This episode is about dopamine. In episode 32, I discussed the pseudoscientific trend of the “dopamine detox” or "dopamine fasting." Instead of talking about pseudoscience in this episode, I discuss the actual science surrounding dopamine and its relationship with the neuroleptics or antipsychotics as they are more commonly known. The effects and side effects of antipsychotics are related to the function of the major dopamine networks of the brain: the mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways. Dopamine levels in each of these pathways can be regulated also by serotonin receptors, and so this episode contains a discussion of how first generation, second generation, and novel antipsychotics affect dopamine by affecting serotonin receptors.
Please leave feedback at https://www.psydactic.com.
References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.
This episode is about dopamine. In episode 32, I discussed the pseudoscientific trend of the “dopamine detox” or "dopamine fasting." Instead of talking about pseudoscience in this episode, I discuss the actual science surrounding dopamine and its relationship with the neuroleptics or antipsychotics as they are more commonly known. The effects and side effects of antipsychotics are related to the function of the major dopamine networks of the brain: the mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways. Dopamine levels in each of these pathways can be regulated also by serotonin receptors, and so this episode contains a discussion of how first generation, second generation, and novel antipsychotics affect dopamine by affecting serotonin receptors.
Please leave feedback at https://www.psydactic.com.
References and readings (when available) are posted at the end of each episode transcript, located at psydactic.buzzsprout.com. All opinions expressed in this podcast are exclusively those of the person speaking and should not be confused with the opinions of anyone else. We reserve the right to be wrong. Nothing in this podcast should be treated as individual medical advice.
Welcome to PsyDactic Residency, today is … and I am Dr. O’Leary, a 4th year psychiatry resident in the national capital region. If this is your first time here, welcome. This is a podcast about psychiatry and neuroscience. I do it as a way to help myself learn and I hope it can help you as well. It is designed for psychiatry residents, but I think it can be just as helpful for residents of other specialties, attendings, medical students, or anyone with an interest in psychology or neuroscience. I am also compelled to let you know that this podcast is, at this moment, solely my own venture. Nothing I say here should be construed as anyone else’s opinion, especially not the federal government, department of defense, or the Viltrumite alliance. It is also not an endorsement of any particular medicine or company that produces or distributes medicines. The only conflicts of interests I am aware of are my interests in my job and my interests in leisure activities.
Today I want to talk more about dopamine. I have mentioned it before. In episode 32, I discussed the pseudoscientific trend of the “dopamine detox” that is a recurrent craze promoted on social media, especially by doctors who want to sell you their special brand of nutritional supplements, or get sponsorships from companies selling you their own particular life hacks. Instead of talking about pseudoscience, I want to talk about some of the actual science surrounding dopamine and its relationship with some of the drugs that psychiatrists give frequently. Specifically, I will talk about the neuroleptics, or antipsychotics as they are more commonly known and how they interact with the neurons in the major dopamine networks of the brain.
The first antipsychotic widely used was chlorpromazine, which was discovered in the 1950s and marketed as thorazine. It was under development to be an antihistamine, and does have these properties. It also had the property of blocking dopamine receptors, specifically D2 receptors and this was incidentally discovered to make people very calm without putting them to sleep. It was later found to treat the positive symptoms of schizophrenia and mania. Because of its ability to reduce hallucinations, agitation, mania, and abnormal goal seeking behaviors in general, it was called a “major tranquillizer.” The term antipsychotic became popular about 10 years later. In the 1950s, drugs didn’t need to go through the kind of approval process we have today. Instead, it was mostly word of mouth and promotion by the drug companies that got drugs onto the shelves. As a result, thorazine was used for just about every psychiatric condition you could imagine. Over time, the down-side of antipsychotics became apparent. Blocking D2 receptors could result in dystonias or akathisia, and over time could result in tardive dyskinesia, which is a permanent motor disorder. Also, many antipsychotics also affect other receptors like histamine receptors, muscarinic receptors, alpha receptors, and serotonin receptors. They can cause weight gain, metabolic syndromes, neutropenia and even agranulocytosis.
