2-Minute Neuroscience: Benzodiazepines

Benzodiazepines are a class of drugs commonly used to treat anxiety disorders and sleep disorders. They are thought to exert their effects in the brain by acting at receptors for the neurotransmitter gamma-aminobutyric acid, or GABA. In this video, I cover the the mechanism of action for benzodiazepines and discuss how it is thought to lead to calming effects.

Know your brain: Raphe nuclei

Where are the raphe nuclei?

approximate locations of the raphe nuclei represented by red dots.

The term "raphe" refers to a line or ridge that separates two symmetrical parts of the body, and was used in the naming of the raphe nuclei because this collection of nuclei are clustered around the midline of the brainstem. The raphe nuclei are composed of a number of nuclei that are found at most levels of the brainstem from the midbrain down to the spinal cord. They are considered part of the reticular formation.

What are the raphe nuclei and what do they do?

The raphe nuclei are the primary location in the brain for the production of the neurotransmitter serotonin, and the serotonin synthesized in the raphe nuclei is then sent throughout the entire central nervous system. Although the raphe nuclei represent the largest collection of serotonin neurons in the brain, it should be noted that the raphe nuclei don't only consist of serotonin neurons. In fact, the proportion of serotonin neurons in the raphe nuclei varies substantially depending on the nucleus in question, ranging from 10-20% to 80%. Thus, neurons that utilize other neurotransmitters contribute significantly to the makeup of the raphe nuclei.

The raphe nuclei are often separated into a rostral group (a group of nuclei that is closer to the front of the body/face) and a caudal group (a group that is closer to the back of the body).

The nuclei of the rostral group contain about 85% of all of the serotonin neurons in the brain. The rostral group includes the following nuclei: the caudal linear nucleus, dorsal raphe nucleus---which is the largest population of serotonin neurons in the brain---and the median raphe nucleus. 

The caudal group represents a substantially smaller collection of serotonin neurons than the rostral group. It consists of the: raphe magnus nucleus, raphe obscurus nucleus, and raphe pallidus nucleus. The raphe pallidus nucleus is the smallest of the raphe nuclei.

The projections from the raphe nuclei are pervasive, carrying serotonin throughout the central nervous system. Thus, the functions that can be linked back to the raphe nuclei are also extensive and complex. There are, however, several functions that have a recognized association with activity in the raphe nuclei. Although, as mentioned above, there are non-serotonin neurons found in the raphe nuclei, their contribution to behavior has been studied much less comprehensively than the contribution of the serotonin neurons from the raphe nuclei.

Serotonin neurons that extend from the dorsal raphe nucleus to other nuclei in the brainstem are thought to be important to the regulation of sleep-wake cycles. These neurons are highly active during wakefulness, but are less active during sleep---and almost completely inactive during REM sleep. Activity in the dorsal raphe and the median raphe is also believed to influence circadian rhythms through communication with the suprachiasmatic nucleus.

The raphe nuclei (specifically the raphe magnus and dorsal raphe) are also involved in the natural inhibition of pain. Neurons from the raphe nuclei extend down to the spinal cord, where they inhibit neurons in the dorsal horn of the spinal cord that are responsible for transmitting pain signals. This allows for some control over the intensity of pain. You can read more about this natural pain-inhibiting mechanism here.

There is also a great deal of evidence suggesting that serotonin is involved (either directly or indirectly) in the regulation of mood and other emotional states. For example, drugs that manipulate serotonin levels (e.g. selective serotonin reuptake inhibitors, or SSRIs) are the most common treatment for depression and are also used to treat various types of anxiety disorders. Additionally, there is evidence linking serotonin to the regulation of aggressive behavior. The true relationship between serotonin and mood (ranging from depression to aggression), however, is still unclear and often controversial (this is perhaps exemplified by the debate about serotonin's true role in depression, described in this article).

Of course, serotonin's actions in the brain are much more extensive then just the few listed here, and serotonin has been implicated in a long list of functions ranging from motor activity to neural development. Serotonin, like other neurotransmitters, is critical to healthy brain function, making the raphe nuclei important structures in the central nervous system.

References (in addition to linked text above):

Hornung, JP. Raphe Nuclei. In: Mai JK and Paxinos G, eds. The Human Nervous System. 3rd ed. New York: Elsevier; 2012.

2-Minute Neuroscience: Caffeine

Caffeine is the most widely-used mind-altering substance in the world. Although it's not completely clear how caffeine causes the stimulant effects it's well-known for, it's thought most of those effects are traceable back to its action as an antagonist at receptors for the neurotransmitter adenosine. In this video, I discuss how that antagonistic action may lead to arousal and wakefulness.

