Like other amino acids, tryptophan is a zwitterion at physiological pH where the amino group is protonated (–NH3+; pKa = 9.39) and the carboxylic acid is deprotonated ( –COO−; pKa = 2.38).
Function
Metabolism of l-tryptophan
into serotonin and melatonin (left) and niacin (right). Transformed
functional groups after each chemical reaction are highlighted in red.
Amino acids, including tryptophan, are used as building blocks in protein biosynthesis, and proteins
are required to sustain life. Many animals (including humans) cannot
synthesize tryptophan: they need to obtain it through their diet, making
it an essential amino acid.
Tryptophan is among the less common amino acids found in proteins, but
it plays important structural or functional roles whenever it occurs.
For instance, tryptophan and tyrosine residues play special roles in "anchoring" membrane proteins within the cell membrane. In addition, tryptophan functions as a biochemical precursor for the following compounds:
The disorder fructose malabsorption causes improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood, and depression.
In bacteria that synthesize tryptophan, high cellular levels of this amino acid activate a repressor protein, which binds to the trp operon. Binding of this repressor to the tryptophan operon prevents transcription
of downstream DNA that codes for the enzymes involved in the
biosynthesis of tryptophan. So high levels of tryptophan prevent
tryptophan synthesis through a negative feedback
loop, and when the cell's tryptophan levels go down again,
transcription from the trp operon resumes. This permits tightly
regulated and rapid responses to changes in the cell's internal and
external tryptophan levels.
In
2002, the U.S. Institute of Medicine set a Recommended Dietary
Allowance (RDA) of 5 mg/kg body weight/day of Tryptophan for adults 19
years and over.
Because tryptophan is converted into 5-hydroxytryptophan
(5-HTP) which is then converted into the neurotransmitter serotonin, it
has been proposed that consumption of tryptophan or 5-HTP may improve
depression symptoms by increasing the level of serotonin in the brain.
Tryptophan is sold over the counter in the United States (after being banned to varying extents between 1989 and 2005) and the United Kingdom as a dietary supplement for use as an antidepressant, anxiolytic, and sleep aid. It is also marketed as a prescription drug in some European countries for the treatment of major depression. There is evidence that blood tryptophan levels are unlikely to be altered by changing the diet,
but consuming purified tryptophan increases the serotonin level in the
brain, whereas eating foods containing tryptophan does not. This is because the transport system that brings tryptophan across the blood–brain barrier also transports other amino acids which are contained in protein food sources. High blood plasma
levels of other large neutral amino acids prevent the plasma
concentration of tryptophan from increasing brain concentration levels.
In 2001 a Cochrane review
of the effect of 5-HTP and tryptophan on depression was published. The
authors included only studies of a high rigor and included both 5-HTP
and tryptophan in their review because of the limited data on either. Of
108 studies of 5-HTP and tryptophan on depression published between
1966 and 2000, only two met the authors' quality standards for
inclusion, totaling 64 study participants. The substances were more
effective than placebo
in the two studies included but the authors state that "the evidence
was of insufficient quality to be conclusive" and note that "because
alternative antidepressants exist which have been proven to be effective
and safe, the clinical usefulness of 5-HTP and tryptophan is limited at
present". The use of tryptophan as an adjunctive therapy in addition to standard treatment for mood and anxiety disorders is not supported by the scientific evidence.
Tryptophan taken as a dietary supplement (such as in tablet form) has the potential to cause serotonin syndrome when combined with antidepressants of the MAOI or SSRI class or other strongly serotonergic drugs. Because tryptophan supplementation has not been thoroughly studied in a clinical setting, its interactions with other drugs are not well known.
Isolation
The isolation of tryptophan was first reported by Frederick Hopkins in 1901. Hopkins recovered tryptophan from hydrolysedcasein, recovering 4–8 g of tryptophan from 600 g of crude casein.
Biosynthesis and industrial production
As
an essential amino acid, tryptophan is not synthesized from simpler
substances in humans and other animals, so it needs to be present in the
diet in the form of tryptophan-containing proteins. Plants and microorganisms commonly synthesize tryptophan from shikimic acid or anthranilate: anthranilate condenses with phosphoribosylpyrophosphate (PRPP), generating pyrophosphate as a by-product. The ring of the ribosemoiety is opened and subjected to reductive decarboxylation, producing indole-3-glycerol phosphate; this, in turn, is transformed into indole. In the last step, tryptophan synthasecatalyzes the formation of tryptophan from indole and the amino acid serine.
