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

Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, US Department of Health and Human Services, 251 Bayview Blvd, Suite 200, Baltimore, MD 21224, United States.
Neuroscience & Biobehavioral Reviews (Impact Factor: 10.28). 02/2010; 35(2):129-50. DOI: 10.1016/j.neubiorev.2010.02.001
Source: PubMed

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.

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    • "The conduction velocities of these fibers are too slow [9] [10] [11] and the refractory periods too long [6] [7] to provide a good match to the inferred properties of the directly stimulated substrate for self-stimulation of the MFB. Moreover, the direction of the DA projections along the MFB is caudal–rostral [15], whereas the behaviorally relevant direction of conduction in at least some of the reward-relevant neural projections is rostral–caudal [11]. The importance of descending diencephalic projections in BSR had been proposed earlier by Huston et al. [16] [17]. "
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    ABSTRACT: The rewarding effect of electrical brain stimulation has been studied extensively for 60 years, yet the identity of the underlying neural circuitry remains unknown. Previous experiments have characterized the directly stimulated ("first-stage") neurons implicated in self-stimulation of the medial forebrain bundle. Their properties are consistent with those of fine myelinated axons, at least some of which project rostro-caudally. These properties do not match those of dopaminergic neurons. The present psychophysical experiment estimates an additional first-stage characteristic: maximum firing frequency. We test a frequency-following model that maps the experimenter-set pulse frequency into the frequency of firing induced in the directly stimulated neurons. As pulse frequency is increased, firing frequency initially increases at the same rate, then becomes probabilistic, and finally levels off. The frequency-following function is based on the counter model which holds that the rewarding effect of a pulse train is determined by the aggregate spike rate triggered in first-stage neurons during a given interval. In 7 self-stimulating rats, we measured current-versus-pulse-frequency trade-off functions. The trade-off data were well described by the frequency-following model, and its upper asymptote was approached at a median value of 362Hz (IQR=46Hz). This value implies a highly excitable, non-dopaminergic population of first-stage neurons. Incorporating the frequency-following function and parameters in Shizgal's 3-dimensional reward-mountain model improves its accuracy and predictive power. Copyright © 2015. Published by Elsevier B.V.
    Behavioural brain research 06/2015; DOI:10.1016/j.bbr.2015.06.008 · 3.39 Impact Factor
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    • "For example, future research will have to continue to identify clusters of GABAergic cells which make up value-processing microcircuits as well as their connections to other value-and non-value related clusters, including other cell types, such that a better understanding of their true function becomes clearer (and probably resulting in clearer delineations between multiple " systems " ). Analogous advances in network neuroscience have been made to identify many major nodes/hubs (i.e., clusters), edges (i.e., connections), and the interactions within and between such brain networks (Behrens and Sporns, 2012)—while most of this work is being done in humans, progress on the vast animal literature has also been made (Ikemoto, 2010). At this point, the greatest advances at the molecular-cellular level of understanding are likely being made through the identification and spatiotemporal electrochemical characterization of value-related microcircuits, for instance in the traditional mesocorticolimbic circuit (e.g., Nieh et al., 2013; Lammel et al., 2014). "
    Frontiers in Systems Neuroscience 05/2015; 9. DOI:10.3389/fnsys.2015.00076
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    • "Converging experimental evidence suggests shared signaling pathways for mechanism of neural plasticity (long term potentiation (LTP), and long term depression (LTD)) and addictions (e.g., Ikemoto, 2010; Self, 2004). It has been proposed that synaptic adaptation that occurs in the NAcc, after repeated drug administration, reflects synaptic scaling "
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    ABSTRACT: The main mystery about sleep is why we do not do more of it. Almost every type of human function or dysfunction involves sleep disruption, from our perception of sleep as an impediment to our social and professional lives, thus direct- ing our schedules to restrict the time we allocate for sleep; to psychiatric disorders, the majority of which interfere with sleep patterns. This is even more enigmatic consider- ing the overlap between sleep regulatory mechanisms and reward systems, as will be outlined here. Like the major- ity of psychiatric disorders, sleep disturbances are a central feature of addictions, with different substances associated with divergent effects on sleep regulation and subjective sleep quality. Clearly, the long- and short-term pharmaco- logical effects of a psychoactive drug alter the functional- ity of brain systems associated with arousal states; hence, it would be expected that continued use of such substances would impact sleep patterns. However, the links between the motivational effects of drug use and sleep are far more complex. I propose a model that will demonstrate that key mechanisms involved in the susceptibility to engage in drug-seeking behaviors and to develop an addiction are linked to sleep and sleep disruption. The emerging model suggests that the same systems that reinforce drug-seeking behaviors are also activated during sleep. As replay patterns during sleep have been linked to consolidation of memories, sleep, per se, may have a role in the creation of addiction. With this in mind, the proposed model may also provide a tentative answer to the questions posed, suggesting that sleep deprivation, at least in a mild form, is reinforcing.
    Modulation of Sleep by Obesity, Diabetes, Age, and Diet, 1st edited by R. Watson, 01/2015: chapter 37: pages 337-347; Elsevier., ISBN: 9780124201682
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