Discuss the possible role of dopamine in incentive salience? How might this lead to some of the symptoms of schizophrenia?

In my essay, I will be focusing how dopamine release in the ventral stria mediates incentive salience which makes the brain direct attention to biological significant stimuli and how incentive salience is disrupted in psychiatric disorders such as schizophrenia which is responsible for some of the symptoms.

Schizophrenia is one of the most severe mental illnesses that affect individuals in their late teens and early twenties.Hallucinations, most commonly auditory ones, delusions and disorders of the form of thinking (“thought disorder”) are implicated in schizophrenia and are so called “positive” symptoms. Patients also suffer from negative symptoms such as apathy, social withdrawal and poverty of speech. The illness commonly follows a characteristic remitting relapsing course of positive symptoms.

The neurochemical basis of schizophrenia is supported by a number of models and these are useful as they provide a testable framework for studying the illness and potentially assist in the development of new treatments. The main leading model of schizophrenia is the dopamine hypothesis and is based on several lines of evidence. The main evidence is that antipsychotic drugs which are key drugs used to treat schizophrenia are antagonists at dopamine D2 receptors. The potency of these drugs has a direct correlation with their affinity for D2 dopamine receptors. Furthermore, there is evidence that rats given amphetamine enhances dopamine release and the rats demonstrate stereotyped recurrent movements which are commonly observed in catatonic schizophrenia. More recently, dopamine overactivity in the ventral striatum such as nucleus accumbens are associated in “incentive salience”. This assigns particular experiences with personal importance and this influences reward-seeking behaviour. This hypothesis in schizophrenia was developed by Shitj Kapur and he proposed that schizophrenia could be an illness of assigning inappropriate personal relevance to external as well as internal events.

When stimuli associated with drug-taking behaviour begin reinforcing themselves, incentive salience happens. Therefore if a person is not addicted to the drug and is again presented with a stimulus that is linked with a drug in the past, the craving for that drug initiates.

The incentive salience theory was based on that addiction was driven by ‘wanting’ and not by ‘liking’. If a given stimulus/event was of relevance (‘salient’), dopamine release in the ventral striatum would signal. Usually this system would be stimulated when there is a relevant appetitive or threat stimulus, so that in future the animal learns to find or avoid these same experiences (Stone et al, 2007).

The co-stimulation of other neural systems suggests the affective meaning of salience (pleasurable/fearful).Taking drugs of abuse would be described as being salient and these drugs stimulate dopamine release in ventral striatum. The stimulation of neural pathways responsible for the experience of pleasure is not relevant to drive drug dependence.

In schizophrenia the presence of abnormal salience (and personal significance) to normal internal and external events results in increased dopamine release by striatal dopaminergic neurons which causes hallucinations and delusions. Therefore in a patient suffering with schizophrenia, each and every stimulus would have its own personal significance and meaning.

Dopamine neurons such as midbrain dopamine neurons of the ventral tegmental area and substantia nigra pars compacta send projections to striatum and prefrontal cortex. These neurons are vital in the processing of rewarding stimuli which give positive reinforcing effects and induce positive hedonic reactions.

Figure 1: This figure shows the reward pathways in the brain. The nucleus accumbens have both ‘wanting’ and ‘liking’ functions. Amphetamine microinjection or 6-OHDA lesions in the accumbens alter ‘wanting’ without modulating ‘liking’.

(Cited from http://www.nida.nih.gov/pubs/teaching/Teaching3/Teaching2.html)

Dopamine encodes reward incentive salience and that it signals a reward prediction-error rule.

In response to unexpected rewarding stimuli, dopaminergic neurons demonstrate rapid and brief bursts of activity in nucleus accumbens.No activity is seen in dopaminergic neurons when an expected reward is presented (Ungless et al, 2004).

