The Hypocretin/Orexin System: Implications for Drug Reward and Relapse

Hypocretins (also known as orexins) are hypothalamic neuropeptides involved in the regulation of sleep/wake states and feeding behavior. Recent studies have also demonstrated an important role for the hypocretin/orexin system in the addictive properties of drugs of abuse, consistent with the reciprocal innervations between hypocretin neurons and brain areas involved in reward processing. This system participates in the primary reinforcing effects of opioids, nicotine, and alcohol. Hypocretins are also involved in the neurobiological mechanisms underlying relapse to drug-seeking behavior induced by drug-related environmental stimuli and stress, as mainly described in the case of psychostimulants. Based on these preclinical studies, the use of selective ligands targeting hypocretin receptors could represent a new therapeutical strategy for the treatment of substance abuse disorders. In this review, we discuss and update the current knowledge about the participation of the hypocretin system in drug addiction and the possible neurobiological mechanisms involved in these processes regulated by hypocretin transmission.     

Reward Anticipation in Ventral Striatum and Individual Sensitivity to Reward: A Pilot Study of a Child-Friendly fMRI Task

Reward processing has been implicated in developmental disorders. However, the classic task to probe reward anticipation, the monetary incentive delay task, has an abstract coding of reward and no storyline and may therefore be less appropriate for use with developmental populations. We modified the task to create a version appropriate for use with children. We investigated whether this child-friendly version could elicit ventral striatal activation during reward anticipation in typically developing children and young adolescents (aged 9.5–14.5). In addition, we tested whether our performance-based measure of reward sensitivity was associated with anticipatory activity in ventral striatum. Reward anticipation was related to activity in bilateral ventral striatum. Moreover, we found an association between individual reward sensitivity and activity in ventral striatum. We conclude that this task assesses ventral striatal activity in a child-friendly paradigm. The combination with a performance-based measure of reward sensitivity potentially makes the task a powerful tool for developmental imaging studies of reward processing.     

The Roles of Reward,Default, and Executive Control Networks in Set-Shifting Impairments in Schizophrenia

Patients with schizophrenia (SZ) show deficits on tasks of rapid reinforcement learning, like probabilistic reversal learning (PRL), but the neural bases for those impairments are not known. Recent evidence of relatively intact sensitivity to negative outcomes in the ventral striatum (VS) in many SZ patients suggests that PRL deficits may be largely attributable to processes downstream from feedback processing, involving both the activation of executive control task regions and deactivation of default mode network (DMN) components. We analyzed data from 29 chronic SZ patients and 21 matched normal controls (NCs) performing a PRL task in an MRI scanner. Subjects were presented with eight pairs of fractal stimuli, for 50 trials each. For each pair, subjects learned to choose the more frequently-rewarded (better) stimulus. Each time a criterion was reached, the better stimulus became the worse one, and the worse became the better. Responses to feedback events were assessed through whole-brain and regions-of-interest (ROI) analyses in DMN. We also assessed correlations between BOLD signal contrasts and clinical measures in SZs. Relative to NCs, SZ patients showed comparable deactivation of VS in response to negative feedback, but reduced deactivation of DMN components including medial prefrontal cortex (mPFC). The magnitudes of patients'' punishment-evoked deactivations in VS and ventromedial PFC correlated significantly with clinical ratings for avolition/anhedonia. These findings suggest that schizophrenia is associated with a reduced ability to deactivate components of default mode networks, following the presentation of informative feedback and that motivational deficits in SZ relate closely to feedback-evoked activity in reward circuit components. These results also confirm a role for ventrolateral and dorsomedial PFC in the execution of response-set shifts.     

Initial D2 Dopamine Receptor Sensitivity Predicts Cocaine Sensitivity and Reward in Rats