There was a large outbreak of eosinophilia-myalgia syndrome (EMS) in the U.S. in 1989, with more than 1,500 cases reported to the CDC and at least 37 deaths. After preliminary investigation revealed that the outbreak was linked to intake of tryptophan, the U.S. Food and Drug Administration (FDA) recalled tryptophan supplements in 1989 and banned most public sales in 1990, with other countries following suit.
Subsequent studies suggested that EMS was linked to specific
batches of L-tryptophan supplied by a single large Japanese
manufacturer, Showa Denko.
It eventually became clear that recent batches of Showa Denko's
L-tryptophan were contaminated by trace impurities, which were
subsequently thought to be responsible for the 1989 EMS outbreak. However, other evidence suggests that tryptophan itself may be a potentially major contributory factor in EMS.
The FDA loosened its restrictions on sales and marketing of tryptophan in February 2001, but continued to limit the importation of tryptophan not intended for an exempted use until 2005.
The fact that the Showa Denko facility used genetically engineered
bacteria to produce the contaminated batches of L-tryptophan later
found to have caused the outbreak of eosinophilia-myalgia syndrome has
been cited as evidence of a need for "close monitoring of the chemical
purity of biotechnology-derived products". Those calling for purity monitoring have, in turn, been criticized as anti-GMO activists who overlook possible non-GMO causes of contamination and threaten the development of biotech.
Turkey meat and drowsiness
A common assertion in the US is that heavy consumption of turkey meat results in drowsiness, due to high levels of tryptophan contained in turkey. However, the amount of tryptophan in turkey is comparable to that contained in other meats. Drowsiness after eating may be caused by other foods eaten with the turkey, particularly carbohydrates. Ingestion of a meal rich in carbohydrates triggers the release of insulin. Insulin in turn stimulates the uptake of large neutral branched-chain amino acids
(BCAA), but not tryptophan, into muscle, increasing the ratio of
tryptophan to BCAA in the blood stream. The resulting increased
tryptophan ratio reduces competition at the large neutral amino acid transporter (which transports both BCAA and aromatic amino acids), resulting in more uptake of tryptophan across the blood–brain barrier into the cerebrospinal fluid (CSF). Once in the CSF, tryptophan is converted into serotonin in the raphe nuclei by the normal enzymatic pathway. The resultant serotonin is further metabolised into melatonin by the pineal gland. Hence, these data suggest that "feast-induced drowsiness"—or postprandial somnolence—may
be the result of a heavy meal rich in carbohydrates, which indirectly
increases the production of melatonin in the brain, and thereby promotes
sleep.
Tryptophan affects brain serotonin synthesis when given orally in
a purified form and is used to modify serotonin levels for research.
Low brain serotonin level is induced by administration of
tryptophan-poor protein in a technique called "acute tryptophan
depletion".
Studies using this method have evaluated the effect of serotonin on
mood and social behavior, finding that serotonin reduces aggression and
increases agreeableness.
Fluorescence
Tryptophan is an important intrinsic fluorescent probe (amino acid),
which can be used to estimate the nature of the microenvironment around
the tryptophan residue. Most of the intrinsic fluorescence emissions of
a folded protein are due to excitation of tryptophan residues.
reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
The reward system is a group of neural structures responsible for incentive salience (i.e., motivation and "wanting", desire, or craving for a reward), associative learning (primarily positive reinforcement and classical conditioning), and positively-valencedemotions, particularly ones which involve pleasure as a core component (e.g., joy, euphoria and ecstasy).
Reward is the attractive and motivational property of a stimulus that
induces appetitive behavior, also known as approach behavior, and
consummatory behavior. In its description of a rewarding stimulus (i.e., "a reward"), a review on reward neuroscience noted, "any
stimulus, object, event, activity, or situation that has the potential
to make us approach and consume it is by definition a reward". In operant conditioning, rewarding stimuli function as positive reinforcers; however, the converse statement also holds true: positive reinforcers are rewarding.