Initially it was thought that too much dopamine in the brain was the cause of schizophrenia. People who take large doses of stimulants that increase available dopamine over long periods of time can become psychotic. They also don’t sleep well, which is known to cause psychosis. There are also drugs that block glutamate receptors like ketamine and PCP, and their effects can mimic psychosis. Strong anticholinergic blockade is associated with psychotic symptoms. Med students may remember the mnemonics for an anticholinergic toxidrome that includes symptoms such as “dry as a bone, mad as a hatter, high as a kite.” Datura or locoweed contains seeds with potent anticholinergic effects that are used at times for recreational or ceremonial activities and can be fatal. It was also noted that drugs like LSD and psilocybin cause psychotic symptoms and they primarily stimulate serotonin receptors. Additionally, there are now antipsychotic medications like pimavanserin that control psychotic symptoms primarily by blocking serotonin receptors, along with many atypical antipsychotic agents that are more likely to block certain serotonin receptors than they are to block D2 receptors. These observations have resulted in different hypotheses for the genesis of psychosis that are not mutually exclusive and each focuses attention on different neurotransmitters, whether it be serotonin, glutamate, dopamine, or acetylcholine.
Today, though, I am going to focus on the role of dopamine and serotonin receptors in various parts of our brain, because these are intimately linked in an exquisite and fragile dance of neural activity that keeps our thoughts organized, grounded in reasonable probabilistic outcomes, and able to distinguish between externally and internally derived perceptions. It will also help me to facilitate a discussion about neuroleptics, or antipsychotics, or major tranquilisers, or whatever you want to call them, which I will go into in more excruciating detail in the next episode.
Dopamine is produced and shipped through at least four major pathways. One dopaminergic neuron may synapse on thousands of other neurons, and of its target neurons may be receiving projections from hundreds of dopamine neurons. This is all to say that this network is extensive and helps to set the tone or gain in the brain by modulating how fast other neurons fire. The dopamine pathways are named the mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways. There are many other less extensive pathways that I will ignore for now. Neurologists have done us a favor by naming things based on where they start and where they end up, so the mesocortical pathway starts in the midbrain in a place called the ventral tegmental area, and ends up in cortical areas, especially the prefrontal cortex. The mesolimbic pathway also starts in the midbrain’s ventral tegmental area, and ends up in our limbic system, especially the nucleus accumbens. The nigrostriatal pathway starts in the substantia nigra and ends in the striatum, especially the dorsal striatum. It should be noted that there is also a mesostriatal pathway from the VTA to the ventral striatum, but this is considered part of the limbic system. Finally, the tuberoinfundibular pathway starts… well I don’t want to put you to sleep, so I’ll save this one for later.
Mesolimbic Pathway
Let’s start by discussing the Mesolimbic Pathway. This is the pathway that feeds dopamine from the ventral tegmental area in the midbrain to much of the limbic system, including the nucleus accumbens (which is part of the ventral striatum) and the amygdala as well as the anterior cingulate gyrus and medial parts of the PFC and the hippocampal formation on the medial temporal lobe. It also connects with other areas of the brain that are usually not highlighted, such as lateral hypothalamus and lateral mammillary bodies. In short it helps fuel the part of our brains that are the most fundamental for survival, including memory, feeding behaviors, motivation and reward seeking, as well as avoidance of aversive stimuli and threats.
With regard to psychotic symptoms, malfunction of the limbic system can contribute to negative symptoms such as apathy or anhedonia, a general lack of drive like failing to eat or care for oneself, withdrawal, inattention, and amotivation. In terms of positive symptoms, these limbic connections likely help to drive delusions of grandeur, persecutory delusions, erotomania (or delusions of love), or excessive goal driven behaviors. Affective states may also contribute to negative symptoms, as (for example), fear tends to reduce feeding and grooming behaviors, so someone who is overtly paranoid is also less likely to be eating or washing themselves.
Dopamine blocking agents acting on the mesolimbic system may mimic the negative symptoms of schizophrenia, with affective blunting and a reduction in goal directed behavior.
Mesocortical Pathway
Next is the mesocortical pathway. The mesocortical pathway ships dopamine to the prefrontal cortex among other cortical regions. The prefrontal cortex does a lot for us. It contains a large part of our working memory, helps us to regulate our emotions, picks out the most important details from our current environment to consider, decides between competing choices, lets us know when our experiences don’t match our expectations, understands social cues, plans for the future, and many other things. In chronic, relapsing psychotic illnesses such as schizophrenia or schizoaffective disorder, there is often a prodromal phase accompanied by changes in personality, lack of concern for forming or maintaining social relationships or conforming to social norms, poor academic performance and inability to meet goals. These negative cognitive symptoms of psychotic illness often are the first to develop and can have a long insidious onset. All these things involve dysfunction in the prefrontal cortex cortex.