The activation of dopamine receptors within the mesolimbic dopamine system is known to be involved in the initiation and maintenance of cocaine use. Expression of the D₂ dopamine receptor subtype has been implicated as both a predisposing factor and consequence of chronic cocaine use. It is unclear whether there is a predictive relationship between D₂ dopamine receptor function and cocaine sensitivity that would enable cocaine abuse. Therefore, we exploited individual differences in behavioral responses to D₂ dopamine receptor stimulation to test its relationship with cocaine-mediated behaviors. Outbred, male Sprague-Dawley rats were initially characterized by their locomotor responsiveness to the D₂ dopamine receptor agonist, quinpirole, in a within-session ascending dose-response regimen (0, 0.1, 0.3 & 1.0 mg/kg, sc). Rats were classified as high or low quinpirole responders (HD₂ and LD₂, respectively) by a median split of their quinpirole-induced locomotor activity. Rats were subsequently tested for differences in the psychostimulant effects of cocaine by measuring changes in cocaine-induced locomotor activity (5 and 15 mg/kg, ip). Rats were also tested for differences in the development of conditioned place preference to a low dose of cocaine (7.5 mg/kg, ip) that does not reliably produce a cocaine conditioned place preference. Finally, rats were tested for acquisition of cocaine self-administration and maintenance responding on fixed ratio 1 and 5 schedules of reinforcement, respectively. Results demonstrate that HD₂ rats have enhanced sensitivity to the locomotor stimulating properties of cocaine, display greater cocaine conditioned place preference, and self-administer more cocaine compared to LD₂ animals. These findings suggest that individual differences in D₂ dopamine receptor sensitivity may be predictive of cocaine sensitivity and reward.     

Insulin,Central Dopamine D2 Receptors,and Monetary Reward Discounting in Obesity

Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index<30) adults were assessed for percent body fat with dual-energy X-ray absorptiometry and for β-cell function using disposition index. Choice of larger, but delayed or less certain, monetary rewards relative to immediate, certain smaller monetary rewards was measured using delayed and probabilistic reward discounting tasks. Positron emission tomography using a non-displaceable D2-specific radioligand, [¹¹C](N-methyl)benperidol quantified striatal D2 receptor binding. Groups differed in body mass index, percent body fat, and disposition index, but not in striatal D2 receptor specific binding or reward discounting. Higher percent body fat in non-obese women related to preference for a smaller, certain reward over a larger, less likely one (greater probabilistic discounting). Lower β-cell function in the total sample and lower insulin sensitivity in obese related to stronger preference for an immediate and smaller monetary reward over delayed receipt of a larger one (greater delay discounting). In obese adults, higher striatal D2 receptor binding related to greater delay discounting. Interestingly, striatal D2 receptor binding was not significantly related to body mass index, percent body fat, or β-cell function in either group. Our findings indicate that individual differences in percent body fat, β-cell function, and striatal D2 receptor binding may each contribute to altered reward discounting behavior in non-obese and obese individuals. These results raise interesting questions about whether and how striatal D2 receptor binding and metabolic factors, including β-cell function, interact to affect reward discounting in humans.     

The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion

Renal dopamine D₁-like receptors (D₁R and D₅R) and the gastrin receptor (CCK_BR) are involved in the maintenance of sodium homeostasis. The D₁R has been found to interact synergistically with CCK_BR in renal proximal tubule (RPT) cells to promote natriuresis and diuresis. D₅R, which has a higher affinity for dopamine than D₁R, has some constitutive activity. Hence, we sought to investigate the interaction between D₅R and CCK_BR in the regulation of renal sodium excretion. In present study, we found D₅R and CCK_BR increase each other’s expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was verified in HEK293 cells heterologously expressing both human D₅R and CCK_BR and in RPT cells from a male normotensive human. The specificity of D₅R in the D₅R and CCK_BR interaction was verified further using a selective D₅R antagonist, LE-PM436. Also, D₅R and CCK_BR colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCK_BR protein expression in plasma membrane-enriched fractions of renal cortex (PMFs) is greater in D₅R^-/- mice than D₅R^+/+ littermates and D₅R protein expression in PMFs is also greater in CCK_BR^-/- mice than CCK_BR^+/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCK_BR and D₅R proteins in PMFs. Disruption of CCK_BR in mice caused hypertension and decreased sodium excretion. The natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCK_BR antagonist and {"type":"entrez-protein","attrs":{"text":"Sch23390","term_id":"1052733334"}}Sch23390, a D₁R/D₅R antagonist. Furthermore, the natriuresis caused by gastrin was blocked by {"type":"entrez-protein","attrs":{"text":"Sch23390","term_id":"1052733334"}}Sch23390 while the natriuresis caused by fenoldopam, a D₁R/D₅R agonist, was blocked by YF476. Taken together, our findings indicate that CCK_BR and D₅R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake.     