Primary rewards are a class of rewarding stimuli which facilitate the survival of one's self and offspring, and include homeostatic (e.g., palatable food) and reproductive (e.g., sexual contact and parental investment) rewards. Intrinsic rewards are unconditioned rewards that are attractive and motivate behavior because they are inherently pleasurable.
Extrinsic rewards (e.g., money or seeing one's favorite sports team
winning a game) are conditioned rewards that are attractive and motivate
behavior, but are not inherently pleasurable. Extrinsic rewards derive their motivational value as a result of a learned association (i.e., conditioning) with intrinsic rewards. Extrinsic rewards may also elicit pleasure (e.g., euphoria from winning a lot of money in a lottery) after being classically conditioned with intrinsic rewards.
Survival for most animal species depends upon maximizing contact
with beneficial stimuli and minimizing contact with harmful stimuli.
Reward cognition serves to increase the likelihood of survival and
reproduction by causing associative learning, eliciting approach and
consummatory behavior, and triggering positively-valenced emotions. Thus, reward is a mechanism that evolved to help increase the adaptive fitness of animals.
Terms that are commonly used to describe behavior related to the
"wanting" or desire component of reward include appetitive behavior,
approach behavior, preparatory behavior, instrumental behavior,
anticipatory behavior, and seeking.
Terms that are commonly used to describe behavior related to the
"liking" or pleasure component of reward include consummatory behavior
and taking behavior.
The three primary functions of rewards are their capacity to:
Most of the dopamine pathways (i.e., neurons that use the neurotransmitterdopamine to communicate with other neurons) that project out of the ventral tegmental area are part of the reward system; in these pathways, dopamine acts on D1-like receptors or D2-like receptors to either stimulate (D1-like) or inhibit (D2-like) the production of cAMP. The GABAergicmedium spiny neurons of the striatum are components of the reward system as well.
The glutamatergic projection nuclei in the subthalamic nucleus,
prefrontal cortex, hippocampus, thalamus, and amygdala connect to other
parts of the reward system via glutamate pathways. The medial forebrain bundle, which is a set of many neural pathways that mediate brain stimulation reward (i.e., reward derived from direct electrochemical stimulation of the lateral hypothalamus), is also a component of the reward system.
Two theories exist with regard to the activity of the nucleus
accumbens and the generation liking and wanting. The inhibition (or
hyperpolarization) hypothesis proposes that the nucleus accumbens
exerts tonic inhibitory effects on downstream structures such as the
ventral pallidum, hypothalamus or ventral tegmental area, and that in
inhibiting MSNs in the nucleus accumbens (NAcc), these structures are excited, "releasing" reward related behavior. While GABA receptoragonists are capable of eliciting both "liking" and "wanting" reactions in the nucleus accumbens, glutaminergic inputs from the basolateral amygdala,
ventral hippocampus, and medial prefrontal cortex can drive incentive
salience. Furthermore, while most studies find that NAcc neurons reduce
firing in response to reward, a number of studies find the opposite
response. This had led to the proposal of the disinhibition (or
depolarization) hypothesis, that proposes that excitation or NAcc
neurons, or at least certain subsets, drives reward related behavior.
After nearly 50 years of research on brain-stimulation reward,
experts have certified that dozens of sites in the brain will maintain intracranial self-stimulation.
Regions include the lateral hypothalamus and medial forebrain bundles,
which are especially effective. Stimulation there activates fibers that
form the ascending pathways; the ascending pathways include the mesolimbic dopamine pathway, which projects from the ventral tegmental area to the nucleus accumbens.
There are several explanations as to why the mesolimbic dopamine
pathway is central to circuits mediating reward. First, there is a
marked increase in dopamine release from the mesolimbic pathway when
animals engage in intracranial self-stimulation.
Second, experiments consistently indicate that brain-stimulation reward
stimulates the reinforcement of pathways that are normally activated by
natural rewards, and drug reward
or intracranial self-stimulation can exert more powerful activation of
central reward mechanisms because they activate the reward center
directly rather than through the peripheral nerves.
Third, when animals are administered addictive drugs or engage in
naturally rewarding behaviors, such as feeding or sexual activity, there
is a marked release of dopamine within the nucleus accumbens. However, dopamine is not the only reward compound in the brain.
