Elsevier

Brain Research Reviews

Volume 56, Issue 1, November 2007, Pages 27-78
Brain Research Reviews

Review
Dopamine reward circuitry: Two projection systems from the ventral midbrain to the nucleus accumbens–olfactory tubercle complex

https://doi.org/10.1016/j.brainresrev.2007.05.004Get rights and content

Abstract

Anatomical and functional refinements of the meso-limbic dopamine system of the rat are discussed. Present experiments suggest that dopaminergic neurons localized in the posteromedial ventral tegmental area (VTA) and central linear nucleus raphe selectively project to the ventromedial striatum (medial olfactory tubercle and medial nucleus accumbens shell), whereas the anteromedial VTA has few if any projections to the ventral striatum, and the lateral VTA largely projects to the ventrolateral striatum (accumbens core, lateral shell and lateral tubercle). These findings complement the recent behavioral findings that cocaine and amphetamine are more rewarding when administered into the ventromedial striatum than into the ventrolateral striatum. Drugs such as nicotine and opiates are more rewarding when administered into the posterior VTA or the central linear nucleus than into the anterior VTA. A review of the literature suggests that (1) the midbrain has corresponding zones for the accumbens core and medial shell; (2) the striatal portion of the olfactory tubercle is a ventral extension of the nucleus accumbens shell; and (3) a model of two dopamine projection systems from the ventral midbrain to the ventral striatum is useful for understanding reward function. The medial projection system is important in the regulation of arousal characterized by affect and drive and plays a different role in goal-directed learning than the lateral projection system, as described in the variation–selection hypothesis of striatal functional organization.

Introduction

The purpose of this review is to refine the neuroanatomical framework of the dopamine reward circuitry, in light of recent observations on drug-reward trigger zones using intracranial self-administration procedures in rats. This review consists of two major parts following this introduction (Section 1). The first part concerns anatomy and consists of two sections. The ascending dopamine projection from the ventral midbrain to the nucleus accumbens and the olfactory tubercle is discussed based on previous studies and present experiments (Section 2). In addition, the data on the efferents from the nucleus accumbens and olfactory tubercle are reviewed (Section 3). The second part of the manuscript reviews behavioral studies and proposes a hypothesis to address how the dopamine projection systems interact with each other in drug reward and motivated behaviors (Section 4).

The meso-limbic dopamine system that projects from the ventral tegmental area (VTA) to the nucleus accumbens has been implicated in the rewarding effects of drugs of abuse (Fibiger and Phillips, 1986, Wise and Bozarth, 1987, Koob, 1992, Wise, 1996, McBride et al., 1999, Pierce and Kumaresan, 2006). Depletion of dopamine in the nucleus accumbens induced by local 6-hydroxydopamine (6-OHDA) injections severely attenuates the rewarding effects of cocaine or amphetamine, as assessed by instrumental responses (Lyness et al., 1979, Roberts et al., 1980, Roberts and Koob, 1982, Pettit et al., 1984, Caine and Koob, 1994, Gerrits and Van Ree, 1996) or conditioned place preference (Spyraki et al., 1982b), another common measure for the positive effects of drugs. In addition, rats learn to lever-press for amphetamine delivery directly into the accumbens (Hoebel et al., 1983, Phillips et al., 1994a, Phillips et al., 1994b). Intra-accumbens administration of amphetamine or dopamine receptor agonists also induces conditioned place preference (Carr and White, 1983, Carr and White, 1986, White et al., 1991).

The shell portion of the accumbens appears to be more important than the core for drug reward. Rats learn to self-administer psychomotor stimulants such as amphetamine or cocaine or dopamine receptor agonists into the accumbens shell, but not the core (Carlezon et al., 1995, Ikemoto et al., 1997a, Rodd-Henricks et al., 2002, Ikemoto, 2003, Ikemoto et al., 2005). In addition, microinjections of dopaminergic antagonists into the shell, but not the core, disrupt conditioned place preference induced by systemic nicotine or morphine (Fenu et al., 2006, Spina et al., 2006). Conditioned place preference induced by intravenous administration of cocaine or amphetamine is attenuated by lesions on dopamine terminals in the shell rather than the core (Sellings and Clarke, 2003, Sellings et al., 2006a, Sellings et al., 2006b). These results confirm functional differences between the two accumbens compartments inferred from anatomical observations that the afferents to and efferents from the accumbens differ significantly between the shell and core (Zahm and Brog, 1992).

The VTA at least partly mediates the rewarding effects of nicotine, opiates, cannabinoids and ethanol. Intravenous self-administration of nicotine in rats is attenuated by selective lesions to VTA dopamine neurons projecting to the ventral striatum (Corrigall et al., 1992) as well as by the blockade of nicotinic receptors administered into the VTA (Corrigall et al., 1994). Mice learn to run on a Y-maze to self-administer nicotine into the VTA, an effect that can be diminished by systemic administration of dopamine antagonists (Maskos et al., 2005, David et al., 2006). Administration of the nicotinic receptor agonists cytisine or nicotine into the vicinity of the VTA induces conditioned place preference (Museo and Wise, 1994, Laviolette and van der Kooy, 2003). Similarly, rats and mice learn to self-administer opiates (Bozarth and Wise, 1981, Welzl et al., 1989, David and Cazala, 1994a, David and Cazala, 1994b, Devine and Wise, 1994), cannabinoids (Zangen et al., 2006), cocaine (David et al., 2004, Rodd et al., 2005) or ethanol (Gatto et al., 1994, Rodd-Henricks et al., 2000) into the VTA. These behavioral effects are mediated by dopaminergic systems as shown by pharmacological manipulations (no data are available on cannabinoids in this context).

