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Evidence for opiate-dopamine cross-sensitization in nucleus accumbens: studies of conditioned reward.

We investigated opiate-amphetamine interactions within the nucleus accumbens in responding for conditioned reward. Separate groups of animals received 4-day intra-accumbens treatment with either saline, morphine (0.5 microgram/0.5 microliter), [D-Ala2 NMe-Phe4 Gly-ol5]-Enkephalin (DAMGO; 1.0 micrograms/0.5 microliter), or [D-Pen2,5]-Enkephalin (DPEN; 2.0 micrograms/0.5 microliter). One two subsequent test days, these rats were given a challenge of d-amphetamine (2.0 and 10.0 micrograms/0.5 microliter) and responding for conditioned reward was measured. In the conditioned reinforcement (CR) procedure, food-deprived animals were trained in an initial phase to associate a food reward (primary reinforcement) with a compound stimulus (light/click). In the next phase, a lever was introduced and responding on the lever produced the compound stimulus alone (secondary reinforcement). Previous evidence shows that psychostimulants but not opiates markedly potentiate responding for conditioned reward. In the present design, animals previously treated with either morphine or DAMGO (preferential mu agonists) showed potentiated lever responding following amphetamine challenges, relative to either DPEN- or saline-treated animals. These findings show that prior exposure of nucleus accumbens neurons to mu-selective opiates induces sensitization to the effects of amphetamine. The results are discussed in terms of opioid effects on dopamine transmission and second messenger systems.

Animals↗

Memory for the changing cost of a reward is mediated by the sublenticular extended amygdala.

The aim of this study was to examine the role of the sublenticular extended amygdala (SEA) in processes of reward and reinforcement. Previous studies have examined the effects of ibotenate lesions in this area on motivation for cocaine reward. In this study, animals were trained to work for sucrose pellets, rather than a drug, on a progressive-ratio schedule of reinforcement. Bilateral intracerebral infusions of ibotenic acid (lesion group) or vehicle (control group) were made into the SEA, following the same procedures as used in previous studies. After recovery from surgery, animals were tested for six sessions on the progressive ratio schedule. The lesion did not result in motivational impairments of the kind that have previously been reported: rather than decreases in breaking point (a measure of motivational strength), the lesion resulted in greater variability of breaking points, with a tendency for lesioned animals to work harder for reward than controls. The SEA-lesioned rats did not show the increase in postreinforcement pause that usually accompanies the increase in perceived work as the number of bar presses for a reward increases. Histological analyses showed that the ibotenate lesions had successfully destroyed the SEA and that damage was also present in adjacent structures. The results are interpreted in terms of a mnemonic, rather than a motivational, deficit.

Amygdala↗

Decreased reward during acute alcohol withdrawal in rats selectively bred for low alcohol drinking.

We have previously hypothesized that increased sensitivity to the dysphoric-like or aversive effects of alcohol withdrawal following an initial exposure to alcohol might be associated with a genetic propensity to avoid alcohol. A decrease in brain reward function, as measured by an elevation in intracranial self-stimulation (ICSS) reward threshold, is one of the few methods available to model dysphoric-like or aversive effects of drug withdrawal in rats. We compared brain reward function during withdrawal following an initial exposure to alcohol in alcohol-naïve rats selectively bred for high (HAD1 line) versus low (LAD1 line) voluntary alcohol consumption. Male HAD1 (n=5) and LAD1 (n=6) rats were implanted with unilateral electrodes in the medial forebrain bundle and trained to bar press for delivery of a 100 microA current that varied in frequency from 45 to 200 Hz. Responding for ICSS was generally stable within subjects across multiple experimental sessions on a given day and across several consecutive days prior to alcohol or water administration. ICSS responding was assessed in both rat lines prior to and at 12, 14, 16, 18, 20, and 24 h following a single intragastric infusion of alcohol (4.0 g/kg body weight) or water. Rats of the LAD1 line, but not those of the HAD1 line, exhibited a decrease in brain reward function as evidenced by a decrease in bar-press responding for ICSS and an increase in ICSS stimulation threshold during alcohol withdrawal. The results suggest that rats selectively bred for low alcohol drinking may experience dysphoric-like effects during withdrawal from an initial exposure to alcohol, while rats selectively bred for high alcohol drinking may not.

Alcohol Drinking↗

Reward and punishment sensitivity in dysfunctional eating and hazardous drinking women: associations with family risk.