Pleasure centers
Pleasure
is a component of reward, but not all rewards are pleasurable (e.g.,
money does not elicit pleasure unless this response is conditioned). Stimuli that are naturally pleasurable, and therefore attractive, are known as intrinsic rewards, whereas stimuli that are attractive and motivate approach behavior, but are not inherently pleasurable, are termed extrinsic rewards. Extrinsic rewards (e.g., money) are rewarding as a result of a learned association with an intrinsic reward.
In other words, extrinsic rewards function as motivational magnets that
elicit "wanting", but not "liking" reactions once they have been
acquired.
The reward system contains pleasure centers or hedonic hotspots – i.e., brain structures that mediate pleasure or "liking" reactions from intrinsic rewards. As of October 2017, hedonic hotspots have been identified in subcompartments within the nucleus accumbens shell, ventral pallidum, parabrachial nucleus, orbitofrontal cortex (OFC), and insular cortex.
The hotspot within the nucleus accumbens shell is located in the
rostrodorsal quadrant of the medial shell, while the hedonic coldspot is
located in a more posterior region. The posterior ventral pallidum
also contains a hedonic hotspot, while the anterior ventral pallidum
contains a hedonic coldspot. Microinjections of opioids, endocannabinoids, and orexin are capable of enhancing liking in these hotspots.
The hedonic hotspots located in the anterior OFC and posterior insula
have been demonstrated to respond to orexin and opioids, as has the
overlapping hedonic coldspot in the anterior insula and posterior OFC. On the other hand, the parabrachial nucleus hotspot has only been demonstrated to respond to benzodiazepine receptor agonists.
Hedonic hotspots are functionally linked, in that activation of
one hotspot results in the recruitment of the others, as indexed by the induced expression of c-Fos, an immediate early gene. Furthermore, inhibition of one hotspot results in the blunting of the effects of activating another hotspot.
Therefore, the simultaneous activation of every hedonic hotspot within
the reward system is believed to be necessary for generating the
sensation of an intense euphoria.
Wanting
Tuning
of appetitive and defensive reactions in the nucleus accumbens shell.
(Above) AMPA blockade requires D1 function in order to produce motivated
behaviors, regardless of valence, and D2 function to produce defensive
behaviors. GABA agonism, on the other hand, does not requires dopamine
receptor function.(Below)The expansion of the anatomical regions that
produce defensive behaviors under stress, and appetitive behaviors in
the home environment produced by AMPA antagonism. This flexibility is
less evident with GABA agonism.
Incentive salience
is the "wanting" or "desire" attribute, which includes a motivational
component, that is assigned to a rewarding stimulus by the nucleus accumbens shell (NAcc shell). The degree of dopamine neurotransmission into the NAcc shell from the mesolimbic pathway is highly correlated with the magnitude of incentive salience for rewarding stimuli.
Activation of the dorsorostral region of the nucleus accumbens
correlates with increases in wanting without concurrent increases in
liking. However, dopaminergic neurotransmission into the nucleus accumbens shell is responsible not only for appetitive motivational salience
(i.e., incentive salience) towards rewarding stimuli, but also for
aversive motivational salience, which directs behavior away from
undesirable stimuli.
In the dorsal striatum, activation of D1 expressing MSNs produces
appetitive incentive salience, while activation of D2 expressing MSNs
produces aversion. In the NAcc, such a dichotomy is not as clear cut,
and activation of both D1 and D2 MSNs is sufficient to enhance
motivation, likely via disinhibiting the VTA through inhibiting the ventral pallidum.
Robinson and Berridge's 1993 incentive-sensitization theory proposed that reward
contains separable psychological components: wanting (incentive) and
liking (pleasure). To explain increasing contact with a certain stimulus
such as chocolate, there are two independent factors at work – our
desire to have the chocolate (wanting) and the pleasure effect of the
chocolate (liking). According to Robinson and Berridge, wanting and
liking are two aspects of the same process, so rewards are usually
wanted and liked to the same degree. However, wanting and liking also
change independently under certain circumstances. For example, rats that
do not eat after receiving dopamine (experiencing a loss of desire for
food) act as though they still like food. In another example, activated
self-stimulation electrodes in the lateral hypothalamus of rats increase
appetite, but also cause more adverse reactions to tastes such as sugar
and salt; apparently, the stimulation increases wanting but not liking.
