosci.
D1 receptors modulate glutamate transmission in the ventral tegmental area
J. Neurosci.
A role for conditioned ventral tegmental glutamate release in cocaine-seeking
J. Neurosci.
Novelty-evoked elevations of nucleus accumbens dopamine: dependence on impulse flow from the ventral subiculum and glutamatergic neurotransmission in the ventral tegmental area
Eur. J. Neurosci.
Chemical stimulation of the ventral hippocampus elevates nucleus accumbens dopamine by activating dopaminergic neurons of the ventral tegmental area
J. Neurosci.
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