Mesolimbic Reward Circuitry Research Articles

Acute Pain and a Motivational Pathway in Adult Rats: Influence of Early Life Pain Experience

BackgroundThe importance of neonatal experience upon behaviour in later life is increasingly recognised. The overlap between pain and reward pathways led us to hypothesise that neonatal pain experience influences reward-related pathways and behaviours in adulthood.Methodology/Principal FindingsRat pups received repeat plantar skin incisions (neonatal IN) or control procedures (neonatal anesthesia only, AN) at postnatal days (P)3, 10 and 17. When adult, rats with neonatal ‘pain history’ showed greater sensory sensitivity than control rats following acute plantar skin incision. Motivational behaviour in the two groups of rats was tested in a novelty-induced hypophagia (NIH) paradigm. The sensitivity of this paradigm to pain-induced changes in motivational behaviour was shown by significant increases in the time spent in the central zone of the arena (43.7±5.9% vs. 22.5±6.7%, p<0.05), close to centrally placed food treats, and decreased number of rears (9.5±1.4 vs. 19.2±2.3, p<0.001) in rats with acute plantar skin incision compared to naive, uninjured animals. Rats with a neonatal ‘pain history’ showed the same pain-induced behaviour in the novelty-induced hypophagia paradigm as controls. However, differences were observed in reward-related neural activity between the two groups. Two hours after behavioural testing, brains were harvested and neuronal activity mapped using c-Fos expression in lateral hypothalamic orexin neurons, part of a specific reward seeking pathway. Pain-induced activity in orexin neurons of control rats (18.4±2.8%) was the same as in uninjured naive animals (15.5±2.6%), but in those rats with a ‘pain history’, orexinergic activity was significantly increased (27.2±4.1%, p<0.01). Furthermore the extent of orexin neuron activation in individual rats with a ‘pain history’ was highly correlated with their motivational behaviour (r = −0.86, p = 0.01).Conclusions/SignificanceThese results show that acute pain alters motivational behaviour and that neonatal pain experience causes long-term changes in brain motivational orexinergic pathways, known to modulate mesolimbic dopaminergic reward circuitry.

Nucleus Accumbens Response to Incentive Stimuli Anticipation in Children of Alcoholics: Relationships with Precursive Behavioral Risk and Lifetime Alcohol Use

Children of alcoholics (COAs) are at elevated risk to develop alcohol and other substance use disorders. The neurobiological underpinnings of this heightened vulnerability are presently not well understood. This study investigated whether, in humans, COAs have different functioning of the mesolimbic reward circuitry beyond previous substance use confounds and examined potential group differences in neural response in relation to alcohol use and behavioral risk. We studied 20 18- to 22-year-old COAs and 20 controls, developmentally well characterized for substance use and selected to match on sex, age, IQ, lifetime substance use and associated problems, and precursive (ages 12-14 years) externalizing behavioral risk. None met criteria for Diagnostic and Statistical Manual of Mental Disorders IV diagnosis. Neural responses to anticipation of reward and loss were assessed using functional magnetic resonance imaging during a monetary incentive delay task. Overall, COAs showed reduced ventral striatum activation during anticipation of monetary reward and loss compared with controls. However, additional analysis revealed that blunted nucleus accumbens (NAcc) response was only observed in COAs who have not demonstrated any problem drinking behavior. In addition, uniquely in COAs, NAcc activation was positively correlated with precursive externalizing risk, as well as current and lifetime alcohol consumption. These findings suggest a multilevel developmental process whereby lower precursive behavioral risk appears protective of later problem alcohol use in COAs, which is further associated with a blunted NAcc response to incentive anticipation, potentially reflecting a resilience mechanism. Moreover, the results suggest that a close association between motivational responses, alcohol consumption, and behavioral risk may underlie addiction vulnerability in COAs.