Such results demonstrate that our reward system includes independent
processes of wanting and liking. The wanting component is thought to be
controlled by dopaminergic pathways, whereas the liking component is thought to be controlled by opiate-benzodiazepine systems.
Other Animals vs. humans
Animals quickly learn to press a bar to obtain an injection of opiates directly into the midbrain tegmentum or the nucleus accumbens. The same animals do not work to obtain the opiates if the dopaminergic neurons of the mesolimbic pathway are inactivated. In this perspective, animals, like humans, engage in behaviors that increase dopamine release.
Kent Berridge, a researcher in affective neuroscience, found that sweet (liked ) and bitter (disliked ) tastes produced distinct orofacial expressions,
and these expressions were similarly displayed by human newborns,
orangutans, and rats. This was evidence that pleasure (specifically, liking)
has objective features and was essentially the same across various
animal species. Most neuroscience studies have shown that the more
dopamine released by the reward, the more effective the reward is. This
is called the hedonic impact, which can be changed by the effort for the
reward and the reward itself. Berridge discovered that blocking
dopamine systems did not seem to change the positive reaction to
something sweet (as measured by facial expression). In other words, the
hedonic impact did not change based on the amount of sugar. This
discounted the conventional assumption that dopamine mediates pleasure.
Even with more-intense dopamine alterations, the data seemed to remain
constant. However, a clinical study from January 2019 that assessed the effect of a dopamine precursor (levodopa), antagonist (risperidone), and a placebo on reward responses to music – including the degree of pleasure experienced during musical chills, as measured by changes in electrodermal activity
as well as subjective ratings – found that the manipulation of dopamine
neurotransmission bidirectionally regulates pleasure cognition
(specifically, the hedonic impact of music) in human subjects. This research demonstrated that increased dopamine neurotransmission acts as a sine qua non condition for pleasurable hedonic reactions to music in humans.
Berridge developed the incentive salience hypothesis to address the wanting
aspect of rewards. It explains the compulsive use of drugs by drug
addicts even when the drug no longer produces euphoria, and the cravings
experienced even after the individual has finished going through
withdrawal. Some addicts respond to certain stimuli involving neural
changes caused by drugs. This sensitization in the brain is similar to
the effect of dopamine because wanting and liking
reactions occur. Human and animal brains and behaviors experience
similar changes regarding reward systems because these systems are so
prominent.
Learning
Rewarding stimuli can drive learning in both the form of classical conditioning (Pavlovian conditioning) and operant conditioning (instrumental conditioning).
In classical conditioning, a reward can act as an unconditioned
stimulus that, when associated with the conditioned stimulus, causes the
conditioned stimulus to elicit both musculoskeletal (in the form of
simple approach and avoidance behaviors) and vegetative responses. In
operant conditioning, a reward may act as a reinforcer in that it increases or supports actions that lead to itself.
Learned behaviors may or may not be sensitive to the value of the
outcomes they lead to; behaviors that are sensitive to the contingency
of an outcome on the performance of an action as well as the outcome
value are goal-directed, while elicited actions that are insensitive to contingency or value are called habits.
This distinction is thought to reflected two forms of learning, model
free and model based. Model free learning involves the simple caching
and updating of values. In contrast, model based learning involves the
storage and construction of an internal model of events that allows
inference and flexible prediction. Although pavlovian conditioning is
generally assumed to be model-free, the incentive salience assigned to a
conditioned stimulus is flexible with regard to changes in internal
motivational states.
Distinct neural systems are responsible for learning associations
between stimuli and outcomes, actions and outcomes, and stimuli and
responses. Although classical conditioning is not limited to the reward
system, the enhancement of instrumental performance by stimuli (i.e., Pavlovian-instrumental transfer) requires the nucleus accumbens. Habitual and goal directed instrumental learning are dependent upon the lateral striatum and the medial striatum, respectively.
During instrumental learning, opposing changes in the ratio of AMPA to NMDA receptors and phosphorylated ERK occurs in the D1-type and D2-type MSNs that constitute the direct and indirect pathways, respectively.
