So this lecture is going to be an overview of psychotic symptoms and the various theories that we believe contribute to the presentation of psychosis and the particular disorder that we will focus on as our prototype will be schizophrenia. And so this particular lecture is going to focus primarily on dopamine and we're going to look at dopamine neurotransmission, the receptors, and the various brain circuits that are affected by dopamine itself. And then we'll kind of try to tie it all together for how dopamine hypothetically contributes to this phenomenon of psychotic symptoms, and in this case, the disorder of schizophrenia. So it's important to understand that psychosis is a syndrome, so that means it's a mixture of symptoms but itself is not a specific disorder.
This syndrome can be associated with many different psychiatric disorders and those are outlined in the DSM or the International Classification of Diseases. At a very minimum though, psychosis essentially means that there are dilutions and or hallucinations. Delusions are fixed beliefs, they're often bizarre, and they have an inadequate rational basis and are pretty much unable to be changed by rational arguments or even evidence that would be contrary to them. Hallucinations, on the other hand, are perceptual experiences of any sensory modality, meaning visual, auditory, smell, taste, touch.
auditory being the most common and these occur without a real external stimulus but they are vivid and clear just like normal perceptions but they're not under voluntary control so delusions and hallucinations are the hallmarks of psychosis and these are often caused called positive symptoms of psychosis other symptoms that can be associated with psychosis would be disorganized speech, disorganized behavior, distortions of reality testing, and negative symptoms of psychosis like diminished emotional expression and decreased motivation, which we'll talk about in further detail later. But the bottom line is that psychosis can be considered to be a set of symptoms in which a person's mental capacity, affective response, and capacity to recognize reality, communicate, and relate to others is impaired. So we'll use schizophrenia as sort of our prototype for discussing psychosis in general.
Schizophrenia as a phenotype can be broken down into symptoms and these symptoms kind of fall into two categories. You have positive symptoms and negative symptoms like I talked about on the other slide. Positive symptoms include delusions and hallucinations whereas negative symptoms include apathy and hedonia, cognitive blunting, and neuroleptic dysphoria. So when you look at the positive symptoms of psychosis the way that I remember this when I was learning is that you know If you saw someone who were displaying these symptoms, you would think they were positively psychotic.
So, it is readily apparent, the symptoms are very obvious to the educated and even uneducated observer, that there is something very much off about the individual. So, that's where you see these symptoms of the disorganized speech and behavior, there can be agitation, as well as the delusions and the hallucinations. All of those are positive symptoms.
The negative symptoms of psychosis, on the other hand, can sometimes be really difficult to detect. They often can kind of mimic depressive symptoms, which at least in my experience seems to be what they frequently are misidentified as in the first place. So you can sort of think of things kind of being taken away the individual sort of withdrawals from the world so there's this diminished uh emotional engagement and reactivity they tend to have apathy this lack of interest or even really lack of will to engage in things and you can see the way that this is manifested So now that we've talked about the positive and the negative symptoms of schizophrenia, this figure here shows you how various brain regions can be associated with some of these signs and symptoms of schizophrenia. And then we ultimately can connect the dots between various circuits that might be malfunctioning and hypothetically related to those symptoms that we see.
So the important concept just to understand here is different symptom domains are affected by different circuitry. So positive symptoms, as you can see, seem to be largely related to the mesolimbic area. And some of the negative symptoms are related more to mesocortical and prefrontal cortex circuitry, as well as reward circuitry. involvement of the nucleus accumbens. Whereas some of the aggressive or impulsive symptoms are related to the orbital frontal cortex as well as the amygdala and you can see kind of the other areas but there's a lot of prefrontal cortex involvement as you can see.
Like almost all of these symptoms aside from like the mesolimbic specifically, all of these other symptoms are in part related to circuitry that affects either the whole or some aspect of the prefrontal cortex so that clearly plays a very big role in the manifestation of schizophrenia and or psychosis and those symptoms so traditionally the dopamine hypothesis of psychosis has been one of the most enduring ideas that we've sort of held in psychopharmacology but we now know and understand that dopamine is not the only neurotransmitter that's linked to psychosis and there's more and more evidence that implicates glutamate and serotonin neural networks as also being involved in the pathophysiology and really the treatment of some forms of psychosis and not just in schizophrenia but psychosis associated with other conditions like parkinson's disease or various forms of dementia and even psychosis that you see with drug use So there are now three major neurotransmitter systems that we believe, hypothetically, to be linked to psychosis. And we will explore each of these in greater detail, but essentially the dopamine theory, which has kind of been the oldest and long-standing theory, is that there's too much dopamine at D2 receptors in the mesolimbic pathway. The glutamate theory is that there's... NMDA receptor hypofunctioning.
