Susana Peciña

Hedonic Hot Spot in Nucleus Accumbens Shell: Where Do μ-Opioids Cause Increased Hedonic Impact of Sweetness?

μ-Opioid systems in the medial shell of the nucleus accumbens contribute to hedonic impact (“liking”) for sweetness, food, and drug rewards. But does the entire medial shell generate reward hedonic impact? Or is there a specific localized site for opioid enhancement of hedonic “liking” in the medial shell? And how does enhanced taste hedonic impact relate to opioid-stimulated increases in food intake? Here, we used a functional mapping procedure based on microinjection Fos plumes to localize opioid substrates in the medial shell of the nucleus accumbens that cause enhanced “liking” reactions to sweet pleasure and that stimulate food intake. We mapped changes in affective orofacial reactions of “liking”/“disliking” elicited by sucrose or quinine tastes after d-Ala2-N-Me-Phe4-Glycol5-enkephalin (DAMGO) microinjections in rats and compared hedonic increases to food intake stimulated at the same sites. Our maps indicate that opioid-induced increases in sucrose hedonic impact are generated by a localized cubic millimeter site in a rostrodorsal region of the medial shell. In contrast, all regions of the medial shell generated DAMGO-induced robust increases in eating behavior and food intake. Thus, our results identify a locus for opioid amplification of hedonic impact and reveal a distinction between opioid mechanisms of food intake and hedonic impact. Opioid circuits for stimulating food intake are widely distributed, whereas hedonic “liking” circuits are more tightly localized in the rostromedial shell of the nucleus accumbens.

Hedonic Hot Spots in the Brain

Hedonic “liking” for sensory pleasures is an important aspect of reward, and excessive ‘liking’ of particular rewards might contribute to excessive consumption and to disorders such as obesity. The present review aims to summarize recent advances in the identification of brain substrates for food ‘liking’ with a focus on opioid hot spots in the nucleus accumbens and ventral pallidum. Drug microinjection studies have shown that opioids in both areas amplify the ‘liking’ of sweet taste rewards. Modern neuroscience tools such as Fos plume mapping have further identified hedonic hot spots within the accumbens and pallidum, where opioids are especially tuned to magnify ‘liking’ of food rewards. Hedonic hot spots in different brain structures may interact with each other within the larger functional circuitry that interconnects them. Better understanding of how brain hedonic hot spots increase the positive affective impact of natural sensory pleasures will help characterize the neural mechanisms potentially involved in ‘liking’ for many rewards.

Ventral pallidal neurons code incentive motivation: amplification by mesolimbic sensitization and amphetamine.

Neurons in ventral pallidum fire to reward and its predictive cues. We tested mesolimbic activation effects on neural reward coding. Rats learned that a Pavlovian conditioned stimulus (CS+1 tone) predicted a second conditioned stimulus (CS+2 feeder click) followed by an unconditioned stimulus (UCS sucrose reward). Some rats were sensitized to amphetamine after training. Electrophysiological activity of ventral pallidal neurons to stimuli was later recorded under the influence of vehicle or acute amphetamine injection. Both sensitization and acute amphetamine increased ventral pallidum firing at CS+2 (population code and rate code). There were no changes at CS+1 and minimal changes to UCS. With a new ‘Profile Analysis’, we show that mesolimbic activation by sensitization/amphetamine incrementally shifted neuronal firing profiles away from prediction signal coding (maximal at CS+1) and toward incentive coding (maximal at CS+2), without changing hedonic impact coding (maximal at UCS). This pattern suggests mesolimbic activation specifically amplifies a motivational transform of CS+ predictive information into incentive salience coded by ventral pallidal neurons. Our results support incentive‐sensitization predictions and suggest why cues temporally proximal to drug presentation may precipitate cue‐triggered relapse in human addicts.

Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress?