Biologically based personality traits such as reward and punishment sensitivity, and family factors, such as maternal dysfunctional eating and parental alcohol abuse, have been linked to hazardous drinking and disordered eating. However, specific relationships between personality and family factors in the development of these disorders are still unclear. A total of 443 women completed measures of reward and punishment sensitivity, family environment, maternal eating and parental drinking. Reward sensitivity was directly associated with both dysfunctional eating and drinking. Punishment sensitivity was associated with dysfunctional eating but not hazardous drinking. Punishment sensitivity mediated a chaotic family environment and daughters' dysfunctional eating. It is suggested that reward and punishment sensitivity are key traits to examine when investigating vulnerability to risky behaviour. Future research into disordered eating is likely to be advanced by an active search for mediators and moderators of family risk.

Adolescent↗

Localized lesions of ventral striatum, but not arcopallium, enhanced impulsiveness in choices based on anticipated spatial proximity of food rewards in domestic chicks.

The effects of bilateral chemical lesions of the ventral striatum (nucleus accumbens and the surrounding areas in the medial striatum) and arcopallium (major descending area of the avian telencephalon) were examined in 1-2-weeks old domestic chicks. Using a Y-maze, we analyzed the lesion effects on the choices that subject chicks made in two tasks with identical economical consequences, i.e., a small-and-close food reward vs. a large-and-distant food reward. In task 1, red, yellow, and green beads were associated with a feeder placed at various distances from the chicks; chicks thus anticipated the spatial proximity of food by the bead's color, whereas the quantity of the food was fixed. In task 2, red and yellow flags on the feeders were associated with various amount of food; the chicks thus anticipated the quantity of food by the flag's color, whereas the proximity of the reward could be directly visually determined. In task 1, bilateral lesions of the ventral striatum (but not the arcopallium) enhanced the impulsiveness of the chicks' choices, suggesting that choices based on the anticipated proximity were selectively changed. In task 2, similar lesions of the ventral striatum did not change choices. In both experiments, motor functions of the chicks remained unchanged, suggesting that the lesions did not affect the foraging efficiency, i.e., objective values of food. Neural correlates of anticipated food rewards in the ventral striatum (but not those in the arcopallium) could allow chicks to invest appropriate amount of work-cost in approaching distant food resources.

Algorithms↗

Anticipating instrumentally obtained and passively-received rewards: a factorial fMRI investigation.

During functional magnetic resonance imaging (fMRI), subjects saw cues signaling probabilities of 1.0, 0.5, and 0 of winning $1 for hitting a subsequent target, and cues signaling similar probabilities of reward delivery requiring no instrumental response. Non-instrumental reward anticipation did not elicit activation. Instrumental reward anticipation activated multiple nodes of the basal ganglia-thalamocortical motor circuit. Ventromesial striatum was activated by joint requirement for an instrumental response together with uncertain (but not certain) reward.

Adult↗

Distinct portions of anterior cingulate cortex and medial prefrontal cortex are activated by reward processing in separable phases of decision-making cognition.

BACKGROUND: Choosing between actions associated with uncertain rewards and punishments is mediated by neural circuitry encompassing the orbitofrontal cortex, anterior cingulate cortex (ACC), and striatum; however, the precise conditions under which these different components are activated during decision-making cognition remain uncertain. METHODS: Fourteen healthy volunteers completed an event-based functional magnetic resonance imaging protocol to investigate blood-oxygenation-level-dependent (BOLD) responses during independently modeled phases of choice cognition. In the "decision phase," participants decided which of two simultaneous visually presented gambles they wished to play for monetary reward. The gambles differed in their magnitude of gains, magnitude of losses, and the probabilities with which these outcomes were delivered. In the "outcome phase," the result of each choice was indicated on the visual display. RESULTS: In the decision phase, choices involving large gains were associated with increased BOLD responses in the pregenual ACC, paracingulate, and right posterior orbitolateral cortex compared with choices involving small gains. In the outcome phase, good outcomes were associated with increased BOLD responses in the posterior orbitomedial cortex, subcallosal ACC, and ventral striatum compared with negative outcomes. There was only limited overlap between reward-related activity in ACC and orbitofrontal cortex during the decision and outcome phases. CONCLUSIONS: Neural activity within the medial and lateral orbitofrontal cortex, pregenual ACC, and striatum mediate distinct representations of reward-related information that are deployed at different stages during a decision-making episode.