Sorting out dopamine's role in reward

Since the 1970s, neuroscientists have been confident that dopamine plays an essential role in the brain's processing of rewarding experiences. And many researchers used to be fairly certain they knew exactly what that role was. Dopamine was, as the thinking went, the "pleasure neurotransmitter"---the substance responsible for producing sensations of pleasure in the brain, regardless of whether that pleasure comes from enjoying a good meal, having sex, or snorting cocaine. This understanding, according to a 1997 article in Time magazine, made the answers to questions about what causes addiction, "simpler than anyone has dared imagine." The article goes on to claim that dopamine "is not just a chemical that transmits pleasure signals but may, in fact, be the master molecule of addiction."

2-Minute neuroscience video on dopamine.

The popular press was not completely unjustified in making this assumption, as they took their cues from scientists---many of whom had, to some degree, become advocates for the "pleasure neurotransmitter" perspective. For example, well-known dopamine researcher Roy Wise said in a 1980 article that dopamine was involved in creating experiences of "pleasure, euphoria, or 'yumminess'."

This all, of course, was an oversimplification of dopamine's role in reward. Some time (and more research) allowed everyone to recognize that dopamine's contribution to processing rewarding experiences is much more complex than a simple equation where dopamine = pleasure. This realization is now becoming pervasive, and googling "dopamine and addiction" will return almost as many articles on the first page that emphasize the nuances of dopamine function as those that stick to the simplistic dopamine = pleasure formula. Wise eventually changed his mind as well, asserting in the late 1990s that he no longer believed "that the amount of pleasure felt is proportional to the amount of dopamine floating around in the brain."

Today, even those who are only modestly familiar with current hypotheses in neuroscience would likely be able to tell you that dopamine is not the pleasure molecule. Still, they might have a hard time answering the question, "What, then, is its role in reward?" That's partially because no one knows the answer to that question for sure. There are, however, a few popular competing hypotheses that have been proposed in an attempt to elucidate dopamine's reward-related functions.

First, the basics

Dopamine pathways in the brain. The blue lines extend from the ventral tegmental area to the nucleus accumbens (red dot) to illustrate the mesolimbic dopamine pathway. Another blue line extends from the ventral tegmental area to the cerebral cortex, making up the mesocortical dopamine pathway. The purple lines represent the nigrostriatal dopamine pathway, which extends from the subdstantia nigra to the striatum.

The early hypotheses about dopamine's role in reward were formulated based on the evidence that collections of dopamine neurons in the brain tend to be activated in response to the administration of addictive drugs (and other substances generally considered to be rewarding, like sweet foods). Activity in one such collection of neurons in particular, a pathway that stretches from a dopamine-rich area in the midbrain called the ventral tegmental area (VTA) to a nucleus in the forebrain called the nucleus accumbens, has consistently been linked to rewarding events. When someone experiences something rewarding (like snorting a line of cocaine), dopamine neurons in the VTA are activated and send dopamine to the nucleus accumbens, causing dopamine levels in the nucleus accumbens to rise.

This pathway from the VTA to the nucleus accumbens is called the mesolimbic dopamine pathway. It has come to be considered the primary component of what is now known as the reward system, which consists of a group of structures that are activated by rewarding or reinforcing stimuli like addictive drugs. The reward system also includes a number of other structures---as well as other dopamine pathways, such as the mesocortical dopamine pathway, which stretches from the nucleus accumbens to destinations in the cerebral cortex.

The case against dopamine as the "pleasure neurotransmitter"

Although it should be said that there is a great deal of evidence that indicates dopamine release is correlated with pleasure, there is also substantial evidence that suggests dopamine isn't responsible for causing pleasure. 

Much of this evidence comes from animal studies. For example, when researchers damaged dopamine neurons in the brains of rats to the point where dopamine in the nucleus accumbens was depleted by up to 99%, rats still exhibited pleasurable reactions to sweet tastes, indicating some component of pleasure was left intact. In monkeys being trained to obtain juice rewards, once they learned the necessary tasks and could predict exactly when they would receive a reward, their dopamine neurons stopped firing in response to such rewards. Yet, they still seemed to enjoy the rewards, suggesting dopamine may be involved in signals about the predictability of rewards, but not the pleasure linked to them. 

There is also evidence from humans that suggests that dopamine is not the substance that generates pleasure. In one study, for example, researchers found that dopamine levels in the ventral striatum (a region of the brain that contains the nucleus accumbens) correlated better with craving for amphetamine than with the pleasure experienced from taking the drug. In another study, administration of a dopamine antagonist (which blocks dopamine activity) did not prevent participants from experiencing euphoria after amphetamine administration.

Additionally, studies have found that mesolimbic dopamine neurons also can be be activated during experiences that are aversive---which only further complicates any attempt to consider dopamine the "pleasure neurotransmitter."