Dopaminergic neurons are only suppressed when expected reward is failed to be presented .This shows that neurons encode a reward prediction error signal. This is relevant because the reward omission event is a motivationally important non-rewarding salient event. This also shows that dopamine neurons are not all stimulated by salient stimuli but only rewarding stimuli. Tobler, Dickinson and Schultz have demonstrated this by suggesting that when a light comes on reward is initiated and when a light is with the association of tone, no reward is presented. In this example the tone predicts the reward omission (this is a stimulus which is known as a conditioned inhibitor) and hence this is non-rewarding, although it can motivate attention. A conditioned inhibitor stimulus suppresses firing of dopaminergic neurons. Therefore the unexpected reward omission or stimulus presentation which leads to a reward omission can cause suppression of dopaminergic firing. These so called events are salient because they are of motivational relevance but not rewarding. Studies show that stimuli which induce behavioural and attentional switching suggest that dopamine neurons are stimulated(Redgrave et al,1999).The experiments demonstrate that reward omission does not induce behavioural change but a perseverance of responding. However these experiments support the idea that reward omission suppresses dopaminergic firing. But others have argued that salient stimuli can also stimulate dopaminergic neurons and these stimuli are of motivational relevance. Stimuli of the aversive kind enhance firing in a few of the putative dopaminergic neurons. Physically salient sensory stimuli for example tones and lights induce rapid phasic excitations in dopaminergic neurons and hence induce dopamine release. These dopaminergic activations could represent generalizations to stimuli that are linked to reward. As the phasic dopamine response is so quick there is insufficient detailed processing of the stimuli and this could possibly result in errors of stimulus generalization (Schultz et al, 1998).

After many presentations of salient stimuli such as lights and tones, phasic stimulations are sustained and the stimuli is no longer needed.

Dopamine is responsible for inducing pleasure associated with reward, the impulse to seek rewards, the ability or reward-related cues to initiate and sustain interest, the anticipation of reward, the ability to distinguish whether the reward was better or worse than expected, the selection of attention to and behaviours which are directed toward the reward and the ability to learn of associations between rewards and their predictive cues (Leyton et al, 2007).

It is well known that mesotelencephalic ...

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After many presentations of salient stimuli such as lights and tones, phasic stimulations are sustained and the stimuli is no longer needed.

It is well known that mesotelencephalic dopamine plays a role in the incentive motivational effects of drugs as well as food and other natural incentives. Signals that predict food or drugs accessibility stimulate brain dopamine systems which enhance dopamine neurotransmission in ventral striatum (Robinson et al, 1993).

Experiments have shown that microinjections of dopamine/amphetamine directly into nucleus accumbens increases responses to conditioned incentive stimuli.

By associating with natural incentive, conditioned incentive stimuli can obtain incentive properties.

Figure 2: This diagram shows the effect of (CS+) conditioned stimulus cue presentations and amphetamine injections on responding for sucrose during extinction conditions. The presentation of the pavlovian sucrose cue initiated a rise in responding on the sucrose-associated lever. As a result of (CS+) conditioned stimulus sucrose, the incentive effect was tripled by intra-accumbens amphetamine injection as shown by the enhanced pressing by the cue. In the absence of the cue, amphetamine had minimal effects on pressing the lever (Wyvell et al, 2000).

Antagonist drugs which inhibit the stimulation of dopamine receptors impair the motivational properties of natural incentives due to a reduction in dopamine activity.

When drugs cause pleasurable responses in people, the ability to take these drugs is enhanced. Most drugs of abuse cause pleasure and euphoria and present with rewarding properties. Studies have shown that the dopaminergic system is responsible for the experience of these pleasurable feelings. Human imaging studies have also shown that striatal dopamine releases is correlated with hedonic effects such as pleasure induced by different types of drugs.

Following amphetamine administration, striatal dopamine was shown to be released and this was positively correlated with ‘drug liking’. So therefore enhanced levels of extracellular dopamine in ventral striatum are correlated with the hedonic effects of drugs of abuse.

However there is conflicting evidence from animal studies that dopamine is solely responsible for incentive salience and not pleasure. Dopamine plays a significant part in mediating natural reactions to the sensory qualities of taste. These studies have commonly used the ‘taste reactivity paradigm’ and are based on natural hedonic and aversive reactions that take place in response to foods (Robinson et al, 1993).

These hedonic reactions describe the pleasure effects and aversive reactions describe unpleasant effects of the food. The reactions of rats to taste are modulated by many of the similar things that regulate human perceptions of taste pleasure. Hunger promotes hedonic reactions of rats to sweet tastes whereas satiety inhibits the hedonic reactions. Hedonic reactions of rats to sweet tastes are replaced by aversive behavioural reactions after associative pairing of the pleasant taste with illness. Drugs which affect opioid or GABA neurotransmission can promote or inhibit the hedonic reactions of rats to tastes. The taste reactivity paradigm demonstrates that dopamine system regulates the incentive motivation of foods but not the taste pleasure and this is supported by three lines of evidence:
(1) Dopamine antagonists suppress incentive salience and they enhance hedonic reactions to pleasurable tastes. This happens vice versa for dopamine agonists.