The mesocortical pathway and the dopamine it employs help to regulate these networks and keep them functioning in tandem with and at times separate from or in anticorrelation with other brain regions. With regard to behavior, the PFC is in competition with the limbic system to learn things and direct behaviors. The cortex is more deliberate, slower to make decisions, and considers more information at the same time. The PFC has been described as being responsible for effort learning (which may require delayed gratification), while the limbic system is more concerned with more immediate rewards and putting in the least amount of effort necessary to get them. It has also been shown that the errors generated by both of these systems with regard to expected outcomes are processed in the ventral striatum in order to come up with a kind of final decision or compromise. The ability to make decisions like this in a complex way is often impaired in psychosis.
In terms of other psychotic symptoms, disorganized behavior and speech comes to mind when thinking about dysfunction of the PFC. Also, the inability to understand social cues, maintain attention on salient aspects of the environment, keep a coherent thought process going, or determine the difference between internally generated thoughts versus externally sensed stimuli may be due to cortical malfunction. Also the PFC in a psychotic state is not doing a very good job regulating the affective network the way it has in the past, and can’t give good analysis of risk-benefit scenarios or the level of actual threat in the environment. Somehow, drugs that block dopamine receptors can help with this, but so can drugs that block certain serotonin receptors. I’ll get back to that soon.
Nigrostriatal Pathway
Regardless of how well we can organize our thinking or control our emotional states, we can’t DO any organized behaviors without the nigrostriatal pathway functioning well. Overall, there are always some tonic levels of signals coming from our motor cortex to our muscles and these are systematically suppressed or fine tuned by the striatum. In Parkinson’s disease, where the substantia nigra is degenerating, the striatum malfunctions and people develop tremors, rigidity, and difficulty relaxing muscles or initiating coordinated actions. The nigrostriatal pathway primarily involves dopaminergic neurons that originate in the substantia nigra and terminate in the dorsal striatum.
The striatum is roughly divided into two regions. The Dorsal striatum is more involved directly in motor functions and also influences cognitive functions via the cortico-striatal-thalamo-cortical tract. The ventral striatum is more associated with limbic structures and in reward vs risk processing, learning, and prediction error processing. This is part of the cortico-ventral basal ganglia circuit and includes the orbitofrontal, anterior cingulate and insular cortex, the ventral striatum, which includes the nucleus accumbens, and the ventral pallidum, as well as our friendly midbrain dopamine neurons in the ventral tegmental area. Part of the mesolimbic pathway could be call the mesostriatal pathway because it sends projections to the ventral striatum.
With regard to the striatum and psychosis there appears to be deficits in facilitating complex behaviors and making decisions when there is conflicting information. The dorsal striatum is likely more involved in learning habitual automated actions, like when you perfect your pirouette. The ventral striatum in learning more complicated and intentional actions, like how to navigate a new course in the iron man competition. The striatum in particular can also help regulate obsessive behaviors. If the striatum is disrupted, it becomes difficult to learn and someone can become stuck on or obsessed with things that in reality have very little salience. In severe mood disorders and some psychotic disorders, disruption of the striatum also plays a huge role in catatonia. With chronic use of neuroleptics, the development of akathisia, dystonias, tardive dyskinesia, or neuroleptic malignant syndrome almost certainly involves dopamine blockade in the dorsal striatum.
Tuberoinfundibular Pathway
I am going to give the tuberoinfundibular pathway a shout out here. Certain antipsychotics have relatively high rates of hyperprolactinemia associated with them, like risperidone, and this is due to the effects of blocking dopamine within the tuberoinfundibular pathway which runs from the hypothalamus to the infundibulum of the pituitary stalk. Tonic levels of dopamine in the hypothalamus and pituitary inhibit the production and release of prolactin. Blocking the action of dopamine here causes more prolactin to be released which can cause side effects such as breast swelling, milk production, or sexual dysfunction. So that is the honorable mention that the tuberoinfundibular pathway gets today.
Here I should also mention that although our language makes it sound like ALL of the dopaminergic neurons to the dorsal striatum come from the substantia nigra and all of the cortical and limbic dopaminergic neurons come from the VTA, but this is not true. There is, in fact, some overlap. Some tracts are dominant, but not exclusive. Also, information flows in both ways. There is feedback from the cortical and limbic regions to the VTA and SN. There are also not ONLY dopaminergic neurons projecting from the VTA and SN. There are also populations of, for example, glutamatergic neurons in these areas that follow parallel efferent pathways with the dopaminergic neurons. That is all to say that to characterize these regions as dopaminergic is only part of the story.
