Transcript:
Hello, and welcome to the NP Psych Navigator’s Clinical Insights video series. I am Moushumi Mukerji, a board-certified psychiatric nurse practitioner and certified nurse-midwife based in northern California.
I’m excited to talk to you today about the psychopharmacology of dopamine and serotonin. We will explore the roles of these 2 neurotransmitters in the brain that are thought to play in various psychiatric conditions.
Learning how these chemicals can be modulated may help healthcare providers such as yourself understand the impact these neurotransmitters may have in psychiatry.
This is quite a complex topic, so let’s get started.
First, let’s briefly review how neurotransmitters are thought to work. Neurotransmitters are signaling molecules that relay information that can affect cellular function in the receiving neuron. They are released from the presynaptic neuron into the synapse, a gap between the presynaptic neuron and the postsynaptic neuron. Neurotransmitters bind to their corresponding receptors on the synaptic surface of the postsynaptic neuron and relay the information that can activate or block certain cellular functions downstream.1,2
Now, let’s go over the roles of some neurotransmitter pathways, starting with dopamine.
Dopamine is produced in the dopaminergic neurons located in the midbrain, specifically the substantia nigra and the ventral tegmental area.3 It can travel to different parts of the brain through 4 major pathways, each with different functions.4
Let’s review the 4 dopamine pathways. First, the mesolimbic pathway, which projects from the ventral tegmental area to the nucleus accumbens in the ventral striatum, may play a role in the regulation of motivation, reward-seeking behavior, compulsion, desire, positive reinforcement, and aversions.1
In patients with schizophrenia, dopamine hyperactivity in the mesolimbic pathway may lead to positive psychotic symptoms, namely delusions and hallucinations, while reduced dopamine signaling in this pathway may lead to depressive symptoms.1
Next, the mesocortical pathway, which projects from the ventral tegmental area to the prefrontal cortex, is thought to be responsible for regulating cognition, executive functions, and emotions.1
Dopamine deficiency in mesocortical projections is thought to be implicated in the negative symptoms of schizophrenia.1
Next, the nigrostriatal pathway, which projects from the substantia nigra to the striatum, is thought to control motor movements as part of the extrapyramidal nervous system.1
Dopamine deficiencies in this pathway may lead to movement disorders such as extrapyramidal symptoms, or EPS. On the other hand, dopamine hyperactivity in the nigrostriatal pathway may be associated with hyperkinetic movement disorders such as chorea, dyskinesias, and tics.1
Lastly, the tuberoinfundibular pathway projects from the hypothalamus to the anterior pituitary.1
The tuberoinfundibular pathway is thought to be involved in the inhibition of prolactin release, and dopamine deficiency in this pathway may lead to elevated prolactin levels. High prolactin levels may be associated with sexual and reproductive side effects.1
Now, let’s further explore the role of dopamine.
Dopamine exerts its activity by binding to dopamine receptors. There are 5 dopamine receptor subtypes, which are divided into 2 families, D1-like and D2-like receptors.4
D1-like receptors, which include D1 and D5 receptors, have an excitatory effect on the postsynaptic neuron, while D2-like receptors, which include D2, D3, and D4 receptors, have an inhibitory effect on the postsynaptic neuron.4
Dopamine receptors are scattered across various brain regions.5
The D2 receptor is present in all known dopaminergic pathways and is thought to play a role in psychosis, EPS, and hyperprolactinemia.1
The D3 receptor has been shown to be mainly expressed in the limbic region of the brain, with the highest concentration found in the nucleus accumbens, the ventral tegmental area, and the substantia nigra.4
The D3 receptor is thought to be associated with the regulation of emotions, reward, motivation, and cognition.6 A pre-clinical study also showed that the D3 receptor may be associated with memory, attention, and cognition.7
These various receptor subtypes transmit signals through different dopamine pathways. They may also represent different points at which dopamine signaling modulation may help to address symptoms of psychiatric disorders.8
Now, let’s turn our attention to another important neurotransmitter, serotonin. Serotonin, also known as 5-HT, is primarily produced in the raphe nuclei, located in the brainstem.4 The raphe nuclei are divided into 2 groups: the front, or rostral, group and the back, or caudal, group.
The rostral group sends connections to most parts of the brain, including a pathway to the cerebellum, and the caudal group mainly connects to the cerebellum, lower brain regions, and the spinal cord.4 Together, these 2 groups of the serotonin pathway innervate most of the central nervous system.9
Consequently, nearly every cell in the brain is in close proximity to a serotonergic fiber. This highlights the possible involvement of serotonin in regulating a wide range of neurological functions.9
Now, let’s review the different types of serotonin receptors mediating the serotonin signals.