And the serotonin theory is that 5-HT2A receptors are hyperfunctioning in the cortex. So the classic and most long-standing theory as far as neurotransmitters go in the pathophysiology, if you will, of psychosis has been the neurotransmitter dopamine. And specifically the classic dopamine theory of psychosis is that there is hyperactive dopamine at D2 receptors in the mesolimbic pathway of the brain. This hypothesis makes some sense because we know that if you agonize those D2 receptors with illicit substances like amphetamine or cocaine, you can induce paranoid psychotic symptoms similar to what you might see in schizophrenia.
And we learned in the past, kind of serendipitously, that medications that can block these D2 receptors are very potent in their antipsychotic effect. So for a very long time, we believed and assumed that this excessive amount of dopamine in this mesolimbic pathway was the cause of the positive symptoms of psychosis. that all treatments therefore had to block those D2 receptors in that particular pathway. But we now know that there is a lot more to psychosis than just mesolimbic dopamine, and there's a lot more treatment to psychosis than just dopamine to antagonists. We'll discuss the treatment of psychosis in a completely different lecture, but before we can really...
understand and kind of update this dopamine hypothesis, we have to understand the dopamine receptors and the brain circuits. So we will review then how dopamine is synthesized, metabolized, regulated, and then the functions of dopamine receptors and where they're localized in pathways throughout the brain. The synthesis of dopamine starts with the amino acid tyrosine and it's taken up into the neuron from the extracellular space and bloodstream by this tyrosine pump or the tyrosine transporter.
We get tyrosine from dietary intake and once that tyrosine is taken up by this tyrosine transporter it's converted into dopamine and there are these two enzymes involved in this process and the first enzyme is the rate limiting enzyme tyrosine hydroxylase which is TOH and then the other enzyme involved is the dopa decarboxylase which is DDC So once it's been broken down and converted into dopamine, it's then taken up into these synaptic vesicles by the vesicular monoamine transporter, or VMAT2. And the dopamine stays in these little vesicles waiting to be used during neurotransmission where it's going to be released. So aside from using dopamine for neurotransmission, What does the cell do with either excessive amounts of dopamine or dopamine that's not used for neurotransmission?
There's really kind of four ways that it can be handled. So the first way would be through reuptake or recycling, and that's done through the dopamine transporter. The dopamine transporter takes dopamine from the synaptic space and it puts it back into the presynaptic neuron. and once inside the presynaptic neuron the VMAT2 transporter can put it back into the vesicle where it can be reused again for later neurotransmission.
In that synaptic space it can be broken down by an enzyme called catechol O-methyltransferase or COMT. And so that's happening outside the cell in that synaptic space. If it's inside the synapse and it's not taken up by the VMAT2 to be put into the vesicles, intracellularly it can be broken down by two enzymes called MAOA or monoamine oxidase A or MAOB, monoamine oxidase B. So that happens inside the cell.
And the last way that it can be handled is similar to the first way except it's done through the norepinephrine transporter. So dopamine can be transported into norepinephrine neurons and it's known as like a false substrate where it's similar enough to norepinephrine but it's dopamine molecules. The receptors for dopamine are then the key regulators of dopamine neurotransmission. So we've already talked about a couple of the receptors for dopamine, and that would be the dopamine transporter, which you'll see abbreviated as DAT, so DAT, and the vesicular monoamine transporter, or VMAT2, and those are two types of receptors.
