The Impact of Dopamine in Neuroplasticity

Neuroplasticity is affected by dopamine is various ways. Daily human activities required the brain to use both motor and cognitive functions. Importantly, neural plasticity plays an essential role in motor and cognitive learning. Neuroplasticity is the cortical remapping of the brain. Fundamentally the brain has the ability to alter cortical structures due to its ability to train and relearn skills. Memory formation and learning are ways in which dopamine aids in brain development. In neuropsychiatric diseases such as schizophrenia and Parkinson’s disease, an individual will undergo a barrier in their cognitive processes, which are usually followed by dopaminergic dysfunctions. The premise of these dopaminergic effects is found to be involved in long-term depression (LTD) and long-term potentiation (LTP) in neuroplasticity. Scientists discovered that by using non-invasive brain stimulation techniques, it could be used to measure the impact dopamine has on plasticity.

These techniques include paired associative stimulation (PAS) and transcranial direct current stimulation (tDCS). Previous research indicates that activation of the D1-receptor sustains LTD and LTP. Dopamine is a neuromodulator in this case because of its ubiquitous function being inhibitory or excitatory. To confirm this claim, experimenters induced plasticity using PAS and tDCS in the human motor cortex. Previous studies were able to accomplish generating LTD and LTP-like cortical excitability for approximately an hour by using this technique. To add, brain stimulation is capable of eliciting receptor dependence from the NMDA receptor itself. Brain stimulation in the motor cortex using tDCS promotes nonfocal plasticity.

Essentially, excitability is not limited to the synaptic subgroups. This technique allows for the glutamatergic system to generate polarity-dependent plasticity, which is not confined to a particular subgroup. Likewise, PAS promotes focal plasticity because it is thought to primarily be specific to the somatosensory motor cortex. Cortical excitability is reinforced through the synchronized activation of neurons in the motor cortex by the synchronized activation of neurons in the motor cortex. This process occurs through the somatosensory afferent neurons. In humans, dopamine has proven to have an effect on neuroplasticity where it demonstrates a nonlinear dose-dependent effect. The precursor to dopamine is L-dopa. Notably, L-dopa reveals to have an effect on plasticity in humans. This drug has confirmed that it has nonlinear dosage-dependent effects on neuroplasticity and cognition. This drug appears to have a beneficial outcome on memory formation and learning. Dopaminergic agents have been demonstrated to be reinstituted PAS-induced plasticity when patients with Parkinson’s disease are given prescription medicine. Because of the nonlinear effect seen in L-dopa researchers are interested in investigating the connection this drug has with plasticity in humans. Furthermore, the current hypothesis these experimenters are particularly interested in is in exploring the importance the activation of the D1-receptor has in neuroplasticity.

For processing learning, the D1 receptor is essential. In an experiment conducted by Fresnoza & colleagues, experimenters were interested in finding the connection between plasticity during D1-receptor activation. Furthermore, they hypothesized that activation of the D1-like receptor would result in nonlinear effects on plasticity. Researchers performed two experiments using the primary motor cortex as a model. Experimenters conducted to experiments for this study. In the first experiment, they blocked D2 receptors with sulpiride that way activation would be displaced towards D1-receptors. They chose to use sulpiride because it is a selective antagonist for the D2 receptor. This mechanism reestablishes plasticity through blocking D2 receptor activity. In the second experiment, researchers combined sulpiride with L-dopa in order to increase D1-receptor activation.

Experimenters chose this indirect approach because, for humans, there is currently no selective D1 receptor agonist accessible. At each experimental session, subjects were administered either a low (25mg), medium (100mg), or high (200mg) dose of L-dopa. The L-dopa was combined with placebo medication or sulpiride for ninety minutes before inducing plasticity. In the first experiment, plasticity was induced by using tDCS. An electrode was placed over the designated cortical region in the motor cortex; above the right supraorbital region, the return electrode was placed. Following placement of the electrode, a current would be administered to the head. For anodal tDCS current was given for 13 minutes and for cathodal tDCS current was administered for 9 minutes. Notably, inducing current allows for the cortical excitability to persist up for an hour following terminating stimulation. In the second experiment, experimenters used PAS to induce plasticity. An electrical pulse was used to deliver current to the wrist level at the right ulnar nerve.