(2)Dopamine depletion from nucleus accumbens and caudate nucleus by a bilateral toxic lesion (6-OHDA) suppresses the incentive motivation to eat and makes natural incentives irrelevant.

(3)Electrical stimulation of lateral hypothalamus also promotes motivational salience and motivates us to eat and this is partly regulated by the dopamine system. This again does not mediate hedonic reactions to pleasurable tastes.

These experiments demonstrate that neural systems responsible for ‘wanting’ food is separate from neural systems regulating ‘liking’ food and that dopamine predominantly stimulates ‘wanting’.

Dopamine is primarily involved in attention processing, especially selective attention. Patients who suffer from Parkinson’s disease have a disrupted dopaminergic system and attention processing is disturbed (Franken et al, 2005).

Dopamine may also promote attentional signalling of reward and this is of great significance in schizophrenia. It was suggested that drug dependence is linked with a raised, sensitized dopaminergic response to drug priming doses and drug-associated conditioned stimuli (Robinson et al, 1993).This sensitised dopamine release is not linked with drug liking because dopaminergic dysfunction prevented motivation for drug intake but not hedonic effects. Robinson and Berridge also suggested that dopaminergic activation of reward system regulates ‘drug wanting’ but not ‘drug liking’. It is the stimulus dependent phasic rise in presynaptic dopamine release which reflects dopaminergic dysfunction in schizophrenia and not upregulation of postsynaptic dopamine receptors (Grace et al, 1991).This was recently demonstrated by Castellana-Dao et al; 1997.The production of striatal stimulus-dependent dopamine release is raised also by blocking NMDA glutamate receptors. This demonstrates that activation of subcortical dopamine release is due to cortical glutamatergic dysfunction. This results in a disinhibition of stimulatory glutamatergic projections to midbrain dopamine cells. The rise in striatal synaptic dopamine concentrations is greatly attributed in the earliest course of the disease and is strongly correlated with positive symptoms. Addictive drugs stimulate the mesolimbic transmission and result in incentive salience. Dopamine has also been involved in transforming the perception of stimuli by attributing them with salience. The incentive sensitisation theory shows that dopamine release in the ventral stria initiates the brain’s attention towards drug associated cues and is not relevant for the hedonic effects of drug taking. Cues which signal reward cause stimulation of dopaminergic activity in the corticostriatal reward circuit which leads to excessive focus on activities that result in further drug intake. These drug-associated cues stimulate phasic dopamine release and in the ventral striatum, this regulates positive appetitive, motivational effects (Heinz et al, 2001).

Figure 3: The above diagram show that before learning a conditioned task, phasic rises of dopamine release is associated with the arrival of the unexpected reward. The diagram below demonstrates that once primate learns that food reward is predicted by a conditioned stimulus, the dopaminergic neurons release dopamine after presentation of the conditioned stimulus (in this case the light).These figures show that phasic dopamine release is commonly associated with unpredicted rewards and conditioned cues that predict reward. In response to these reward-linked cues, incentive salience occurs but is not needed for the pleasure of reward consumption (Heinz et al, 2001).

In the prefrontal cortex, neurons responsible for working memory and which encode important information on the reward that has been previously linked with the stimulus are stimulated by phasic dopamine release.

Sensitization occurs when the drug is consumed repeatedly, enhancement of behaviour arises (Schmidt et al, 2006).This happens in the case of psychostimulant drugs as a result of increased dopaminergic activity in the ventral tegmental area and nucleus accumbens.Sensitization is correlated with an augmented spine density in the core of the nucleus accumbens (Li et al, 2004).Once the process of sensitization has occurred, there is a memory for the context evoking the sensitized response. Hence dopamine-mediated incentive learning is the main reason for the sensitization process. When incentive learning occurs, dopaminergic neurons are stimulated, primarily by rewards. Hence previously neutral stimuli that are linked with reward have incentive salience and therefore in the future are capable to induce approach and other responses. This kind of learning will lead to an enhanced response with repeated pairings of similar stimuli with reward (Schmidt et al, 2006). The process involved in incentive learning is due to dopamine mediated alterations in glutamatergic synaptic strength. The mechanism of sensitisation demonstrates that drug associated cues become incentive salient stimuli up to a certain point at which they attain control over voluntary behaviour.