Adult↗

Ventral striatal hyporesponsiveness during reward anticipation in attention-deficit/hyperactivity disorder.

BACKGROUND: Although abnormalities in reward processing have been proposed to underlie attention-deficit/hyperactivity disorder (ADHD), this link has not been tested explicitly with neural probes. METHODS: This hypothesis was tested by using fMRI to compare neural activity within the striatum in individuals with ADHD and healthy controls during a reward-anticipation task that has been shown previously to produce reliable increases in ventral striatum activity in healthy adults and healthy adolescents. Eleven adolescents with ADHD (5 off medication and 6 medication-naïve) and 11 healthy controls (ages 12-17 y) were included. Groups were matched for age, gender, and intelligence quotient. RESULTS: We found reduced ventral striatal activation in adolescents with ADHD during reward anticipation, relative to healthy controls. Moreover, ventral striatal activation was negatively correlated with parent-rated hyperactive/impulsive symptoms across the entire sample. CONCLUSIONS: These findings provide neural evidence that symptoms of ADHD, and impulsivity or hyperactivity in particular, may involve diminished reward anticipation, in addition to commonly observed executive dysfunction.

Adolescent↗

Tumor necrosis factor-alpha and its inducer inhibit morphine-induced rewarding effects and sensitization.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is emerging as an important modulator of the function of the central nervous system (CNS). We have demonstrated that TNF-alpha or Leu-Ile, a TNF-alpha inducer, inhibits methamphetamine-induced rewarding effects and sensitization. In this study, we investigated the effects of TNF-alpha or Leu-Ile on morphine (MOR)-induced rewarding effects and sensitization. METHODS: Levels of TNF-alpha messenger RNA (mRNA) and protein were determined by real-time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Effects of TNF-alpha or Leu-Ile on MOR-induced rewarding effects and sensitization were investigated by conditioned place preference and locomotor activity tests. Extracellular dopamine levels were examined using in vivo microdialysis. Effects of TNF-alpha or Leu-Ile on MOR-induced antinociceptive effect and withdrawal symptoms were examined by hot plate test and naloxone-precipitated withdrawal. RESULTS: Morphine induced TNF-alpha mRNA expression via dopamine and opioid receptors. Posttreatment with TNF-alpha or Leu-Ile attenuated the MOR-induced place preference and sensitization even after their development, as well as pretreatment with TNF-alpha or Leu-Ile blocked them. An inhibitory effect of Leu-Ile on MOR-induced place preference was not observed in TNF-alpha knockout mice. Tumor necrosis factor-alpha or Leu-Ile inhibited the increase in extracellular dopamine levels in the nucleus accumbens induced by repeated MOR treatment. CONCLUSIONS: These results suggest that TNF-alpha inhibits MOR-induced rewarding effect and sensitization by regulating extracellular dopamine levels, and Leu-Ile inhibits them via the induction of TNF-alpha.

Animals↗

The corticostriatal input to giant aspiny interneurons in the rat: a candidate pathway for synchronising the response to reward-related cues.

Tonically active neurons (TANs) in the mammalian striatum show a pause in their ongoing firing activity in response to an auditory cue that is paired with a reward. This response to reward-related cues develops through learning and becomes expressed synchronously by TANs located throughout the striatum. The pause response is abolished by inactivating the thalamic inputs to the striatum but a short-latency excitatory response to reward-related cues remains, which may originate in the cortex. We investigated the cortical inputs to striatal neurons to determine the electrophysiological properties of their cortical projections. We made in vivo intracellular recordings from 14 giant aspiny interneurons (which correspond to the TANs) and from a control group of spiny projection neurons (n=18) in urethane-anaesthetised rats. All giant aspiny interneurons were tonically active (firing rate: 3.0+/-1.5 Hz) and displayed small-amplitude subthreshold fluctuations in membrane potential. These fluctuations in membrane potential were correlated with the cortical electroencephalogram (EEG). Test stimulation of the contralateral cortex induced postsynaptic potentials (PSPs) in giant aspiny interneurons. These PSPs were significantly shorter in latency (5.1+/-1.6 ms) than those measured in spiny projection neurons (9.3+/-2.8 ms; p<0.01), whereas the latencies of ipsilaterally evoked PSPs did not differ. Taken together, these observations suggest that giant aspiny interneurons are under the significant influence of spontaneous excitatory inputs and receive specialised input from either faster conducting or less branching cortical fibres than spiny projection neurons. These inputs may be involved in the synchronised convergence of reward-related cues from spatially distinct cortical areas onto giant aspiny interneurons.