Electroencephalographic (EEG) Measurements of Mindfulness-based Triarchic Body-pathway Relaxation Technique: A Pilot Study

Objective The “Triarchic body-pathway relaxation technique” (TBRT) is a form of ancient Chinese mindfulness-based meditation professed to give rise to positive emotions and a specific state of consciousness in which deep relaxation and internalized attention coexist. The purpose of this study was to examine the EEG pattern generated during the practice of this mindfulness exercise, and compare it to music listening which has been shown to induce positive emotions. Methods Nineteen college students (aged 19–22 years) participated in the study. Each participant listened to both the TBRT and music audiotapes while EEG was recorded. The order of presentation was counterbalanced to avoid order effect. Two EEG indicators were used: (1) alpha asymmetry index, an indicator for left-sided anterior activation, as measure of positive emotions, and (2) frontal midline theta activity, as a measure for internalized attention. Results Increased left-sided activation, a pattern associated with positive emotions, was found during both TBRT exercise and music conditions. However, only TBRT exercise was shown to exhibit greater frontal midline theta power, a pattern associated with internalized attention. Conclusions These results provided evidence to support that the TBRT gives rise to positive emotional experience, accompanied by focused internalized attention.     

The Neural Circuitry of Reward Processing in Complex Social Comparison: Evidence from an Event-Related fMRI Study

In this study, Functional magnetic resonance imaging (fMRI) was conducted to investigate the mechanisms by which the brain activity in a complex social comparison context. One true subject and two pseudo-subjects were asked to complete a simple number estimate task at the same time which including upward and downward comparisons. Two categories of social comparison rewards (fair and unfair rewards distributions) were mainly presented by comparing the true subject with other two pseudo-subjects. Particularly, there were five conditions of unfair distribution when all the three subjects were correct but received different rewards. Behavioral data indicated that the ability to self-regulate was important in satisfaction judgment when the subject perceived an unfair reward distribution. fMRI data indicated that the interaction between the ventral striatum and the prefrontal cortex was important in self-regulation under specific conditions in complex social comparison, especially under condition of reward processing when there were two different reward values and the subject failed to exhibit upward comparison.     

Electroencephalographic Patterns in Chronic Pain: A Systematic Review of the Literature

The main objective of this study is to review and summarize recent findings on electroencephalographic patterns in individuals with chronic pain. We also discuss recent advances in the use of quantitative Electroencephalography (qEEG) for the assessment of pathophysiology and biopsychosocial factors involved in its maintenance over time. Data collection took place from February 2014 to July 2015 in PubMed, SciELO and PEDro databases. Data from cross-sectional studies and longitudinal studies, as well as clinical trials involving chronic pain participants were incorporated into the final analysis. Our primary findings related to chronic pain were an increase of theta and alpha EEG power at rest, and a decrease in the amplitude of evoked potentials after sensory stimulation and cognitive tasks. This review suggests that qEEG could be considered as a simple and objective tool for the study of brain mechanisms involved in chronic pain, as well as for identifying the specific characteristics of chronic pain condition. In addition, results show that qEEG probably is a relevant outcome measure for assessing changes in therapeutic studies.     

A Nectar Reward: Is More Better?1

Characters involved in pollinator attraction are likely maintained by selection. Plants that invest more in floral displays and/or rewards are expected to attract more pollinators than those that do not. A large number of plants, however, are severely pollen-limited yet either produce small rewards or none at all. The orchid, Comparettia falcata, is a pollinator-dependent, self-compatible epiphyte distributed throughout the Greater Antilles, Central and South America. In Puerto Rico where it is pollinated by the hummingbird Chlorostilbon maugaeus, C. falcata presents a smaller nectar reward than most other plants pollinated by the same species. To determine whether or not selection would favor the production of higher nectar levels, we enhanced the quantity of nectar offered by flowers in a Puerto Rican population for two flowering seasons. We monitored visitation frequencies, pollen movement, and reproductive success at three sites with different canopy coverages. Daily censuses of hummingbirds provided estimates of relative pollinator abundance. A multiway contingency test employing Wal?s statistic showed no overall differences in reproductive success between plants with enhanced rewards and unmanipulated controls. Site differences, however, were clear. Plants of the mid- and high-light sites had greater success than those of the low-light site, and the differences were usually at least two-fold. There was a significant site-treatment interaction in reproductive success that could be attributed to the overall trend whereby controls of both mid- and high-light sites did better than the nectar-enhanced plants. Most of the observed pollinations (85%) with stained pollinia resulted in self-pollinations that did not differ among treatments. Seed crops from self- and cross-pollinations revealed no differences in the number of viable seeds. Because we found little evidence of selection for increasing nectar reward via inbreeding depression or male and female reproductive success, and previous studies have indicated that meager natural levels of reward are better than none at all, we suspect that reward production in C. falcata may be driven by a combination of pollination-limitation and resource constraints.     

