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 ( NA c) 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 NA c 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). NA c 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 NA c 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. Surges in the level of motivation elicited by reward cues (i.e., changes cue‐triggered ‘wanting’) are mediated by opioid and‐or dopamine stimulations that increase reactivity of mesocorticolimbic brain circuits involving the nucleus accumbens, which dynamically compute incentive salience for a cue. Nearly the entire medial shell and the entire core can similarly mediate dopamine and opioid enhancements.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98326/1/ejn12174.pd

Instant Transformation of Learned Repulsion into Motivational “Wanting”

SummaryBackgroundLearned cues for pleasant reward often elicit desire, which, in addicts, may become compulsive. According to the dominant view in addiction neuroscience and reinforcement modeling, such desires are the simple products of learning, coming from a past association with reward outcome.ResultsWe demonstrate that cravings are more than merely the products of accumulated pleasure memories—even a repulsive learned cue for unpleasantness can become suddenly desired via the activation of mesocorticolimbic circuitry. Rats learned repulsion toward a Pavlovian cue (a briefly-inserted metal lever) that always predicted an unpleasant Dead Sea saltiness sensation. Yet, upon first reencounter in a novel sodium-depletion state to promote mesocorticolimbic reactivity (reflected by elevated Fos activation in ventral tegmentum, nucleus accumbens, ventral pallidum, and the orbitofrontal prefrontal cortex), the learned cue was instantly transformed into an attractive and powerful motivational magnet. Rats jumped and gnawed on the suddenly attractive Pavlovian lever cue, despite never having tasted intense saltiness as anything other than disgusting.ConclusionsInstant desire transformation of a learned cue contradicts views that Pavlovian desires are essentially based on previously learned values (e.g., prediction error or temporal difference models). Instead desire is recomputed at reencounter by integrating Pavlovian information with the current brain/physiological state. This powerful brain transformation reverses strong learned revulsion into avid attraction. When applied to addiction, related mesocorticolimbic transformations (e.g., drugs or neural sensitization) of cues for already-pleasant drug experiences could create even more intense cravings. This cue/state transformation helps define what it means to say that addiction hijacks brain limbic circuits of natural reward

The psychology and neurobiology of addiction: an incentive–sensitization view

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75373/1/j.1360-0443.95.8s2.19.x.pd

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

BACKGROUND: Corticotropin-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. RESULTS: Microinjections 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. CONCLUSION: We 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

Evolving Concepts of Emotion and Motivation

This review takes a historical perspective on concepts in the psychology of motivation and emotion, and surveys recent developments, debates and applications. Old debates over emotion have recently risen again. For example, are emotions necessarily subjective feelings? Do animals have emotions? I review evidence that emotions exist as core psychological processes, which have objectively detectable features, and which can occur either with subjective feelings or without them. Evidence is offered also that studies of emotion in animals can give new insights into human emotions. Beyond emotion, motivation concepts have changed over decades too, and debates still continue. Motivation was once thought in terms of aversive drives, and reward was thought of in terms of drive reduction. Motivation-as-drive concepts were largely replaced by motivation-as-incentive concepts, yet aversive drive concepts still occasionally surface in reward neuroscience today. Among incentive concepts, incentive salience is a core motivation process, mediated by brain mesocorticolimbic systems (dopamine-related systems) and sometimes called ‘wanting’ (in quotation marks), to distinguish it from cognitive forms of desire (wanting without quotation marks). Incentive salience as ‘wanting’ is separable also from pleasure ‘liking’ for the same reward, which has important implications for several human clinical disorders. Ordinarily, incentive salience adds motivational urgency to cognitive desires, but ‘wanting’ and cognitive desires can dissociate in some conditions. Excessive incentive salience can cause addictions, in which excessive ‘wanting’ can diverge from cognitive desires. Conversely, lack of incentive salience may cause motivational forms of anhedonia in depression or schizophrenia, whereas a negatively-valenced form of ‘fearful salience’ may contribute to paranoia. Finally, negative ‘fear’ and ‘disgust’ have both partial overlap but also important neural differences

Sequential super-stereotypy of an instinctive fixed action pattern in hyper-dopaminergic mutant mice: a model of obsessive compulsive disorder and Tourette's