AS30-01 - Imaging studies on cue-reactivity in pathological gambling and multiuser internet games

Pathological gambling and multiuser internet gaming is characterized by recurrent maladaptive behaviour that resembles substance-related addictions. Some studies suggest comparable alterations in mesolimbic reward circuitry which characterize drug dependence and pathological gambling. In a recent study we observed that excessive computer game players exhibit an attentional bias toward game-related as well as positive stimuli. Among the game players, this effect was accompanied by an increased cerebral activity in midbrain, orbitofrontal cortex, medial prefrontal cortex (mPFC) and anterior cingulate gyrus. For cue-reactivity, increased activation was found in lingual gyrus, hippocampus and inferior frontal gyrus (IFG). Connectivity analyses revealed a strengthened coupling between right IFG and mPFC in excessive game players. Further studies from our group focused on anticipation and processing of monetary gain or loss. First analyses of the functional data, controlled for age and brain volume, revealed increased activation in the ventral striatum in pathological gamblers compared to alcohol-dependent patients during anticipation and processing of losses. Further, results from a VBM study point to an increased local gray matter volume in subjects with pathological gambling compared to healthy controls in ventral striatum and ventrolateral prefrontal cortex, both brain areas involved in reward-related decision making. The observed volumetric and functional changes in pathological gambling and multiuser internet gaming may reflect salience attribution to gambling-related stimuli and outcomes and help to explain why subjects decisions making is biased toward gambling-related activities. The question whether these neurobiological changes are a disposition or a consequence of excessive gambling has yet to be clarified.

Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

Stress and exposure to glucocorticoids (GC) during early life render individuals vulnerable to brain disorders by inducing structural and chemical alterations in specific neural substrates. Here we show that adult rats that had been exposed to in utero GCs (iuGC) display increased preference for opiates and ethanol, and are more responsive to the psychostimulatory actions of morphine. These animals presented prominent changes in the nucleus accumbens (NAcc), a key component of the mesolimbic reward circuitry; specifically, cell numbers and dopamine (DA) levels were significantly reduced, whereas DA receptor 2 (Drd2) mRNA expression levels were markedly upregulated in the NAcc. Interestingly, repeated morphine exposure significantly downregulated Drd2 expression in iuGC-exposed animals, in parallel with increased DNA methylation of the Drd2 gene. Administration of a therapeutic dose of L-dopa reverted the hypodopaminergic state in the NAcc of iuGC animals, normalized Drd2 expression and prevented morphine-induced hypermethylation of the Drd2 promoter. In addition, L-dopa treatment promoted dendritic and synaptic plasticity in the NAcc and, importantly, reversed drug-seeking behavior. These results reveal a new mechanism through which drug-seeking behaviors may emerge and suggest that a brief and simple pharmacological intervention can restrain these behaviors in vulnerable individuals.

Role of ghrelin in food reward: impact of ghrelin on sucrose self‐administration and mesolimbic dopamine and acetylcholine receptor gene expression

The decision to eat is strongly influenced by non-homeostatic factors such as food palatability. Indeed, the rewarding and motivational value of food can override homeostatic signals, leading to increased consumption and hence, obesity. Ghrelin, a gut-derived orexigenic hormone, has a prominent role in homeostatic feeding. Recently, however, it has emerged as a potent modulator of the mesolimbic dopaminergic reward pathway, suggesting a role for ghrelin in food reward. Here, we sought to determine whether ghrelin and its receptors are important for reinforcing motivation for natural sugar reward by examining the role of ghrelin receptor (GHS-R1A) stimulation and blockade for sucrose progressive ratio operant conditioning, a procedure used to measure motivational drive to obtain a reward. Peripherally and centrally administered ghrelin significantly increased operant responding and therefore, incentive motivation for sucrose. Utilizing the GHS-R1A antagonist JMV2959, we demonstrated that blockade of GHS-R1A signaling significantly decreased operant responding for sucrose. We further investigated ghrelin's effects on key mesolimbic reward nodes, the ventral tegmental area (VTA) and nucleus accumbens (NAcc), by evaluating the effects of chronic central ghrelin treatment on the expression of genes encoding major reward neurotransmitter receptors, namely dopamine and acetylcholine. Ghrelin treatment was associated with an increased dopamine receptor D5 and acetylcholine receptor nAChRβ2 gene expression in the VTA and decreased expression of D1, D3, D5 and nAChRα3 in the NAcc. Our data indicate that ghrelin plays an important role in motivation and reinforcement for sucrose and impacts on the expression of dopamine and acetylcholine encoding genes in the mesolimbic reward circuitry. These findings suggest that ghrelin antagonists have therapeutic potential for the treatment of obesity and to suppress the overconsumption of sweet food.