These changes in synaptic plasticity and the accompanying learning is
dependent upon activation of striatal D1 and NMDA receptors. The
intracellular cascade activated by D1 receptors involves the recruitment
of protein kinase A, and through resulting phosphorylation of DARPP-32, the inhibition of phosphatases that deactivate ERK. NMDA receptors activate ERK through a different but interrelated Ras-Raf-MEK-ERK pathway.
Alone NMDA mediated activation of ERK is self-limited, as NMDA
activation also inhibits PKA mediated inhibition of ERK deactivating
phosphatases. However, when D1 and NMDA cascades are co-activated, they
work synergistically, and the resultant activation of ERK regulates
synaptic plasticity in the form of spine restructuring, transport of
AMPA receptors, regulation of CREB, and increasing cellular excitability via inhibiting Kv4.2
History
Skinner box
The first clue to the presence of a reward system in the brain came
with an accident discovery by James Olds and Peter Milner in 1954. They
discovered that rats would perform behaviors such as pressing a bar, to
administer a brief burst of electrical stimulation to specific sites in
their brains. This phenomenon is called intracranial self-stimulation or brain stimulation reward.
Typically, rats will press a lever hundreds or thousands of times per
hour to obtain this brain stimulation, stopping only when they are
exhausted. While trying to teach rats how to solve problems and run
mazes, stimulation of certain regions of the brain where the stimulation
was found seemed to give pleasure to the animals. They tried the same
thing with humans and the results were similar. The explanation to why
animals engage in a behavior that has no value to the survival of either
themselves or their species is that the brain stimulation is activating
the system underlying reward.
In a fundamental discovery made in 1954, researchers James Olds
and Peter Milner found that low-voltage electrical stimulation of
certain regions of the brain of the rat acted as a reward in teaching
the animals to run mazes and solve problems. It seemed that stimulation of those parts of the brain gave the animals pleasure, and in later work humans reported pleasurable sensations from such stimulation. When rats were tested in Skinner boxes where they could stimulate the reward system by pressing a lever, the rats pressed for hours. Research in the next two decades established that dopamine is one of the main chemicals aiding neural signaling in these regions, and dopamine was suggested to be the brain's "pleasure chemical".
Ivan Pavlov was a psychologist who used the reward system to study classical conditioning.
Pavlov used the reward system by rewarding dogs with food after they
had heard a bell or another stimulus. Pavlov was rewarding the dogs so
that the dogs associated food, the reward, with the bell, the stimulus.
Edward L. Thorndike used the reward system to study operant
conditioning. He began by putting cats in a puzzle box and placing food
outside of the box so that the cat wanted to escape. The cats worked to
get out of the puzzle box to get to the food. Although the cats ate the
food after they escaped the box, Thorndike learned that the cats
attempted to escape the box without the reward of food. Thorndike used
the rewards of food and freedom to stimulate the reward system of the
cats. Thorndike used this to see how the cats learned to escape the box.
The lateral hypothalamus and medial forebrain bundle
has been the most-frequently-studied brain-stimulation reward site,
particularly in studies of the effects of drugs on brain stimulation
reward.
The neurotransmitter system that has been most-clearly identified with
the habit-forming actions of drugs-of-abuse is the mesolimbic dopamine
system, with its efferent targets in the nucleus accumbens and its local GABAergic afferents.
The reward-relevant actions of amphetamine and cocaine are in the
dopaminergic synapses of the nucleus accumbens and perhaps the medial prefrontal cortex.
Rats also learn to lever-press for cocaine injections into the medial
prefrontal cortex, which works by increasing dopamine turnover in the
nucleus accumbens.
Nicotine infused directly into the nucleus accumbens also enhances
local dopamine release, presumably by a presynaptic action on the
dopaminergic terminals of this region. Nicotinic receptors localize to
dopaminergic cell bodies and local nicotine injections increase
dopaminergic cell firing that is critical for nicotinic reward. Some additional habit-forming drugs are also likely to decrease the output of medium spiny neurons
as a consequence, despite activating dopaminergic projections. For
opiates, the lowest-threshold site for reward effects involves actions
on GABAergic neurons in the ventral tegmental area,
a secondary site of opiate-rewarding actions on medium spiny output
neurons of the nucleus accumbens. Thus the following form the core of
currently characterised drug-reward circuitry; GABAergic afferents
to the mesolimbic dopamine neurons (primary substrate of opiate
reward), the mesolimbic dopamine neurons themselves (primary substrate
of psychomotor stimulant reward), and GABAergic efferents to the
mesolimbic dopamine neurons (a secondary site of opiate reward).