Kappur suggested that an “enhanced dopamine release independent of and out of synchrony with the context’ causes psychosis, known to be one of the symptoms of schizophrenia (Kappur et al, 2003).This excess of dopamine release causes disrupted incentive salience and attention is focused on unimportant internal and external stimuli.

In addition to reward related stimuli, punishing stimuli can also cause increased dopaminergic activity in the nucleus accumbens.But in some studies, it was suggested that dopamine is solely responsible for reward signalling(Ungless,2004).Dopamine can initiate attention specifically to conditioned incentives.

Salient sensory stimuli can also be considered to have potential rewarding properties however this may not be apparent to the experimenter and could possibly be treated as rewards by the animal, therefore resulting in stimulations of dopaminergic neurons. An example of this is when rats are presented with a choice of two levers and they prefer one of the two levers which will give rise to a visual stimulus when pressed. Auditory stimulus however can dampen responses demonstrating that this sort of stimulus has aversive properties (Reed et al, 1996).

Schultz et al have found that in non-human primate studies, unexpected reward presentation is associated with phasic dopamine release in ventral striatum and also in the prefrontal cortex and dorsal striatum. As soon as the primate learns, that food reward can be gained by the operant responding after a conditioned stimulus, the dopaminergic neurons release dopamine. This occurs after the presentation of the conditioned cue and not when the food reward is actually presented. Schultz et al have found that the pleasure associated with ingestion of food does not rely on phasic dopamine release and that the main function of the dopaminergic reward system is to drive attention towards reward-indicating stimuli and to predict reward.

Prefrontal dopaminergic neurotransmission is responsible for executive function and working memory. Dopamine release in ventral striatum induces motivation as well as interacting with psychomotor functioning (Heinz et al, 2001).In schizophrenia, a decrease in prefrontal dopamine release was found to be in conjunction with negative symptoms for example cognitive or motivational deficits. However positive symptoms such as delusions and hallucinations are associated with dysfunction of striatal dopamine release in the ventral striatum (nucleus accumbens).

Under normal conditions, the context driven activity of the dopaminergic system regulates novelty experience and the attribution of motivational salience. But in abnormal conditions such as schizophrenia, genetic and environmental predispositions causes disruption in the dopamine system and dopamine is released, independently of cue and context (Kapur et al, 2004).The normal mechanism of context driven novelty and salience acquisition is wrongly assumed by the endogenously driven assignment of novelty and salience in response to stimuli. Hence in schizophrenia the dopaminergic system creates aberrant salience and this reflects psychosis. Delusions and hallucinations reflect the psychotic state but some schizophrenic patients are said to be in a prodromal state and during this period, there is context-inappropriate firing of dopaminergic neurons and release of dopamine. This creates a sense of novelty in these sufferers. They also continue to acquire several experiences of modulated novelty and salience to previously neutral stimuli in the absence of any explanations. The patients continue to feel perplexed and confused and present with mood and behavioural modulations. They eventually feel deluded and ‘makes sense of the situations (Kapur et al, 2004).

Hence the patients explain these aberrant salience situations using a delusional framework which plays a role in guiding cognitive scheme. The disruption in the dopamine system induces delusions in psychotic patients and in combination with the patient’s personal and cultural history, this gives a concise form of the delusions. Hallucinations in this delusional framework result from a similar and a direct mechanism. This is the irregular salience of internal representations of percepts, language and memories (Kapur et al, 2003).Eventually these psychotic symptoms such as delusions and hallucinations have a major impact on the patient’s behaviour and this is when antipsychotics are introduced to the patients. Therefore in Schizophrenia, hyperactivity of the dopaminergic system results in exaggerated incentive learning, which sensitizes the individuals to environmental stimuli that would be neutral under normal circumstances(Schmidt et al,2006).It is precisely the subcortical mesolimbic dopamine projections that are hyperactive which causes hyperactivation of D2 receptors and therefore positive symptoms(Abi-dargham et al,2003).It was found from post mortem studies that there is enhanced density of striatal dopamine D2 receptors in schizophrenic patients (Seeman et al,1984).

Antipsychotics do not immediately relieve positive symptoms. They work by slowly decreasing the salience of stimuli and with each individual stimuli presentation, the salience is greatly reduced and positive symptoms are alleviated.