These are just a handful of examples that contradict the idea that dopamine is the primary pleasure-causing substance in our brains. The whole body of evidence that is at odds with the perspective is much larger, and it is widely accepted in neuroscience today that dopamine's role in reward is more complicated than the "pleasure neurotransmitter" moniker implies.

Other hypotheses: reward learning, reward prediction, and incentive salience

Reward learning

When it became clear to most researchers that dopamine was not responsible for creating sensations of pleasure, new roles were suggested for dopamine. Many scientists, for example, postulated that the neurotransmitter is involved in some aspect of learning about rewards. Along these lines, it has been suggested that dopamine is involved in the process of linking a pleasurable experience to a stimulus that previously had no value----like associating the pleasure of inebriation with alcohol after drinking it for the first time.

When someone experiences something pleasurable, their brain creates a strong association between that experience and whatever is thought to have caused it. Thus, the brain of someone who drinks alcohol for the first time (and enjoys it) will make a strong connection between alcohol and pleasure (previously alcohol would not have had any value to them because they never would have experienced its effects). Dopamine may be responsible for making that connection. 

Similarly, others have proposed that dopamine not only allows for the learning of a new association between some stimulus and pleasure, but that it also is involved in the acquisition of new habits dedicated to obtaining that rewarding stimulus again in the future. In the case of addictive drugs, these habits can become especially persistent, generating patterns of compulsive behavior that persist long after the value of the reward has diminished. 

Reward prediction

Perhaps the most popular hypothesis that posits a role for dopamine in reward learning is the suggestion that dopamine is involved in identifying potentially rewarding stimuli, predicting how valuable those rewards are likely to be, and then responding strongly whenever something turns out to be more rewarding than was originally expected. This type of signaling is often referred to as reward prediction error signaling. 

According to the reward prediction error hypothesis, dopamine neurons are highly active when rewards turn out to be more valuable than predicted and their activity is depressed when a reward is found to be less valuable than expected. This dopamine signaling acts as a mechanism to help us learn what to expect from rewards in the future; in other words, it helps to "train" the brain about what value a potential reward is likely to have. This information can be used to guide behavior, as it can help us determine which rewards are most desirable---and thus which we should pursue.

Additionally, the reward prediction error hypothesis provides us with a way of explaining addiction. According to this hypothesis, addiction can occur when addictive drugs (or other experiences or substances) generate high levels of dopamine release that lead to a reward being overvalued. This causes an individual to develop exceedingly high expectations of the pleasure that will be obtained from the drug reward, which leads to compulsive drug seeking. In essence then, addiction occurs because high levels of dopamine release cause an addict to consistently predict a drug will make them feel better than it really will. This corresponds to anecdotal accounts of drug addiction, where many addicts describe their drug-using experience as a series of failed attempts to recreate the pleasure they felt from their first high.

Incentive salience

Another related, but slightly different perspective asserts that it is critically important to separate behavior surrounding a reward into (at least) two responses that are distinctly different but often confused for one another: "wanting" and "liking." "Liking" refers to the pleasurable response to a reward, while "wanting" refers only to the motivation to obtain a reward.

Think, for example, of a time when you were eating at a delicious restaurant but near the end of the main course you were uncomfortably full. Perhaps the waiter, however, left your plate sitting in front of you for some time (maybe while the rest of your party finished). During that time, you may have continued to occasionally take more bites of the food even though your ability to enjoy it was completely diminished due to your fullness. This could be considered an example of the difference between "liking" and "wanting." You still wanted the food and compulsively took bites of it because your brain had identified it as rewarding, but you no longer really liked the food due to your current state of fullness.

Proponents of the incentive salience hypothesis suggest that dopamine plays a critical role in generating "wanting"---a motivated response to attain rewards based on a previous experience with those rewards in which they were deemed to be valuable. Incentive salience involves "wanting" that is associated with some motivational goal (like obtaining a drug).

According to the incentive salience perspective, when we experience something rewarding, our brains (with the help of dopamine) assign incentive salience not only to whatever directly caused the rewarding experience (e.g. a drug), but also to any other stimuli associated with the reward. In the process, our brains become hypersensitive to the rewarding stimulus and anything we have come to associate with it. This hypersensitivity and increased propensity to generate strong feelings of desire can form the basis of an addiction.

For example, someone who has never smoked a cigarette likely would find the smell of cigarette smoke to be unpleasant---or at best neither pleasant nor unpleasant. In the brain of a smoker, on the other hand, an association has been made between the smell of cigarette smoke and reward---incentive salience has been attributed to the smoke because the brain has deemed it an important part of the rewarding experience of cigarette smoking. Thus, upon smelling cigarette smoke, the brain will likely stimulate mechanisms that prompt "wanting" of a cigarette, also known as craving.