I mentioned previously that the striatum feeds back to the cortex, and this might happen through thalamic connections or feedback to the ventral tegmental area or substantia nigra. In one study, transgenic mice designed to have a relative increase in D2 receptor expression in the striatum also showed decreased gabaergic action in the PFC, which meant that the PFC was more sensitive to dopamine; and additionally stimulating D2 receptors in the striatum resulted in signals to the VTA that reduced tonic dopamine delivery to the PFC. More dopamine shipped to the striatum may result in less dopamine available to the PFC, not because it is being used up, but because it is being suppressed by signals from the striatum.
Antipsychotics
Now that I have completely lost your attention, I want to move on to the mechanism of action of the antipsychotics that I first mentioned. Honestly, we don’t really fully know how they control psychosis or what even ultimately causes psychosis, but we do know that the original antipsychotics were strong D2 blockers and this led to some improvements, especially in the positive symptoms of psychosis and in dampening down mania. Some models suggest something to the effect of: there is excess dopamine throughout the brain which is like turning up the gain on different brain regions. This in turn caused them to be far more active or easily activated, which results in a lot more noise, and this noise makes it hard to think, hard to pay attention, hard to follow a logical thought, and hard to distinguish between internally and externally signals. Over time this results in neuronal cell death, or loss of synaptic connections between different regions. This model likely has some truth to it, but it is demonstrably overly simplistic. It doesn’t account for the wide range of different kinds of psychotic symptoms or the fact that psychotic symptoms are not limited to the positive symptoms of schizophrenia or mania and also occur for example in depression with psychotic features or PTSD or in brief psychotic episodes that were not substance induced, or in delirium. Psychosis seems to be a state of brain failure that can result from many different things.
However, there is definitely some aspect of over-activity of certain brain regions relative to others in at least some cases, and D2 blockers can help put things back into a relative balance. I say “a relative over-activity” because in the brains of people with chronic psychotic disorders there is often global volume loss with decreased gray matter volume in their brains. Also, compared with controls, different brain regions appear less connected with each other. It is unclear what the brains of people with prodromal psychotic illnesses look like. There is also the fact that none of our neurotransmitters act alone. Dopamine receptors on glutamatergic or gabaergic or serotonergic neurons regulate the release of those neurotransmitters and vice versa, and intra versa, and extra versa and into-the-spider-versa.
With respect to the antipsychotics we use, the most common receptors other than the D2 receptor that pharmacologic agents act on are serotonin receptors, especially the 5HT2A receptor. The cell bodies and terminal regions of all three DA pathways I just talked about receive inputs from serotonergic neurons originating in the raphe nuclei. Neurons that are, for example, part of the mesolimbic system and mesocortical system have 5HT2A receptors that help regulate their activity. Blocking these receptors reduces the transmission of dopamine to the cortex and limbic system. That may be why antipsychotics that block 5HT2A help reduce psychotic symptoms in many people. Blocking 5HT2A receptors in the nigrostriatal pathway has been reported to have the opposite effect on dopamine signaling, by increasing the activation of dopamine neurons to the dorsal striatum. This can explain why the antipsychotics that have a greater affinity for and blockade of 5HT2A versus D2 receptors also have far lower potential to cause movement disorders. Many of what are called “second generation” or “atypical” antipsychotics don’t block D2 receptors as strongly as they do 5HT2A receptors, and some new and novel antipsychotics don’t block the D2 receptors at all.
Another possible action of the 5HT2A receptor antagonists or reverse agonists is to regulate glutamate release in the cortex. At the cellular level, 5-HT2A receptors are highly expressed on cortical glutamatergic pyramidal cells, where they regulate pyramidal cell excitability. Antipsychotics that block 5HT2A may be exerting their effects by modulation of both glutamate and dopamine simultaneously.
Some of the antipsychotics or their metabolites are also 5HT1A agonists which can increase dopamine release in the prefrontal cortex and reduce glutamate release, which can have procognitive effects.
I want to stop here for today. I just discussed in some detail three of the dopaminergic pathways that are thought to be causally involved in the symptoms of some patients with psychosis. I have discussed some of the ways in which this model is vastly oversimplistic. I have summarized how the main mechanisms of action of neuroleptics affect dopamine in these pathways and on the regions they supply. In the next episode, I am going to discuss many of the antipsychotics that are available, what they do and how this results in their efficacy, their side effects, and their dangers.
Thank you for listening. I am Dr. O and this has been an episode of PsyDactic - Residency.
David Nutt, Simon Davies and Blanca M. Bolea-Alamanac
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