BackgroundCorticotropin-releasing factor (CRF) is typically considered to mediate aversive aspects of stress, fear and anxiety. However, CRF release in the brain is also elicited by natural rewards and incentive cues, raising the possibility that some CRF systems in the brain mediate an independent function of positive incentive motivation, such as amplifying incentive salience. Here we asked whether activation of a limbic CRF subsystem magnifies the increase in positive motivation for reward elicited by incentive cues previously associated with that reward, in a way that might exacerbate cue-triggered binge pursuit of food or other incentives? We assessed the impact of CRF microinjections into the medial shell of nucleus accumbens using a pure incentive version of Pavlovian-Instrumental transfer, a measure specifically sensitive to the incentive salience of reward cues (which it separates from influences of aversive stress, stress reduction, frustration and other traditional explanations for stress-increased behavior). Rats were first trained to press one of two levers to obtain sucrose pellets, and then separately conditioned to associate a Pavlovian cue with free sucrose pellets. On test days, rats received microinjections of vehicle, CRF (250 or 500 ng/0.2 μl) or amphetamine (20 μg/0.2 μl). Lever pressing was assessed in the presence or absence of the Pavlovian cues during a half-hour test.ResultsMicroinjections of the highest dose of CRF (500 ng) or amphetamine (20 μg) selectively enhanced the ability of Pavlovian reward cues to trigger phasic peaks of increased instrumental performance for a sucrose reward, each peak lasting a minute or so before decaying after the cue. Lever pressing was not enhanced by CRF microinjections in the baseline absence of the Pavlovian cue or during the presentation without a cue, showing that the CRF enhancement could not be explained as a result of generalized motor arousal, frustration or stress, or by persistent attempts to ameliorate aversive states.ConclusionWe conclude that CRF in nucleus accumbens shell amplifies positive motivation for cued rewards, in particular by magnifying incentive salience that is attributed to Pavlovian cues previously associated with those rewards. CRF-induced magnification of incentive salience provides a novel explanation as to why stress may produce cue-triggered bursts of binge eating, drug addiction relapse, or other excessive pursuits of rewards.

Dopamine or opioid stimulation of nucleus accumbens similarly amplify cue-triggered ‘wanting’ for reward: entire core and medial shell mapped as substrates for PIT enhancement

Pavlovian cues [conditioned stimulus (CS+)] often trigger intense motivation to pursue and consume related reward [unconditioned stimulus (UCS)]. But cues do not always trigger the same intensity of motivation. Encountering a reward cue can be more tempting on some occasions than on others. What makes the same cue trigger more intense motivation to pursue reward on a particular encounter? The answer may be the level of incentive salience (‘wanting’) that is dynamically generated by mesocorticolimbic brain systems, influenced especially by dopamine and opioid neurotransmission in the nucleus accumbens (NAc) at that moment. We tested the ability of dopamine stimulation (by amphetamine microinjection) vs. mu opioid stimulation [by d‐Ala, nMe‐Phe, Glyol‐enkephalin (DAMGO) microinjection] of either the core or shell of the NAc to amplify cue‐triggered levels of motivation to pursue sucrose reward, measured with a Pavlovian‐Instrumental Transfer (PIT) procedure, a relatively pure assay of incentive salience. Cue‐triggered ‘wanting’ in PIT was enhanced by amphetamine or DAMGO microinjections equally, and also equally at nearly all sites throughout the entire core and medial shell (except for a small far‐rostral strip of shell). NAc dopamine/opioid stimulations specifically enhanced CS+ ability to trigger phasic peaks of ‘wanting’ to obtain UCS, without altering baseline efforts when CS+ was absent. We conclude that dopamine/opioid stimulation throughout nearly the entire NAc can causally amplify the reactivity of mesocorticolimbic circuits, and so magnify incentive salience or phasic UCS ‘wanting’ peaks triggered by a CS+. Mesolimbic amplification of incentive salience may explain why a particular cue encounter can become irresistibly tempting, even when previous encounters were successfully resisted before.

Sparing of behavior and basal extracellular dopamine after 6-hydroxydopamine lesions of the nigrostriatal pathway in rats exposed to a prelesion sensitizing regimen of amphetamine

Repeated administration of amphetamine leads to enduring augmentation of its behavioral-activating effects, enhanced dopamine (DA) release in striatal regions, and morphological changes in DA target neurons. Here we show that exposure to a 2-week escalating-dose regimen of amphetamine prevents behavioral asymmetries of forelimb use and spontaneous (drug-independent) turning behavior following unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway made 7-14 days after termination of amphetamine treatment (Experiments 1-3). Exposure to three nonescalating injections of amphetamine 7 days before 6-OHDA lesions had no effect (Experiment 2). Prelesion amphetamine treatment led to normalization of basal extracellular levels of striatal DA as measured by microdialysis on days 11-14 and 25-28 after lesioning (Experiment 3). However, there were no significant differences between treatment groups in postmortem tissue levels of DA and its metabolites, indicating a dissociation between the DA depletion and the extracellular levels of DA as measured by microdialysis. Finally, rats exposed to the escalating amphetamine regimen had reduced lesion-induced loss of TH-IR cells in the ipsilateral DA cell body regions (Experiment 3). Thus, prelesion exposure to the escalating doses of amphetamine may render the cells resistant to the consequences of damage after subsequent 6-OHDA lesions, possibly by accelerating the development of compensatory changes in the DA neurons that typically accompany behavioral recovery. The potential role of amphetamine-induced endogenous neurotrophic factors in the behavioral sparing and normalization of basal extracellular DA levels observed after subsequent 6-OHDA lesions is discussed.