Taken together, these data suggest that dopaminergic neurons localized in the VTA projecting to the nucleus accumbens, particularly the shell, are activated by administration of drugs of abuse, and the activation of this system is rewarding.

Recent intracranial self-administration studies in rats have refined our understanding of specific zones within the ventral striatum and VTA that are responsible for the rewarding effects of drugs of abuse (Ikemoto and Wise, 2004). Although rats learn to self-administer amphetamine into the medial accumbens shell, they do not readily learn to self-administer it into the lateral shell (Ikemoto et al., 2005). In addition, rats readily learn to lever-press for cocaine or amphetamine into the olfactory tubercle, localized just ventral to the nucleus accumbens (Fig. 1), though the medial portion of the tubercle is more responsive to the rewarding effects of these drugs than the lateral portion (Ikemoto, 2003, Ikemoto et al., 2005). Consistently, lesions on dopaminergic terminals in the medial olfactory tubercle disrupt conditioned place preference induced by intravenous psychomotor stimulants (Sellings et al., 2006a, Sellings et al., 2006b). These data suggest that the medial olfactory tubercle is involved in drug reward and shares a common function with the medial shell; they further suggest that the accumbens shell is functionally heterogeneous, as is the olfactory tubercle.

The mechanisms of drug reward in the vicinity of the VTA are more complex than previously thought. Rats learn to lever-press for administration of drugs such as nicotine (Ikemoto et al., 2006), carbachol (Ikemoto and Wise, 2002), opiates (Zangen et al., 2002), cannabinoids (Zangen et al., 2006), cocaine (Rodd et al., 2005), ethanol (Rodd-Henricks et al., 2000) and its metabolite acetaldehyde (Rodd et al., 2004) into the posterior VTA more readily than into the anterior VTA. Data obtained with viral technology also indicate that the anterior and posterior VTA play different roles in conditioned place preference induced by systemic cocaine or opiate administration (Carlezon et al., 2000, Bolanos et al., 2003, Olson et al., 2005). In addition to the posterior VTA, the central (or caudal) linear nucleus raphe, localized posterodorsal to the VTA, is involved in drug reward. Rats learn to self-administer nicotine and other drugs into the central linear nucleus (Ikemoto et al., 1998, Ikemoto et al., 2006). Interestingly, this midline structure contains both dopaminergic (Phillipson, 1979b, Swanson, 1982) and serotonergic (Steinbusch, 1981, Halliday and Tork, 1989) neurons.

Section snippets

Dopaminergic projections from the ventral midbrain to the ventral striatum

The pattern of drug-reward trigger zones described above appears to be partly explained by cellular connectivity between the ventral midbrain and the ventral striatum. Previous data clearly suggest that the neurons in the VTA project into the nucleus accumbens with mediolateral topography (Fallon and Moore, 1978, Nauta et al., 1978, Beckstead et al., 1979, Phillipson and Griffiths, 1985, Brog et al., 1993a, Brog et al., 1993b, Hasue and Shammah-Lagnado, 2002). Similar mediolateral topography

Downstream circuits and hierarchical organization

This section reviews data on efferent projections from the nucleus accumbens–olfactory tubercle complex. The reviewed data suggest strong mediolateral topography for the outputs from the ventral striatum. Fig. 13 summarizes, in a schematic manner, how the outputs of the meso-striatal dopamine systems are organized with parallel circuits (Alexander et al., 1986) and split circuits (Joel and Weiner, 1994) leading to a hierarchy. This is a working model designed for understanding dopamine reward

Functional roles of the meso-ventromedial and ventrolateral dopamine systems

One aspect of ESB [electrical brain stimulation] that made it appear most artificial was that there was no external embodiment of the incentive object from which the pleasurable sensations arose. No taste, smell, or tactile sources of positive affect, and no consummatory behavior associated with it. Another feature of EBS that puzzled many was that there appeared to be no motive for taking it, no naturally occurring drive for it, and that, paradoxically, it could induce motivated behaviors such

Future investigations

As discussed above, the meso-ventromedial striatal dopamine system is involved in several behavioral functions: positive and negative affective states, general drive states and stimulus–outcome learning. These differential functions may partly arise from the ways in which ventromedial striatal dopamine stimulates its target receptors. Table 4 summarizes possible functional roles of dopamine, which need to be substantiated by future investigations.

Phasic dopamine signals in the ventromedial

Cytoarchitectonic features of the VTA and surrounding area

As discussed above, the precise boundaries of the VTA are difficult to determine. The boundaries of the VTA shown in Fig. 2 are adopted from those of Swanson (1982) for several reasons. His boundaries of the VTA (1) are explicit, (2) have remained the same over decades (Swanson, 2004), (3) are almost identical to those of Paxinos and Watson (1986) and (4) are adopted by many researchers who study function.

Cytoarchitectonic features of the ventral midbrain were examined in horizontal, coronal

Acknowledgments

The present work was supported by the Intramural Research Program of NIDA, NIH. The author would like to thank Stefanie Geisler and Yavin Shaham for comments on an earlier draft of the paper, Roy Wise for comments and discussions on related conceptual issues, Robert Ator for technical assistance, Marisela Morales for advice on immunohistochemistry and Emily Wentzell and the NIH Fellows Editorial Board for editorial assistance.

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