Cross-sectional evaluation of cognitive functioning in children, adolescents and young adults with ADHD

Attention-deficit/hyperactivity disorder (ADHD) often persists into adulthood, albeit with changes in clinical symptoms throughout the life span. Although effect sizes of neuropsychological deficits in ADHD are well established, developmental approaches have rarely been explored and little is yet known about age-dependent changes in cognitive dysfunction from childhood to adulthood. In this cross-sectional study, 20 male children (8-12 years), 20 adolescents (13-16 years), and 20 adults (18-40 years) with ADHD and a matched control group were investigated using six experimental paradigms tapping into different domains of cognitive dysfunction. Subjects with ADHD were more delay-aversive and showed deficits in time discrimination and time reproduction, but they were not impaired in working memory, interference control or time production. Independent of age, the most robust group differences were observed with respect to delay aversion and time reproduction, pointing to persistent dysfunction in the mesolimbic reward circuitry and in the frontal-striatal-cerebellar timing system in subjects with ADHD. Across all tasks, effect sizes were lowest for adolescents with ADHD compared to age-matched controls. Developmental dissociations were found only for simple stimuli comparison, which was particularly impaired in ADHD children. Thus, in line with current multiple-pathway approaches to ADHD, our data suggest that deficits in different cognitive domains are persistent across the lifespan, albeit less pronounced in adolescents with ADHD.

Mesolimbic Functional Magnetic Resonance Imaging Activations during Reward Anticipation Correlate with Reward-Related Ventral Striatal Dopamine Release

The dopaminergic mechanisms that control reward-motivated behavior are the subject of intense study, but it is yet unclear how, in humans, neural activity in mesolimbic reward-circuitry and its functional neuroimaging correlates are related to dopamine release. To address this question, we obtained functional magnetic resonance imaging (fMRI) measures of reward-related neural activity and [(11)C]raclopride positron emission tomography measures of dopamine release in the same human participants, while they performed a delayed monetary incentive task. Across the cohort, a positive correlation emerged between neural activity of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic neurotransmission, during reward anticipation and reward-related [(11)C]raclopride displacement as an index of dopamine release in the ventral striatum, major target of SN/VTA dopamine neurons. Neural activity in the ventral striatum/nucleus accumbens itself also correlated with ventral striatal dopamine release. Additionally, high-reward-related dopamine release was associated with increased activation of limbic structures, such as the amygdala and the hippocampus. The observed correlations of reward-related mesolimbic fMRI activation and dopamine release provide evidence that dopaminergic neurotransmission plays a quantitative role in human mesolimbic reward processing. Moreover, the combined neurochemical and hemodynamic imaging approach used here opens up new perspectives for the investigation of molecular mechanisms underlying human cognition.

Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): a commentary

Background and hypothesisBased on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors (D1-D5), whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA) at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing proliferation of D2 receptors.Proposal and conclusionThe authors propose that D2 receptor stimulation can be accomplished via the use of Synapatmine™, a natural but therapeutic nutraceutical formulation that potentially induces DA release, causing the same induction of D2-directed mRNA and thus proliferation of D2 receptors in the human. This proliferation of D2 receptors in turn will induce the attenuation of craving behavior. In fact as mentioned earlier, this model has been proven in research showing DNA-directed compensatory overexpression (a form of gene therapy) of the DRD2 receptors, resulting in a significant reduction in alcohol craving behavior in alcohol preferring rodents. Utilizing natural dopaminergic repletion therapy to promote long term dopaminergic activation will ultimately lead to a common, safe and effective modality to treat Reward Deficiency Syndrome (RDS) behaviors including Substance Use Disorders (SUD), Attention Deficit Hyperactivity Disorder (ADHD), Obesity and other reward deficient aberrant behaviors. This concept is further supported by the more comprehensive understanding of the role of dopamine in the NAc as a "wanting" messenger in the meso-limbic DA system.