Now there are tons of of dopamine receptors that exist and there's at least five of them that are considered to be pharmacological subtypes and within those there's all these molecular isoforms but currently dopamine receptors are divided into two groups the first group is the d1 like receptors and that includes d1 and d5 receptors and the other group is the d2 like receptors which includes d2 d3 and d4 with these receptors they can be located either presynaptic or postsynaptic and we'll get into much more discussion of their locations and the significance of their locations and other slides so first we're going to talk about postsynaptic dopamine receptors so notice that All five of these pharmacological subtypes can be found postsynaptically. And remember that they're divided into these two groups. You have the D1-like and the D2-like.
So the D1-like group is made up of D1 and D5. And these are excitatory. They stimulate the postsynaptic neuron and they are positively linked to adenylate cyclase.
This other group, the D2-like receptors, are believed to be inhibitory. So they will then inhibit the postsynaptic neuron from firing. And they are negatively linked to this adenylate cyclase. So as you remember from the other slide, receptors for dopamine can be found postsynaptically.
So all five of the pharmacological receptors anyhow. The subtypes are found on that post-synaptic dopamine neuron. However, D2 and D3 dopamine receptors can also be found on the presynaptic neuron.
And their role here is to act as autoreceptors, which we'll go into a bit more detail on another slide. But its ultimate function in that role is to inhibit further dopamine release. So if you look at this picture here you'll notice that there's a difference between the D2 and D3 receptors as far as their sensitivity to the dopamine concentrations there in that synaptic space.
So the D3 receptor is much more sensitive to dopamine so it requires much less of a concentration of dopamine in that synapse in order to be activated and therefore turn off further dopamine release. The D2 receptor on the other hand is less sensitive to dopamine, so it requires much more of a higher concentration of dopamine molecules to be in that synaptic space in order to activate it and therefore turn off further dopamine release. So the presynaptic dopamine to and dopamine 3 receptors act as these gatekeepers or as auto receptors so what that means is when they are unoccupied or when there's not dopamine occupying that receptor the gate is open and it allows dopamine to go through basically but when they are occupied the gate closes and they further prevent any more dopamine to move through the cell.
These receptors are located either on the axon terminal or on the other end of the neuron in the somatodendric area of the dopamine neuron, but in both cases they're considered presynaptic and when they're occupied provides this negative feedback input where you could think of it as putting the brakes on the release of dopamine from that presynaptic dopamine neuron. Dopamine neurons therefore can be regulated quite differently depending upon which dopamine receptors are present and where they're located. So we'll look at some of those differences between mesocortical dopamine neurons and mesostriatal which would include the mesolimbic and nigrostriatal neuron pathways.
So mesocortical dopamine neurons arise from this part of the brainstem called the ventral tegmental area, which is the VTA. And they project to the prefrontal cortex, and there they either have D2 or D3 autoreceptors on their cell bodies in the ventral tegmental area. But in that prefrontal cortex, there's very few D2 and D3 receptors there.
pre or post synaptically and without auto receptors on axon terminals there in the prefrontal cortex dopamine release then is not shut off by that mechanism so it's a lot more free to diffuse away from the synapse where it is released and you can see that in this picture here on the left where the dopamine is freely diffusing away from that cell to the dopamine receptors Also notice that mesocortical dopamine neurons have very few, if any, dopamine transporters on their presynaptic nerve terminal in the prefrontal cortex. So without those dopamine transporters to take all that dopamine that's in that synaptic space back into that presynaptic neuron, or also not having D2 or D3 presynaptic... autoreceptors to turn off dopamine release there in that synaptic space as it's accumulating, this allows for a much larger diffusion radius of dopamine away from the presynaptic terminals. So that might be a good thing since the predominant post-synaptic receptor in the prefrontal cortex is this D1 receptor, as you can see there. And the D1 receptor is the least sensitive to dopamine, so it requires a much higher concentration of dopamine to be present in order for it to be activated compared to the D2 or the D3 receptors.
So that also means that with greater diffusion of dopamine, you can have the possibility of volume neurotransmission. So dopamine from one presynaptic terminal can communicate with dopamine 1 receptors anywhere within the brain. its diffusion radius in that prefrontal cortex and beyond the synapse where it originally came from so when we compare the cortical dopamine to the striatal dopamine receptors you can see some differences here so the mesostriatal dopamine neurons have either presynaptic d2 or d3 receptors present not only on the cell bodies in the ventral tegmental area and the substantia nigra, but they also have them on the presynaptic nerve terminals and postsynaptic sites in the striatum. You can also see that there are dopamine transporters present on the presynaptic nerve terminals in the striatum of these dopamine neurons.