BACKGROUND: Excessive sequential stereotypy of behavioral patterns (sequential super-stereotypy) in Tourette's syndrome and obsessive compulsive disorder (OCD) is thought to involve dysfunction in nigrostriatal dopamine systems. In sequential super-stereotypy, patients become trapped in overly rigid sequential patterns of action, language, or thought. Some instinctive behavioral patterns of animals, such as the syntactic grooming chain pattern of rodents, have sufficiently complex and stereotyped serial structure to detect potential production of overly-rigid sequential patterns. A syntactic grooming chain is a fixed action pattern that serially links up to 25 grooming movements into 4 predictable phases that follow 1 syntactic rule. New mutant mouse models allow gene-based manipulation of brain function relevant to sequential patterns, but no current animal model of spontaneous OCD-like behaviors has so far been reported to exhibit sequential super-stereotypy in the sense of a whole complex serial pattern that becomes stronger and excessively rigid. Here we used a hyper-dopaminergic mutant mouse to examine whether an OCD-like behavioral sequence in animals shows sequential super-stereotypy. Knockdown mutation of the dopamine transporter gene (DAT) causes extracellular dopamine levels in the neostriatum of these adult mutant mice to rise to 170% of wild-type control levels. RESULTS: We found that the serial pattern of this instinctive behavioral sequence becomes strengthened as an entire entity in hyper-dopaminergic mutants, and more resistant to interruption. Hyper-dopaminergic mutant mice have stronger and more rigid syntactic grooming chain patterns than wild-type control mice. Mutants showed sequential super-stereotypy in the sense of having more stereotyped and predictable syntactic grooming sequences, and were also more likely to resist disruption of the pattern en route, by returning after a disruption to complete the pattern from the appropriate point in the sequence. By contrast, wild-type mice exhibited weaker forms of the fixed action pattern, and often failed to complete the full sequence. CONCLUSIONS: Sequential super-stereotypy occurs in the complex fixed action patterns of hyper-dopaminergic mutant mice. Elucidation of the basis for sequential super-stereotypy of instinctive behavior in DAT knockdown mutant mice may offer insights into neural mechanisms of overly-rigid sequences of action or thought in human patients with disorders such as Tourette's or OCD

Cortex, striatum and cerebellum: control of serial order in a grooming sequence

Rats emit grooming actions in sequences that follow characteristic patterns of serial order. One of these patterns, a syntactic chain, has a particularly stereotyped order that recurs spontaneously during grooming thousands of times more often than could occur by chance. Previous studies have shown that performance of this sequence is impaired by excitotoxin lesions of the corpus striatum. In this study we examined whether the striatum is unique in its importance to this behavioral sequence or whether control of the sequence instead depends equally upon the cortex and cerebellum. In two experiments, a fine-grained behavioral analysis compared the effects of striatal ablation to the effects of motor cortex ablation, ablation of the entire neocortex, or ablation of the cerebellum. Cortical and cerebellar aspiration produced mere temporary deficits in grooming sequences, which appeared to reflect a general factor that was nonsequential in nature. Only striatal damage produced a permanent sequential deficit in the coordination of this syntactic grooming chain. We conclude that the striatum has a unique role in the control of behavioral serial order. This striatal role may be related to a number of sequential disorders observed in human diseases involving the striatum.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46562/1/221_2004_Article_BF00227239.pd

What psychological processes mediate feeding evoked by lateral hypothalamic electrical stimulation?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29232/1/0000287.pd

Where does damage lead to enhanced food aversion: the ventral pallidum/substantia innominata or lateral hypothalamus?

It is well known that lesions of the lateral hypothalamus (LH) produce aphagia. Several previous studies have reported that lateral hypothalamus damage produces food aversion in addition to aphagia. However, damage to other regions near the LH also produce aphagia and enhanced aversion. The purpose of this study was to resolve where the site or sites for aversion-inducing lesions is/are located. Small, bilateral excitotoxin lesions (QUIN, 10 [mu]g in 1 [mu]l or IBO, 15 [mu]g in 1 [mu]l) or bilateral sham injections of vehicle were made into the globus pallidus (GP), the ventral pallidum/substantia innominata (VP/SI) or the lateral hypothalamus (LH). Affective reactions to taste were elicited by infusing sucrose solutions (1 M) into the mouth via chronic oral cannulae. The number of aversive responses (gapes, chin-rubbing, head-shaking and forelimb flails) emitted was tallied. Individual lesions were mapped and a single `necessary and sufficient' site for damage-induced aversion was identified (the area of overlapping damage common to all rats that showed enhanced aversive reactions). To identify the lesions, two lesion-mapping techniques were used: (1) a conventional neuron-counting procedure in which an attempt is made to count all neurons within a brain region, and (2) a new modified `fractionator' procedure consisting of exhaustive 400 x magnification counts at point locations within a brain region. Results indicated that aversive reactions to food are enhanced only following bilateral neuron loss (>70%) from the caudal ventromedial VP/SI alone. This shared site has a lateral diameter of 1.0 mm, a dorsoventral diameter of 0.5 mm and a rostrocaudal diameter of 1.0 mm. Damage restricted to the LH never produced enhanced aversion even when it produced aphagia. The crucial region for aversion is located ventral and medial to the globus pallidus and dorsal and lateral to the lateral hypothalamus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30517/1/0000147.pd