Motivation
Dysfunctional motivational salience appears in a number of psychiatric symptoms and disorders. Anhedonia,
traditionally defined as a reduced capacity to feel pleasure, has been
reexamined as reflecting blunted incentive salience, as most anhedonic
populations exhibit intact “liking”.
On the other end of the spectrum, heightened incentive salience that
is narrowed for specific stimuli is characteristic of behavioral and
drug addictions. In the case of fear or paranoia, dysfunction may lie
in elevated aversive salience.
Neuroimaging studies across diagnoses associated with anhedonia have reported reduced activity in the OFC and ventral striatum.
One meta analysis reported anhedonia was associated with reduced
neural response to reward anticipation in the caudate nucleus, putamen,
nucleus accumbens and medial prefrontal cortex (mPFC).
Mood disorders
Certain
types of depression are associated with reduced motivation, as assessed
by willingness to expend effort for reward. These abnormalities have
been tentatively linked to reduced activity in areas of the striatum,
and while dopaminergic abnormalities are hypothesized to play a role,
most studies probing dopamine function in depression have reported
inconsistent results.[76][77]
Although postmortem and neuroimaging studies have found abnormalities
in numerous regions of the reward system, few findings are consistently
replicated. Some studies have reported reduced NAcc, hippocampus,
medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC)
activity, as well as elevated basolateral amygdala and subgenual cingulate cortex (sgACC)
activity during tasks related to reward or positive stimuli. These
neuroimaging abnormalities are complemented by little post mortem
research, but what little research has been done suggests reduced
excitatory synapses in the mPFC. Reduced activity in the mPFC during reward related tasks appears to be localized to more dorsal regions(i.e. the pregenual cingulate cortex), while the more ventral sgACC is hyperactive in depression.
Attempts to investigate underlying neural circuitry in animal
models has also yielded conflicting results. Two paradigms are commonly
used to simulate depression, chronic social defeat (CSDS), and chronic
mild stress (CMS), although many exist. CSDS produces reduced preference
for sucrose, reduced social interactions, and increased immobility in
the forced swim test. CMS similarly reduces sucrose preference, and
behavioral despair as assessed by tail suspension and forced swim tests.
Animals susceptible to CSDS exhibit increased phasic VTA firing, and
inhibition of VTA-NAcc projections attenuates behavioral deficits
induced by CSDS. However, inhibition of VTA-mPFC
projections exacerbates social withdrawal. On the other hand, CMS
associated reductions in sucrose preference and immobility were
attenuated and exacerbated by VTA excitation and inhibition,
respectively.
Although these differences may be attributable to different
stimulation protocols or poor translational paradigms, variable results
may also lie in the heterogenous functionality of reward related
regions.
Optogenetic
stimulation of the mPFC as a whole produces antidepressant effects.
This effect appears localized to the rodent homologue of the pgACC (the
prelimbic cortex), as stimulation of the rodent homologue of the sgACC
(the infralimbic cortex) produces no behavioral effects. Furthermore,
deep brain stimulation in the infralimbic cortex, which is thought to
have an inhibitory effect, also produces an antidepressant effect. This
finding is congruent with the observation that pharmacological
inhibition of the infralimbic cortex attenuates depressive behaviors.
Schizophrenia
Schizophrenia is associated with deficits in motivation, commonly grouped under other negative symptoms such as reduced spontaneous speech. The experience of “liking” is frequently reported to be intact, both behaviorally and neurally, although results may be specific to certain stimuli, such as monetary rewards. Furthermore, implicit learning and simple reward related tasks are also intact in schizophrenia.
Rather, deficits in the reward system present during reward related
tasks that are cognitively complex. These deficits are associated with
both abnormal striatal and OFC activity, as well as abnormalities in
regions associated with cognitive functions such as the dorsolateral prefrontal cortex (dlPFC).
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