So in conclusion, dopamine regulates the “salience” of environmental situations and internal representations. Dopamine is more vital to incentive salience attributions to the neural representations of reward related stimuli. Dopamine neurotransmission is necessary for normal incentive salience and enhanced dopamine transmission magnifies a unique form of ‘wanting’ for reward that is specifically focused on conditioned stimuli and unconditioned stimuli. In schizophrenia hyperactivity of the dopaminergic system occurs. This results in an aberrant assignment of salience which in turn causes psychosis. Delusions experienced by the patients are a cognitive effort to make sense of these aberrantly salient situations and hallucinations demonstrate a direct experience of the aberrant salience of internal representation. Antipsychotics inhibit dopamine transmission and dampen the motivational salience of the symptoms.

References

Abi-dargham A Moore H. Prefrontal DA transmission at D1 receptors and pathology of schizophrenia (2003) Neuroscientist. 9:404-416.
Berridge K.C. The debate over dopamine's role in reward: The case for incentive salience (2007). Psychopharmacology. 191:391-431.
Dao-Castellana M.H Paillere-Martinot ML Hantraye P Attar-Levy D Remy P., Crouzel C., Artiges E., Feline A., Syrota A., Martinot J.-L. Presynaptic dopaminergic function in the striatum of schizophrenic patients(1997). Schizophrenia Research. 23:167-174.
Franken I.H.A Booij J Van Den Brink W. The role of dopamine in human addiction: From reward to motivated attention(2005). European Journal of Pharmacology. 526:199-206.
Grace A.A. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: A hypothesis for the etiology of schizophrenia(1991) Neuroscience. 41:1-24.
Heinz A. Dopaminergic dysfunction in alcoholism and schizophrenia-psychopathological and behavioral correlates(2002). Eur. Psychiatry. 17:9-16.
Kapur S. How antipsychotics become anti-'psychotic' - From dopamine to salience to psychosis(2004). Trends in Pharmacological Sciences. 25:402-406.
Kapur S. Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia(2003). American Journal of Psychiatry. 160 :13-23.
Leyton M Aan Het Rot M Booij L Baker G.B Young S.N Benkelfat C. Mood-elevating effects of d-amphetamine and incentive salience: The effect of acute dopamine precursor depletion(2007). Journal of Psychiatry and Neuroscience. 32:129-136.
Li Y Acerbo MJ., Robinson TE. The induction of behavioural sensitization is associated with cocaine-induced structural plasticity in the core (but not shell) of the nucleus accumbens(2004). European Journal of Neuroscience. 20:1647-1654.
Redgrave P Prescott T.J Gurney K. Is the short-latency dopamine response too short to signal reward error?(1999).Trends in Neurosciences. 22:146-151.
Reed P Mitchell C Nokes T. Intrinsic reinforcing properties of putatively neutral stimuli in an instrumental two-lever discrimination task (1996) Animal Learning and Behavior. 24:38-45.
Robinson T.E Berridge K.C. The neural basis of drug craving: An incentive-sensitization theory of addiction(1993) Brain Research Reviews. 18:247-291.
Schmidt WJ and RJ Beninger. Behavioural sensitization in addiction, schizophrenia, Parkinson's disease and dyskinesia (2006) Neurotox. Res. 10:161-166.
Schultz W. Erratum: Predictive reward signal of dopamine neurons(1998).Journal of Neurophysiology.80:1-7.
Seeman P Ulpian C Bergeron C. Bimodal distribution of dopamine receptor densities in brains of schizophrenics(1984). Science. 225:728-730
Stone J.M Morrison P.D Pilowsky L.S. Glutamate and dopamine dysregulation in schizophrenia - A synthesis and selective review(2007). Journal of Psychopharmacology. 21:440-452.
Ungless M.A. Dopamine: The salient issue (2004). Trends in Neurosciences. 27:702-706), 2004.
Wyvell C.L Berridge K.C. Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: Enhancement of reward 'wanting' without enhanced 'liking' or response reinforcement (2000).Journal of Neuroscience. 20: 8122-8130.
Dr Stone’s Lecture notes on Schizophrenia.
http://www.nida.nih.gov/pubs/teaching/Teaching3/Teaching2.html

Discuss the possible role of dopamine in incentive salience? How might this lead to some of the symptoms of schizophrenia?

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