So neurons with D2 autoreceptors have a wider diffusion radius compared to those with D3 autoreceptors. So that provides a range of possibilities for regulating dopamine release in those striatal pathways. So this figure here shows you the five major pathways that dopamine has within the brain.
And at least for our purposes, there's really only four pathways that we're really concerned about. because this fifth pathway doesn't seem to play a huge role in schizophrenia at least as far as we understand it and really what it does we're still trying to figure out so the four out of the five key pathways that dopamine follows in the brain are important as far as understanding some of the pathophysiology of psychosis and ultimately schizophrenia but then also understanding kind of what happens when we utilize various medications that help treat the symptoms of schizophrenia so if we understand some of the hypothesized pathophysiology then we can understand how some of those drugs work but we can also understand the side effects of some of these drugs as well so the four main dopamine pathways are the mesolimbic the mesocortical the nigrostriatal and the tuberoinfundibular now of these four pathways the first two seem to be where the problems lie as far as dopamine's action and the manifestations of psychosis and or schizophrenia the nigrostriatal and the tuberoinfantibular under normal circumstances and someone who is not being treated for schizophrenia or psychosis that is functioning normally but it's when we start to introduce various treatments for schizophrenia and psychosis that we start to cause problems there and you'll learn more about this as we talk about the various medications that we use to treat psychosis but the problem lies in that these medications will affect all of the dopamine pathways so we don't have super selective drugs that will only target one pathway in one way and not mess with the other ones so it's important to understand how dopamine acts on these pathways because you'll understand ultimately how the signs and symptoms of schizophrenia manifest hypothetically but then ultimately how the drugs help and sometimes harm our patients with schizophrenia and in what ways it helps and possibly harms. The mesolimbic dopamine pathway projects from dopamine cell bodies that are located in the ventral tegmental area of the brain stem, which is also known as the mesencephalon, to the nucleus accumbens, which is in the ventral striatum.
And all of this is part of the limbic system, so this is where it gets the name the mesolimbic. Dopamine release from this pathway is thought to have a very important role in several normal emotional behaviors like motivation, pleasure, and reward. And that mesolimbic dopamine pathway might be the final common pathway of all reward and reinforcement. That's including normal positive rewards such as the pleasure of eating good food, listening to music, sexual activity, and also emotions experienced when rewards are too high or too low like you would see with substance use too much dopamine in this pathway traditionally has been thought to cause the positive symptoms of psychosis as well as the artificial reward or the drug-induced high of substance use and too little dopamine in this pathway hypothetically causes the symptoms of anhedonia apathy and lack of energy that's seen in conditions like bipolar and unipolar depression, and the negative symptoms of schizophrenia.
So the traditional hypothesis of the dopamine cause of the positive symptoms of schizophrenia and psychosis has always been that there's too much dopamine activity in that mesolimbic pathway that's causing the positive symptoms of psychosis. But now we have some newer understanding of how this dopamine hypothesis of the positive symptoms of psychosis are manifesting and it is involving the nigrostriatal pathway as well as the mesolimbic so classically dopamine projections from the substantia nigra to the dorsal striatum had been considered to regulate motor movements and they were believed to be in parallel with pathways from the ventral tegmental area to the ventral striatum and the nucleus accumbens that regulate emotions. And so this dorsal or upper striatum that's associated with motor movements was considered, you know, the neurologist's striatum since it's more of like a physical motor area.