Action Potentials↗

Motivating forces of human actions. Neuroimaging reward and social interaction.

In neuroeconomics, reward and social interaction are central concepts to understand what motivates human behaviour. Both concepts are investigated in humans using neuroimaging methods. In this paper, we provide an overview about these results and discuss their relevance for economic behaviour. For reward it has been shown that a system exists in humans that is involved in predicting rewards and thus guides behaviour, involving a circuit including the striatum, the orbitofrontal cortex and the amygdala. Recent studies on social interaction revealed a mentalizing system representing the mental states of others. A central part of this system is the medial prefrontal cortex, in particular the anterior paracingulate cortex. The reward as well as the mentalizing system is engaged in economic decision-making. We will discuss implications of this study for neuromarketing as well as general implications of these results that may help to provide deeper insights into the motivating forces of human behaviour.

Decision Making↗

Burden, reward and family functioning of caregivers for relatives with mood disorders: 1-year follow-up.

BACKGROUND: Longitudinal caregiver studies of patients with mood disorders report no consistent pattern in burden over time. This naturalistic study of caregivers of patients with mood disorders assesses caregiver perceptions of burden, reward and family functioning at hospitalization and at 1 year follow-up. METHODS: Thirty-nine caregivers of patients with mood disorders were recruited during their relative's in-patient psychiatric hospitalization. Caregivers were given an assessment packet to complete at the time of enrollment and identical assessment packets were mailed to the caregivers at 1 year. RESULTS: Caregivers of bipolar disorder relatives reported less reward, more subjective burden and worse family functioning than depression caregivers, at recruitment. Bipolar caregivers showed a significant reduction in burden 1 year after their relative was discharged from the hospital, whereas depression caregivers showed no change at 1 year. At 1 year, overall family functioning was unchanged and was in the unhealthy range in all dimensions except for behavior control. Limitations of the study include the small sample size, the selective recruitment from a hospital setting where family members did not actively seek out help and the high drop-out rate. CONCLUSIONS: Caregivers of relatives with mood disorders show a different pattern of burden and reward, over time, depending on the patient diagnosis. In all cases, however, family functioning was significantly impaired. CLINICAL RELEVANCE: Short-term family interventions can be offered at the time of hospitalization to try to reduce caregiver burden and increase caregiver reward.

Activities of Daily Living↗

Brain-stimulation reward, morphine-induced oral stereotypy, and sensitization: implications for abuse.

Early professionals believed that it was unlikely that anyone but the emotionally unstable received pleasure and became addicted to narcotic drugs. This position was well entrenched and influenced much of the thinking well into the latter half of the last century. Although the discovery of a brain reward system was made early in the 1950's it was not until 20 years later that this discovery was applied to the study of the mechanisms involved in the rewarding aspects of abused substances. Along this vein results will be shown in which opiate antagonist block the dopamine agonist activation of the brain reward system as well as the corollary. Sensitization of the reward system suggests that a driving force for drug use is 'liking' and not just 'wanting.' Basal changes in cerebral metabolic rates of glucose are seen in the presence of cues associated with morphine experience, giving evidence for the role of drug related cues in craving. Finally we asked the question 'Do old rats have as much fun as young rats?'

Animals↗

Prenatal and neonatal exposure to low-dose of bisphenol-A enhance the morphine-induced hyperlocomotion and rewarding effect.

Bisphenol-A has been extensively evaluated for toxicity in a variety of tests as the most common environmental endocrine disruptors. In the previous study, we reported that prenatal and neonatal exposure to high-dose of bisphenol-A affects the development of central dopaminergic system in the mouse limbic area. The present study was then undertaken to investigate whether prenatal and neonatal exposure to lower dose of bisphenol-A could change the morphine-induced several pharmacological actions such as rewarding effect and hyperlocomotion in mice. Prenatal and neonatal exposure to low-dose of bisphenol-A enhanced the morphine-induced hyperlocomotion and rewarding effect. Additionally, the treatment with bisphenol-A produced an up-regulation of dopamine receptor function to activate G-protein in the mouse limbic forebrain, which is thought to play a critical role for hyperlocomotion and rewarding effects by drugs of abuse. These findings suggest that prenatal and neonatal exposure to low-dose of bisphenol-A can potentiate the central dopamine receptor-dependent neurotransmission, resulting in the supersensitivity of the morphine-induced hyperlocomotion and rewarding effects in the mouse.