These associations between "wanting" and smoking-related stimuli can lead to cravings every time a smoker is exposed to a smoking-related stimulus (e.g. the smell of smoke, seeing someone else smoking, etc.)---which can lead to the type of repetitive smoking that has the propensity to precipitate or intensify addiction to nicotine. According to the incentive salience hypothesis, this increased sensitivity to reward-related stimuli can persist for years, which could help to explain why those who develop an addiction often feel as if they are always susceptible to it---even after years of sobriety.

The broad view

These perspectives are not mutually exclusive, and there is clearly some overlap among them. For example, reward prediction and the attribution of incentive salience are both likely to be important aspects of learning about rewards. Thus, it is not improbable that some elements of each hypothesis accurately explain the role of dopamine in reward. 

It's important to remember, too, that there is no contradiction in saying that dopamine may be involved in all of these components of reward processing (as well as with processing aversive experiences). Dopamine, like other neurotransmitters, may exert different actions depending on the subtype of receptors it acts on, the part of the brain its action is occurring in, and even the time course by which it is being released. We must become comfortable giving up our attempts to define neurotransmitters by a short list of actions, as such a simplistic view of neurotransmitter function does not seem to be based in reality.

The consensus, then, is that dopamine is not the substance in our brains that causes pleasure. Instead, it is thought to be involved in some other aspects of reward, but its precise role is still being debated. Regardless, dopamine seems to be more closely associated with reward than most other neurotransmitters, and it is likely to play a paramount role both in processing rewarding experiences and in the pathological states, like addiction, that are linked to faulty reward valuation.

References (in addition to linked text above):

Berridge KC. The debate over dopamine's role in reward: the case for incentive salience. Psychopharmacology (Berl). 2007 Apr;191(3):391-431. Epub 2006 Oct 27.

Further reading:

Know your brain: Reward system

Know your brain: Nucleus accumbens

Know your brain: Locus coeruleus

Where is the locus coeruleus?

The locus coeruleus, which I'll refer to as the LC from here on out to avoid an inevitable misspelling, is a nucleus found in the pons. It is located near the floor of the fourth ventricle.

What is the locus coeruleus and what does it do?

The first descriptions of the LC date back to the late 1700s when French anatomist Félix Vicq d’Azyr detailed a blue-colored area of tissue in the pons. In the early 1800s, the term locus coeruleus, which means "blue spot" in Latin, was used to refer to that pigmented region. It wasn't until the second half of the twentieth century, however, that new techniques allowed scientists to learn that the blue coloring in the LC is caused by the production of a pigment formed by chemical reactions involving the neurotransmitter norepinephrine (also known as noradrenaline).

It is now known that the LC is the primary site of norepinephrine production in the brain. The nucleus sends norepinephrine throughout the cerebral cortex as well as to a variety of other structures including the amygdala, hippocampus, cerebellum, and spinal cord. In fact, the LC sends projections to virtually all brain regions except the basal ganglia, which seems to be lacking noradrenergic (i.e. noradrenaline/norepinephrine-related) input.

Because of the diversity of its projections and the diversity of the actions of norepinephrine as a neurotransmitter, the LC is involved in a long list of functions. It is perhaps most strongly linked, however, to arousal, vigilance, and attention. Neurons in the LC are less active during quiet wakefulness and their activity is even more diminished during sleep (indeed they are completely quiet during rapid eye movement, or REM, sleep), but they display increased activity in response to arousing stimuli. And optimal levels of norepinephrine in areas of the brain involved with attention, like the prefrontal cortex, have been found to be important to the facilitation of attention-related tasks.

Additionally, the LC and the norepinephrine it produces are thought to be integral to a number of higher cognitive functions ranging from motivation to working memory. It also seems to play a role in fine-tuning sensory signals to increase acuity across multiple sense modalities. It should be noted, however, that norepinephrine has wide-ranging actions throughout the brain and any attempt to briefly summarize its functions (or, by extension those of the LC) is an oversimplification.

Aging is associated with a significant loss of neurons in the LC, and a number of disorders---including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy---are linked to deficits in the number of LC neurons. In fact, in Alzheimer's disease the number of LC neurons lost exceeds the number of acetylcholine neurons lost in the nucleus basalis and in Parkinson's disease the number of LC neurons lost exceeds the number of dopamine neurons lost in the substantia nigra. This is notable because neuronal loss in the nucleus basalis and substantia nigra are considered hallmark signs of Alzheimer's disease and Parkinson's disease, respectively. Although the impact of LC loss in these diseases is not fully understood, it is thought to contribute significantly to the pathology of these conditions.

References:

Counts SE, Mufson EJ. Locus Coeruleus. In: Mai JK and Paxinos G, eds. The Human Nervous System. 3rd ed. New York: Elsevier; 2012.

Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009 Mar;10(3):211-23. doi: 10.1038/nrn2573.