Ikemoto S. Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory. Neurosci Biobehav Rev 35: 129-150

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: 8.8). 02/2010; 35(2):129-50. DOI: 10.1016/j.neubiorev.2010.02.001
Source: PubMed


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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Available from: Satoshi Ikemoto
    • "To test the hypothesis, we employed rats, trained in an operant chamber, to self-administer ethanol directly in the pVTA. The intracranial self-administration paradigm has been widely used to identify the precise reward and reinforcement circuitry (Rodd-Henricks et al. 2000; Ikemoto 2010). Using this assay, we show that (1) the noradrenergic tone in pVTA and (2) two-way communication between pVTA and LC are critically important for the reinforcement behavior. "
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    ABSTRACT: Although dysregulation of the dopaminergic mesolimbic system is generally considered central to addiction, the involvement of other circuits is increasingly being appreciated. An interaction between locus coeruleus (LC) noradrenergic neurons and the posterior ventral tegmental area (pVTA) dopaminergic system, in the processing of drug-triggered reward, has been suggested, but not demonstrated in behaving animals. Herein, we try to tease out the precise role of noradrenergic neurons in the LC-VTA circuit in mediating reward and reinforcement behavior associated with ethanol. In the standard two-lever (active/inactive) operant paradigm, the rats were trained to self-administer ethanol in pVTA and subjected to pharmacological intervention. Intra-pVTA administration of phenylephrine (alpha-1 adrenoceptor agonist) increased ethanol self-administration, while prazosin and disulfiram (agents that reduce noradrenergic tone) produced opposite effects. While degeneration [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, DSP-4, intraperitoneal route] or silencing (lidocaine or muscimol, both via intra-LC route) of the LC noradrenergic neurons decreased, phenylephrine via the intra-LC route reinstated ethanol self-administration. Furthermore, lidocaine reduced ethanol self-administration, but the effect was fully attenuated by noradrenaline given directly in the pVTA. This suggests that the feedback signals from LC to pVTA are necessary to sustain the ethanol self-infusion activity. Ethanol self-administration significantly increased tyrosine hydroxylase immunoreactivity in pVTA and LC; the response was blocked by DSP-4 pre-treatment. While dopamine D1 , but not D2 , receptors were localized on noradrenergic LC neurons, pre-treatment with SCH-23390 (intra-LC) dampened the lever press activity. We suggest that two-way communications between VTA and LC regions is essential for ethanol-triggered reinforcement behavior.
    No preview · Article · Nov 2015 · Addiction Biology
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    • "Our results converge with these findings and suggest a possible role of limbic white matter structures in PNS. The limbic system is central to motivation, emotions, hedonic impact and reward as well as cognition (Bush et al., 2000, Ikemoto, 2010, Keedwell et al., 2012). Given that our sample had more prominent anhedonia symptoms, which are also part of the " amotivation " construct, this may have contributed to the group difference and the correlations with white matter tracts of the limbic system. "
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    ABSTRACT: Aberrant white matter structures in fronto-temporal regions have previously been identified in patients with schizophrenia. However, scant research has focused on white matter integrity in patients presenting with a first episode of psychosis (FEP) with persistent negative symptoms (PNS). This study aimed to explore microstructure in the neurocircuitry proposed to be involved in PNS, by using a region-of-interest approach. Secondly, the relationship between individual negative symptoms and white matter were explored. Fractional anisotropy (FA) was measured in the fornix and three other tracts bilaterally including the uncinate fasciculus, superior longitudinal fasciculus and the cingulum bundle. Twelve patients with PNS were compared to a non-PNS group (52) and a healthy control group (51). Results showed that the PNS group had significantly lower FA values in the fornix when compared to healthy controls and that the non-PNS group had significantly lower FA values in the right uncinate fasciculus compared to healthy controls. Significant correlations were observed between SANS global score for anhedonia-asociality and lower FA values in the right cingulum bundle. Our results suggest that fronto-temporal white matter might be more closely related to PNS and that this relationship may possibly be mediated by greater anhedonia in PNS patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jul 2015 · Psychiatry Research: Neuroimaging
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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.
    Full-text · Article · Jun 2015 · Behavioural brain research
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