And the ventral striatum or the lower striatum was thought to be exclusively for emotional regulation, so sort of known as the psychiatrist's striatum. And these concepts came about from anatomy and pharmacology studies and animals and humans and recently with neuroimaging techniques that showed sort of these different areas being as separate have made us revisit this notion that maybe there's more of a connection here than we initially So with the neuroimaging of dopamine activity in the striatum of living unmedicated patients with schizophrenia, it didn't show the expected excess amount of dopamine activity just in that ventral striatum, like you would think, since that's the emotional area. Instead, it seems that this excess dopamine activity might be present in this sort of in-between, this limbo area. intermediate part of the striatum that they're calling the associative striatum and it receives input from the substantia nigra but not from the ventral tegmental area so the findings from those imaging studies really create a much more complicated formulation of the dopamine pathways and that might be what's going on to help better understand the excess amount of dopamine that's seen in schizophrenia and psychosis so the excessive dopamine projects not only from the ventral tegmental area but perhaps from this medial and lateral substantia nigra and those might be important in mediating the positive symptoms of schizophrenia so interestingly now you know what used to be thought is mostly just a motor area it might have some components in emotional regulation in addition to motor components. another dopamine pathway that also rises from cell bodies in the ventral tegmental area but projects to areas of the prefrontal cortex is known as the mesocortical dopamine pathway so the branches that go to the dorsolateral prefrontal cortex have hypothetically been linked to cognition and executive functioning where the branches that go to the ventral medial parts of the prefrontal cortex have hypothetically been linked to emotional regulation and affect and the exact role of how this pathway mediates the symptoms of schizophrenia is sort of still in the works and under debate but traditionally many have believed that this is where the cognitive and negative symptoms of schizophrenia are manifesting and that's been due to a lack of dopamine or a dopamine deficiency in this medical mesocortical pathway and the deficits suggested by these negative symptoms has implied underactivity or lack of properly functioning mesocortical dopamine projections and a leading theory as to why this is happening is that it might be the consequence of neurodevelopmental abnormalities in the NMDA glutamate system which there will be a separate lecture that talks about that The nigrostriatal dopamine pathway starts from the substantia nigra and projects to the basal ganglia or the striatum.
And it's traditionally been thought to be part of the extrapyramidal nervous system and plays a key role in regulating movements. And it does this through its connections with the thalamus and cortex and the corticostriatal thalamocortical circuits or the CSTC loops. Too little dopamine in this area can cause parkinsonism with tremor, rigidity, and bradykinesia. When there's too much dopamine here, it can cause hyperkinetic movements like tics and dyskinesias. In an untreated schizophrenic individual, this pathway is believed to function normally.
And on the next slide, we'll talk more about how dopamine itself can regulate motor movement directly and indirectly. Dopamine regulates these CSTC loops and motor movements in the striatum in a direct and indirect pathway. The so-called direct pathway is populated primarily with dopamine 1 receptors and they are excitatory.
They project directly from the striatum to the globus pallidus interna and they stimulate movements so you can think of this as the go pathway the indirect pathway on the other hand is populated with d2 dopamine receptors and they are inhibitory they project indirectly to the globus pallidus interna via the globus pallidus externa and subthalamic nuclei normally this pathway blocks motor movements So you can think of this as the stop pathway. So dopamine inhibits this action at the D2 receptors in the indirect pathway. So it says don't stop to the stop pathway, or another way to think of that is go more.
So to summarize, dopamine stimulates motor movements both in a direct and indirect motor pathway, and the synchronizing...... outputs of these pathways is thought to lead to the smooth execution of motor movements normally. So GABA neurons are also involved in this direct and indirect pathway in terms of activating motor movement.
And so in the direct pathway, which remember the direct pathway is the GO pathway, A GABA neuron that projects from the striatum to the globus pallidus interna is activated. And when that happens, GABA is then released and it inhibits activity of another GABA neuron that projects to the thalamus. So in the absence of GABA release in the thalamus, a glutamate neuron is activated.
And it releases glutamate into the cortex, and that therefore will stimulate movement. Over on the indirect pathway, a gaba neuron would be projecting from the striatum to the globus pallidus externa which would then be activated and gaba then would be released which would inhibit the activity of another gaba neuron that projects to the subthalamus nucleus. So without GABA release in that subthalamic nucleus, a glutamate neuron would be activated and it would release glutamate into the globus pallidus interna, which then would stimulate a GABA neuron to release GABA into the thalamus. So when the GABA that's released there in the thalamus binds to a glutamate neuron, it inhibits that neuron from releasing glutamate into the cortex. So then that would inhibit.
movement from happening. The dopamine neurons that project from the hypothalamus to anterior pituitary gland are known as the tubero-infundibular dopamine pathway. Normally these neurons are tonically active and they inhibit prolactin release. But in cases like postpartum, however, the activity of these dopamine neurons is decreased.