Currently, there are 7 known serotonin receptor families, each with its own unique function and localization in different parts of the brain.4
Of the 7 families, 5-HT1A, 5-HT2A, and 5-HT2C are of interest due to their potential involvement in some psychiatric conditions. Let’s examine each of their roles.
The 5-HT1A receptor, located primarily in midbrain, limbic, and cortical regions,10 may be involved in the regulation of mood and stress responses. Decreased 5-HT1A receptor binding may be implicated in depression.4,11
The 5-HT2A receptor is found to be widely distributed in the brain. It is the most present at high levels in the cortex, followed by the hippocampus, basal ganglia, and forebrain.1,10 These receptors are thought to help modulate cognition, perception, and mood. Pre-clinical in vivo studies have shown decreased 5-HT2A receptor binding in the cortex of patients with schizophrenia and major depressive disorder.4,12,13
The 5-HT2C receptor, located in the choroid plexus, substantia nigra, and basal ganglia,4 is believed to help regulate appetite, mood, and reward pathways. Dysregulation of the 5-HT2C receptor is thought to be associated with depression.4,14
We have reviewed in detail some key players in the dopamine and serotonin pathways in the brain. Now, how do we apply this knowledge to psychiatry? One way we can think about neurotransmitters is by considering the downstream effects of targeting specific pathways.
As mentioned earlier, the dysregulation of dopamine and serotonin may be associated with various psychiatric conditions. Some psychopharmacologic agents target dopamine and serotonin receptors, which, in turn, may help regulate the release of these neurotransmitters downstream.
For example, in schizophrenia patients, reducing dopamine levels in the mesolimbic pathway with D2 receptor antagonists may help alleviate positive psychotic symptoms. However, blocking D2 receptors throughout the brain may potentially lead to unintended consequences such as EPS, anhedonia, hyperprolactinemia, and neuroleptic-induced deficit syndrome.1
Reducing antagonism on the D2 receptors specifically in the nigrostriatal and tuberoinfundibular pathways, which are thought to be involved in regulating motor movements and prolactin release, respectively, may help to avoid these side effects.1
In addition to the downstream effects that they each may activate, the dopamine and serotonin pathways may be interconnected through their regulation of each other. Specifically, activation or inhibition of serotonin receptors can modulate the release of dopamine downstream.
For example, it is theorized that the activation of 5HT1A receptors in the cortex indirectly enhances dopamine release in the striatum. On the other hand, activating 5HT2A receptors is thought to inhibit dopamine release, while blocking them is theorized to increase dopamine release.1
Therefore, either activating 5HT1A or blocking 5HT2A serotonin receptors may lead to the stimulation of dopamine release downstream.1
Let’s take a look at some ways in which dopamine and serotonin receptors can be regulated simultaneously and may help modulate downstream events.
Antagonizing both D2 and 5HT2A receptors, which leads to increased dopamine release, may theoretically reduce the risk of effects such as EPS. As mentioned earlier, blocking D2 receptors, which may be associated with positive symptoms of psychosis, may also result in dopamine inhibition in pathways regulating other functions and may lead to unintended effects. However, simultaneous antagonism of 5HT2A receptors may prevent the downstream inhibition of dopamine release, potentially increasing dopamine concentration in the striatum.1
The increase in dopamine level allows dopamine molecules to overcome D2 antagonism, reducing the effect of blocked D2 receptors.1
In another example, serotonin and dopamine are thought to have opposing effects on the regulation of prolactin secretion. Dopamine is thought to suppress prolactin release by stimulating D2 receptors, whereas serotonin is thought to promote prolactin release via activation of 5HT2A receptors.1
If the D2 receptor is antagonized alone, dopamine binding may be disrupted, which may lead to elevated prolactin levels. However, if 5HT2A receptors are blocked simultaneously with D2 receptors, this may increase dopamine levels, and potentially help alleviate the hyperprolactinemia caused by the D2 receptor blockade alone.1
As you have seen today, dopamine and serotonin are thought to be important targets in psychopharmacology, and they are dynamically controlled by components of their respective pathways.
Thank you for joining me today! We covered a lot of ground. I hope this video has been informative for your understanding of the underlying mechanisms that may be implicated in psychiatric conditions. Remember to check out NP Psych Navigator for other resources to learn more about psychopharmacology.