Animals↗

Imaging gene-substance interactions: the effect of the DRD2 TaqIA polymorphism and the dopamine agonist bromocriptine on the brain activation during the anticipation of reward.

Dopamine is known as the main neurotransmitter modulating the activation of the reward system of the brain. The DRD2 TaqIA polymorphism is associated with dopamine D2 receptor density which plays an important role in the context of reward. Persons carrying an A1 allele have a lower D2 receptor density and a higher risk to show substance abuse. The present study was designed to investigate the influence of the DRD2 TaqIA polymorphism and the selective D2 receptor agonist bromociptine on the activation of the reward system by means of functional magnetic resonance imaging (fMRI). In a double-blind crossover study with 24 participants we found an increase of reward system activation from placebo to bromocriptine only in subjects carrying the A1 allele. Furthermore, only A1 carrier showed an increase of performance under bromocriptine. The results are interpreted as reflecting a specific sensitivity for dopamine agonists in persons carrying an A1 allele and may complement actual data and theories of the development of addiction disorders postulating a higher genetic risk for substance abuse in carrier of the A1 allele.

Adolescent↗

Brain mechanism of reward prediction under predictable and unpredictable environmental dynamics.

In learning goal-directed behaviors, an agent has to consider not only the reward given at each state but also the consequences of dynamic state transitions associated with action selection. To understand brain mechanisms for action learning under predictable and unpredictable environmental dynamics, we measured brain activities by functional magnetic resonance imaging (fMRI) during a Markov decision task with predictable and unpredictable state transitions. Whereas the striatum and orbitofrontal cortex (OFC) were significantly activated both under predictable and unpredictable state transition rules, the dorsolateral prefrontal cortex (DLPFC) was more strongly activated under predictable than under unpredictable state transition rules. We then modelled subjects' choice behaviours using a reinforcement learning model and a Bayesian estimation framework and found that the subjects took larger temporal discount factors under predictable state transition rules. Model-based analysis of fMRI data revealed different engagement of striatum in reward prediction under different state transition dynamics. The ventral striatum was involved in reward prediction under both unpredictable and predictable state transition rules, although the dorsal striatum was dominantly involved in reward prediction under predictable rules. These results suggest different learning systems in the cortico-striatum loops depending on the dynamics of the environment: the OFC-ventral striatum loop is involved in action learning based on the present state, while the DLPFC-dorsal striatum loop is involved in action learning based on predictable future states.

Brain↗

The rewards of music listening: response and physiological connectivity of the mesolimbic system.

Although the neural underpinnings of music cognition have been widely studied in the last 5 years, relatively little is known about the neuroscience underlying emotional reactions that music induces in listeners. Many people spend a significant amount of time listening to music, and its emotional power is assumed but not well understood. Here, we use functional and effective connectivity analyses to show for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Responses in the NAc and the VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Responses in the NAc and the hypothalamus were also strongly correlated across subjects, suggesting a mechanism by which listening to pleasant music evokes physiological reactions. Effective connectivity confirmed these findings, and showed significant VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences.

Acoustic Stimulation↗

Nucleus accumbens neurons are innately tuned for rewarding and aversive taste stimuli, encode their predictors, and are linked to motor output.

The nucleus accumbens (NAc) is a key component of the brain's reward pathway, yet little is known of how NAc cells respond to primary rewarding or aversive stimuli. Here, naive rats received brief intraoral infusions of sucrose and quinine paired with cues in a classical conditioning paradigm while the electrophysiological activity of individual NAc neurons was recorded. NAc neurons (102) were typically inhibited by sucrose (39 of 52, 75%) or excited by quinine (30 of 40, 75%) infusions. Changes in firing rate were correlated with the oromotor response to intraoral infusions. Most taste-responsive neurons responded to only one of the stimuli. NAc neurons developed responses to the cues paired with sucrose and quinine. Thus, NAc neurons are innately tuned to rewarding and aversive stimuli and rapidly develop responses to predictive cues. The results indicate that the output of the NAc is very different when rats taste rewarding versus aversive stimuli.

Action Potentials↗