Review
Brain reward circuitry beyond the mesolimbic dopamine system: A neurobiological theory

https://doi.org/10.1016/j.neubiorev.2010.02.001Get rights and content

Abstract

Reductionist attempts to dissect complex mechanisms into simpler elements are necessary, but not sufficient for understanding how biological properties like reward emerge out of neuronal activity. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures—the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. In addition, studies found roles of non-dopaminergic mechanisms of the supramammillary, rostromedial tegmental and midbrain raphe nuclei in reward.

To explain intracranial self-administration and related effects of various drug manipulations, I outlined a neurobiological theory claiming that there is an intrinsic central process that coordinates various selective functions (including perceptual, visceral, and reinforcement processes) into a global function of approach. Further, this coordinating process for approach arises from interactions between brain structures including those structures mentioned above and their closely linked regions: the medial prefrontal cortex, septal area, ventral pallidum, bed nucleus of stria terminalis, preoptic area, lateral hypothalamic areas, lateral habenula, periaqueductal gray, laterodorsal tegmental nucleus and parabrachical area.

Introduction

Reward research has traditionally focused on brain dopamine. Early experiments showed that systemic injections of low doses of dopamine receptor antagonists exert extinction-like effects on instrumental responding maintained by food or brain stimulation reward (Wise, 1982) and that drugs abused by humans increase extracellular dopamine in the brain (Di Chiara and Imperato, 1988). Although dopamine's exact functions must still be clarified, the notion that dopamine plays a role in simple sensory pleasure is disputed. For example, the blockade of dopamine receptors in the ventral striatum disrupts instrumental responding for sucrose solutions, but not the consumption of sucrose (Ikemoto and Panksepp, 1996); similarly, lesions of dopamine terminals do not disrupt oral movements associated with palatable food (Berridge and Robinson, 1998). Dopamine appears to play a key role in reward in the sense that it energizes approach and induces conditioned approach (Ikemoto and Panksepp, 1999, Ikemoto, 2007).

The site of dopamine's release appears to determine the role that it plays. A major source of brain dopamine is localized in the ventral midbrain – ventral tegmental area (VTA) and substantia nigra, which primarily projects to the striatal complex – ventral striatum (VS) and dorsal striatum, in mediolateral topography. In turn, the striatal complex projects to both the pallidum and the ventral midbrain in mediolateral topography. The existence of a largely parallel organization of circuits linking the striatal complex to the midbrain and pallido-thalamo-cortex suggests that dopamine's function depends on its release site (Alexander et al., 1986, Haber, 2003, Ikemoto, 2007, Voorn et al., 2004, Yin and Knowlton, 2006). Drug self-administration and electrical self-stimulation studies have shown that dopaminergic projection from the VTA to the VS is particularly important in reward (Fibiger and Phillips, 1986, Koob, 1992, McBride et al., 1999, Pierce and Kumaresan, 2006, Wise and Bozarth, 1987). For example, depletion of dopamine in the VS or VTA severely attenuates instrumental responding for cocaine or amphetamine (Lyness et al., 1979, Roberts and Koob, 1982, Roberts et al., 1977, Roberts et al., 1980). Moreover, rats learn to self-administer amphetamine, cocaine or dopamine receptor agonists directly into the VS (Carlezon et al., 1995, Hoebel et al., 1983, Ikemoto et al., 1997a, Rodd-Henricks et al., 2002), suggesting that increased dopamine transmission is rewarding. More recent intracranial self-administration studies suggest that the medial part of the VTA–VS dopamine system plays a more important role in triggering reward than the lateral part (Ikemoto, 2007).

It seems logical that while dopamine plays a key role in reward, it is not a sole mediator. Most biological properties arise from the collective properties of many components: Reductionist approach of dissecting mechanisms into smaller elements is necessary but not sufficient for understanding how biological properties emerge (Hartwell et al., 1999). However, circuitry through which dopamine mediates reward is not clearly understood. The major claim of this paper is that the medial VTA–VS dopamine system's ability to mediate reward arises from its interactions with certain brain structures that collectively coordinate various selective functions (including perceptual, visceral and reinforcement processes) for a global function of approach. To support this claim, I will first review findings from self-stimulation studies that suggest that no single region is responsible for reward, supporting the view that reward arises from interactions of neurons localized over multiple brain regions (Section 2). I will next describe recent intracranial self-administration studies that show that the medial part of the VTA–VS dopamine system is particularly important for mediating reward, and that other neurotransmitters in other regions such as GABAergic and glutamatergic mechanisms in the supramammillary and midbrain raphe nuclei also mediate reward (Section 3). Section 4 presents a theoretical framework that provides explanations for intracranial self-administration findings. I will also review findings that support this neurobiological theory of reward. Section 5 reviews tract tracer data suggesting that drug trigger zones for reward are closely connected with certain brain regions that are associated with visceral and arousal functions. I propose that they are key components of the brain reward circuitry through which dopamine mediates reward.

Section snippets

Lessons from self-stimulation studies: reward emerges from dynamic interactions of neurons localized in multiple brain regions

Olds and Milner (1954) discovered that rats learn an instrumental task to deliver brief (typically less than 1 s) electrical stimulation through an implanted electrode aimed at a discrete brain site. This behavior is referred to as intracranial self-stimulation. Previous studies have shown that brain sites supporting self-stimulation in rats are widespread, yet associated with specific structures including the olfactory bulb and specific subregions of the cortex, hypothalamus, midbrain and

Intracranial self-administration studies

Brain stimulation reward experiments are useful in many ways, but suffer from some shortcomings. The parameters of electrical stimulation that are routinely used for self-stimulation most likely excite axons of passage rather than cell bodies and myelinated rather than unmyelinated axons (Ranck, 1975). This property of brain stimulation reward makes it difficult to define what exactly the stimulation is activating. For example, rats learn to self-stimulate at the VTA; yet, it is unclear what

Defining reward with neurobiological terms: other effects of injection manipulations that mediate self-administration

For the most part, modern biological research has taken reductionist approaches to mechanisms of behavior. For example, experiments examining single brain sites reduce complex biological functional mechanisms into their constituent components. As discussed above in the case of self-stimulation, behavioral neuroscientists have studied psychological functions by lesioning particular brain regions. This approach is useful for examining the function localized within the size of lesions or organized

Structural components and their organization of reward

Theories are useful when they help to generate testable hypotheses. In light of the neurobiological theory described above, I will discuss specific components of the brain reward circuitry. However, no guidelines exist for defining the structural components of network modules. I will construct structural components of approach coordinator module on the basis of closeness in connectivity with the drug trigger zones discussed above, using tract tracer data. But, proposed structural components

Implications

Because the approach coordinator module orchestrates the activities of many brain functions into adaptive approach, this process is essential for daily activity. Malfunction of this system might thus lead to various motivational disorders. Symptoms of mania seem to be analogous to persistent activation of approach coordinating process. On the other hand, symptoms of depression seem analogous to tonic inhibition of approach coordinating process.

Although understanding the approach coordinator

Acknowledgements

The present work was supported by the Intramural Research Program of the National Institute on Drug Abuse. I would like to thank Dr. Emily Wentzell for editorial assistance and my group's members – Fiori Vollrath-Smith, Sierra Webb, Drs. Tom Jhou and Mingliang Tang – for comments on an earlier version of the manuscript. Tom also helped me on the RMTg section.

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