Ischemic preconditioning procedure induces behavioral deficits in the absence of brain injury

Abstract Preconditioning describes a phenomenon whereby a sub–injury inducing insult can protect against a later larger injury. Thus, short–term cerebral ischemia can protect against a prolonged ischemia (ischemic preconditioning). This study examines rats undergoing ischemic preconditioning to test whether preconditioning may cause changes in behavior even though they do not cause an identifiable brain lesion. Rats had a transient (15 minutes) middle cerebral artery occlusion or a sham occlusion. Forelimb placing and forelimb use asymmetry tests were used to assess behavioral deficits. Brain histology, microglia activation, heat shock protein and ferritin levels were also examined. Ischemic preconditioning did not cause brain infarction, but induced behavioral changes. There were no significant differences between ischemic preconditioning and sham rats in the two behavioral tests at day one. However, the ischemic preconditioning group showed impaired forelimb placing at days 3, 7 and 14 (p<0.05). That group also had a significant (p<0.05) behavioral deficit in the forelimb use asymmetry test at days 3 and 7 (but not 14). Our present study demonstrated that a behavioral deficit occurred in ischemic preconditioning. This raises the question of whether induction of protective mechanisms by preconditioning stimuli necessarily involves some form of brain injury, detectable by changes in behavior though not by a lesion. This would be consistent with data suggesting that brain injury can initiate mechanisms potentially favorable to neuroplasticity and neuroprotection.

Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: Implications for anhedonia, anxiety and treatment response

Dopamine (DA) neurotransmission within the brains reward circuit has been implicated in the pathophysiology of depression and in both, cognitive and pharmacological mechanisms of treatment response. Still, a direct relationship between measures of DA neurotransmission and reward-related deficits in patients with depression has not been demonstrated. To gain insight into the symptom-specific alterations in the DA system in patients with depression, we used positron emission tomography (PET) and the D2/3 receptor-selective radiotracer [11C]raclopride in twenty-three non-smoking un-medicated Major Depressive Disorder (MDD) patients and sixteen healthy controls (HC). We investigated the relationship between D2/3 receptor availability and baseline measures of depression severity, anxiety, anhedonia, and cognitive and pharmacological mechanisms of treatment response. We found that, compared to controls, patients with depression showed greater D2/3 receptor availability in several striatal regions, including the bilateral ventral pallidum/nucleus accumbens (vPAL/NAc), and the right ventral caudate and putamen. In the depressed sample, D2/3 receptor availability in the caudal portion of the ventral striatum (NAc/vPAL) correlated with higher anxiety symptoms, whereas D2/3 receptor availability in the rostral area of the ventral striatum correlated negatively with the severity of motivational anhedonia. Finally, MDD non-remitters showed greater baseline anxiety, greater D2/3 availability in the NAc/vPAL, and greater placebo-induced DA release in the bilateral NAc. Our results demonstrate abnormally high D2/3 receptor availability in the ventral striatum of patients with MDD, which seem to be associated with comorbid anxiety symptoms and lack of response to antidepressants.

Implicit learning and emotional responses in nine-month-old infants

ABSTRACT To study the interplay between motor learning and emotional responses of young infants, we developed a contingent learning paradigm that included two related, difficult, operant tasks. We also coded facial expression to characterise emotional response to learning. In a sample of nine-month-old healthy Chinese infants, 44.7% achieved learning threshold during this challenging arm-conditioning test. Some evidence of learning was observed at the beginning of the second task. The lowest period of negative emotions coincided with the period of maximum movement responses after the initiation of the second task, and movement responses negatively correlated with the frequency of negative emotions. Positive emotions, while generally low throughout the task, increased during peak performance especially for learners. Peak frequency of movement responses was positively correlated with the frequency of positive emotions. Despite the weak evidence of learning this difficult task, our results from the learners would suggest that increasing positive emotions, and perhaps down-regulating negative emotional responses, may be important for improving performance and learning a complex operant task in infancy. Further studies are necessary to determine the role of emotions in learning difficult tasks in infancy.