Alterations of Monetary Reward and Punishment Processing in Chronic Cannabis Users: An fMRI Study

Alterations in reward and punishment processing have been reported in adults suffering from long-term cannabis use. However, previous findings regarding the chronic effects of cannabis on reward and punishment processing have been inconsistent. In the present study, we used functional magnetic resonance imaging (fMRI) to reveal the neural correlates of reward and punishment processing in long-term cannabis users (n = 15) and in healthy control subjects (n = 15) with no history of drug abuse. For this purpose, we used the well-established Monetary Incentive Delay (MID) task, a reliable experimental paradigm that allows the differentiation between anticipatory and consummatory aspects of reward and punishment processing. Regarding the gain anticipation period, no significant group differences were observed. In the left caudate and the left inferior frontal gyrus, cannabis users were – in contrast to healthy controls – not able to differentiate between the conditions feedback of reward and control. In addition, cannabis users showed stronger activations in the left caudate and the bilateral inferior frontal gyrus following feedback of no punishment as compared to healthy controls. We interpreted these deficits in dorsal striatal functioning as altered stimulus-reward or action-contingent learning in cannabis users. In addition, the enhanced lateral prefrontal activation in cannabis users that is related to non-punishing feedback may reflect a deficit in emotion regulation or cognitive reappraisal in these subjects.     

Effects of Ambient Temperature on Sleep and Cardiovascular Regulation in Mice: The Role of Hypocretin/Orexin Neurons

The central neural pathways underlying the physiological coordination between thermoregulation and the controls of the wake-sleep behavior and cardiovascular function remain insufficiently understood. Growing evidence supports the involvement of hypocretin (orexin) peptides in behavioral, cardiovascular, and thermoregulatory functions. We investigated whether the effects of ambient temperature on wake-sleep behavior and cardiovascular control depend on the hypothalamic neurons that release hypocretin peptides. Orexin-ataxin3 transgenic mice with genetic ablation of hypocretin neurons (n = 11) and wild-type controls (n = 12) were instrumented with electrodes for sleep scoring and a telemetric blood pressure transducer. Simultaneous sleep and blood pressure recordings were performed on freely-behaving mice at ambient temperatures ranging between mild cold (20°C) and the thermoneutral zone (30°C). In both mouse groups, the time spent awake and blood pressure were higher at 20°C than at 30°C. The cold-related increase in blood pressure was significantly smaller in rapid-eye-movement sleep (REMS) than either in non-rapid-eye-movement sleep (NREMS) or wakefulness. Blood pressure was higher in wakefulness than either in NREMS or REMS at both ambient temperatures. This effect was significantly blunted in orexin-ataxin3 mice irrespective of ambient temperature and particularly during REMS. These data demonstrate that hypocretin neurons are not a necessary part of the central pathways that coordinate thermoregulation with wake-sleep behavior and cardiovascular control. Data also support the hypothesis that hypocretin neurons modulate changes in blood pressure between wakefulness and the sleep states. These concepts may have clinical implications in patients with narcolepsy with cataplexy, who lack hypocretin neurons.     

Sustained Dopamine Release Induced by Secretoneurin in the Striatum of the Rat: A Microdialysis Study

Abstract: Secretoneurin (SN) is a neuropeptide derived from secretogranin II that is found in brain and endocrine tissues. The aim of the present study was to determine the influence of this novel peptide on dopamine (DA) release from rat striatum using the microdialysis technique. Rat SN (1–30 µmol/L added to the dialysis buffer) enhanced DA outflow of awake rats in a concentration-dependent way without marked effects on the outflow of 3,4-dihydroxyphenylacetic acid or homovanillic acid. The increase in extracellular DA content caused by the peptide was observed throughout the entire period of administration (up to 4 h). Human SN and its 15-amino-acid C-terminal sequence also increased DA outflow, but the effects were smaller than those of rat SN. Two other peptides derived from secretogranin II were without effect on DA efflux. These results establish that SN has a pronounced effect on DA release under in vivo conditions.