Desarrollo cerebral y asunción de riesgos durante la adolescencia

Recently, the use in neuroscience research of Magnetic Resonance Imaging has generated very interesting data about changes in the brain during the years of adolescence. Those changes occur mainly in the prefrontal cortex, a brain region, involved in many cognitive processes, that experiences an important development after puberty and which does not mature fully until early adulthood. Also, the mesolimbic dopamine reward circuitry experiences significant changes due to hormonal activity during puberty. As a consequence of those changes, during early adolescence arises a lack of balance between the cognitive and motivational brain systems. This imbalance could create a certain vulnerability during adolescence that justify the increase in some behaviours such as impulsivity and risk-taking. Those finding and some practical applications for education and social policy are presented and discussed.

(636): Affective analgesia following carbachol microinjections in anterior and posterior ventral tegmental area

Activation of mesolimbic reward circuitry is postulated to preferentially suppress affective reactions to noxious stimuli (affective analgesia). The ventral tegmental area (VTA) is the origin of mesolimbic projections that control the brain reward circuitry. VTA dopamine neurons are activated via cholinergic inputs, and we observed that microinjections of the acetylcholine agonist carbachol suppressed vocalizations of rats that occur following administration of brief (1 sec) tail-shocks (vocalization afterdischarges = VAD).

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.

The unfolding cannabinoid story on energy homeostasis: central or peripheral site of action?

Presentations in this symposium addressed effects and modes of action of endocannabinoids in various tissues in relation to metabolic disorders. Endocannabinoids are produced and exert their effect in various brain sites, including the mesolimbic reward circuitry and the hypothalamus. Both of these regions have direct ties to energy metabolism regulation, particularly food intake and energy expenditure. These data clearly suggest that the observed beneficial effects of CB1 (cannabinoid receptor 1) receptor antagonists on obesity may be related to the central endocannabinoid system. On the other hand, data presented on cannabinoid action in the liver and white adipose tissues clearly indicate that CB1-mediated events in affecting metabolic phenotype may occur in peripheral tissues as well. This together with the reported results from human trials on CB1 antagonists showing that the initial anorectic effect of rimonabant is diminished after the first weeks while longer lasting weight loss is achieved do indicate that peripheral action of cannabinoids are very important in body weight regulation. Should this hold true in the long run, antagonizing CB1 receptors with compound not crossing the blood-brain barrier could revolutionize pharmaceutical approaches to obesity by offering a tool that short cuts the central nervous system.

Brief Communication: Tobacco Addiction as a Marker of Age at Onset of Schizophrenia

Schizophrenia is a heterogenous disorder, with diversity in symptoms, course, prognosis, and probably etiology. The timing of its onset (i.e., early vs. late) not only predicts outcome of illness, but also corresponds to fundamental neurochemical and neuroendocrine distinctions. There is recent evidence that early age at onset of schizophrenia is associated with more prominent negative symptoms, which are associated with decreased dopaminergic functions in the limbic system. Since addictive behaviour may be related to decreased dopamine activity in the mesolimbic reward circuitry, we predict a higher prevalence of tobacco addiction in patients with an earlier age at onset of schizophrenia. To investigate this hypothesis, we studied the association of cigarette smoking to age at onset of illness in a sample of 142 chronic schizophrenic inpatients, 73 of whom were smokers. We found that patients who smoked had a significantly earlier age at onset of psychiatric illness as compared to the nonsmokers (p less than .01). Since damage to dopaminergic systems at the lateral hypothalamic level of the medial forebrain bundle and in the ventral tegmental reward system produces the strongest indication of reward, our data suggest that alterations in dopaminergic functions in these systems may be linked to the timing of onset of schizophrenic symptoms.