So when prolactin levels rise during breastfeeding, lactation occurs. If the functioning of this tubero-infantibular dopamine neuron is disrupted either by tumors or some of the drugs that we prescribe, prolactin levels can also rise. Elevated prolactin levels are associated with symptoms like galacteria, which is breast secretions, gynecomastia, which is enlarged breasts especially seen in men, amenorrhea which is the loss of ovulation and menstrual periods, and possibly other problems like sexual dysfunction and bone demineralization. These problems can occur after treatment with many drugs for psychosis that end up blocking dopamine d2 receptors.
We'll discuss those particular drugs later on. If in an untreated schizophrenic individual though The functioning of this tubero-infandibular pathway is generally preserved and there aren't any abnormalities here. So as you can see on this slide here, there are many things that can contribute to elevated prolactin levels that are not exclusively due to antipsychotic or D2 dopamine receptor blockade.
You can look at all of these examples here, but it's important to consider that there could be other comorbid and contributing causes to elevated dopamine besides the medications that we use to treat psychosis. Because many times people fail to work up alternative causes and thus can lead to unnecessary medication changes or unnecessary disruptions in treatment. So when should a prolactin level be checked?
Well, it used to be common practice that if we had patients on antipsychotics that we would periodically and routinely check prolactin levels. More current guidelines, particularly from the Endocrine Society from 2011, they recommend that you do not routinely check prolactin levels in a patient who is otherwise asymptomatic. Of course, many of the signs and symptoms of elevated prolactin are not going to be readily apparent to you as the provider so that's going to require the patient to either spontaneously report those signs and symptoms or probably a better approach would be for you as the provider to ask about signs and symptoms of elevated prolactin but when you're going to check a prolactin level remember that it peaks during sleep So ideally you want to check your prolactin level in the morning, preferably a few hours after waking. And the patient should be fasting since food or having eaten a large meal can affect prolactin levels. And the patient should avoid strenuous exercise 20 to 30 minutes before the lab is drawn since strenuous exercise can also affect your prolactin levels and elevate them.
If a patient has this horrific fear of prolactin, of needles then that's something you need to consider and actually address beforehand because stress or anxiety can also lead to falsely elevated prolactin levels in animal studies there's a dopamine pathway that's been discovered that innervates the thalamus and it arises from multiple sites within the brain including the periaqueductal gray matter the ventral mesencephalon from various hypothalamic nuclei and from the lateral parabrachial nucleus. As far as its functions in humans goes, that's still a matter of research and investigation, but it's possibly involved in sleep and arousal mechanisms by gating information that passes through the thalamus to the cortex and other brain areas. As far as abnormal findings or functioning goes with individuals with schizophrenia, there's no evidence, as far as we know, that there's any kind of abnormal functioning going on with this particular pathway.
So to summarize everything that we've talked about, one of the leading theories of what causes psychosis and ultimately can contribute to the symptoms we see in the disorder we call schizophrenia. One of the leading theories has been problems with dopamine and we talked about the various pathways that dopamine follows in the brain and four of those seem to play a large role in either the symptoms of schizophrenia or in the treatment of schizophrenia and from that the major theory that we call the dopamine hypothesis of psychosis and schizophrenia has been that there's over activity of the mesolimbic dopamine system and that leads to the positive symptoms of psychosis and under activity of the mesocortical dopamine system seems to lead more to the negative cognitive and affective symptoms of schizophrenia and traditionally the tuberoinfundibular pathway has been thought to be unaffected by the process by which schizophrenia happens so in people with schizophrenia whether without treatment the the tuberoinfundibular pathway seems to be unaffected but when we start introducing medications to treat schizophrenia that's where we can cause problems in that pathway and see side effects of elevated prolactin similarly in the nigrostriatal pathways we typically have believed this to be uninvolved in the pathophysiology of schizophrenia and it's not been impacted by the pathophysiology of schizophrenia until we start introducing medications to treat schizophrenia and that's where we see a lot of the motor movements occur but now with new understanding of maybe a connection or the associated striatal complex there seems to be a role of that area between the dorsal and ventral striatum that might play a role in emotional regulation and so it variable could be that excessive dopamine in schizophrenia might be more mesostriatal and not just mesolimbic