For thirty minutes, 90 pairs of stimuli were conducted to cause cortical excitability reduction (PAS10) or enhancement (PAS25) for approximately an hour following ceasing stimulation. This method is useful because researchers found that the combination of sulpiride and L-dopa altered induced plasticity using the tDCS technique. These results show that D1 receptor activation demonstrates a nonlinear dosage dependency on plasticity. to add, activation of the D1-receptor shows to have an effect on memory formation and learning. In humans, in order for D1-like plasticity to be generated in the motor cortex, a peak amount of D1-like receptor activation would be needed. Researchers do theorize that the mechanism in which D1 receptor activation occurs is through GABAergeic and glutamatergic systems. GABAergic and glutamatergic activity has been proven to enhance the activation of the D1 receptors. The combination of sulpiride with L-Dopa with low dosage administration enhances D1 receptor activation and blocks D2 receptors by collectively strengthening GABAergic activity.

The researchers in this study were able to effectively distinguish activation of the D1 receptor had an effect on plasticity during brain stimulation using PAS and tDCS. this nonlinear effect may be useful to explore the ways in which memory formation and learning are acquired when the D1 receptor is stimulated. Furthermore, this could be used as a possible treatment for individuals with Parkinson’s disease. The activation of D1 receptors through brain stimulation could be effective for improving cognitive functions where there is a reduction in the dopamine receptors. In addition, this technique of targeting activation of the D1 receptors could be useful for treating individuals with schizophrenia. Notably, a limitation to this study is that researchers likely activated other dopamine receptors since they used an indirect approach in this experiment. They believe that D3 receptors could have been activated in this study. To add, sulpiride could be used to block D3 receptors activation.

In the neocortex, one of the most predominant dopamine receptors is the D1 receptor. Researchers have proven that in the dorsolateral prefrontal cortex (DLPFC), reorganization of dopamine signaling to D1 receptors could be responsible for the functional changes in working memory found in individuals with schizophrenia. In a study conducted by Abi-Dargham et. Al, experimenters were interested in assessing the availability of D1 receptors in the DLPFC in individuals with schizophrenia. They matched participants with healthy controls to compare the working memory performance and D1 receptor availability. Importantly, experimenters in this study found that enhanced postsynaptic sensitivity to release dopamine during the assigned task performance could be due to the activation of D1 receptors in the DLPFC. This study could also be useful in discovering the impact the activation of D1 receptors has on plasticity, however further research is still needed.

In an experiment conducted by Bergner and colleagues, they were also interested in exploring the ways in which D1 receptor activation is involved in neural plasticity. to test this hypothesis, the methods used in this experiment is similar to the method used in the experiment performed by Frenezo et. Al. they also used the human motor cortex as a model. They used brain stimulation techniques of PAS and tDCS-induced plasticity to test the effect of sulpiride combined with L-dopa. When experimenters induced plasticity using PAS in the first experiment, patients were administered sulpiride or placebo (PLC) medication. Experimenters found that cortical excitability was able to be induced and lasted approximately thirty minutes following stimulation unaided with drug conditions. However, they observed that excitability ceased effects for iPAS under sulpiride. In the second experiment, experimenters used tDCS-induced plasticity to measure the consequences of sulpiride combined with L-dopa. They observed no substantive cortical excitability. Notably, neuroplasticity was not able to be sustained under drug combinations of sulpiride and L-dopa.

The results of this study were able to prove that D1 receptor activation does have a dose-dependent effect on plasticity. They discovered that D1 receptor activation has an evident effect on plasticity with L-Dopa alone. The techniques used in this experiment were useful in demonstrating that sulpiride has the ability to block D2 receptors which implicates activation of the D1 receptors, resulting in the absence of focal iPAS-induced inhibitory plasticity. Evidence to see nonfocal induced plasticity generated by anodal tDCS would require D2 activity to be inhibited. Authors do note that in schizophrenia the D2 receptors are hyperactive, which causes individuals to have intrusive thoughts and are easily distractible, and disorganized behavior. This study could be used to help understand the dopaminergic dysfunctions in this disease. Activation of the D1 receptors and blocking of D2 receptors could be essential in being able to stabilize processing information. This could be used as a treatment for patients with schizophrenia.

In the central nervous system, dopamine plays a significant role as a neuromodulator. As previously mentioned, dopamine is important for memory processes and learning. Thirugnanasambandam and colleagues conducted an experiment that tested the effects involving L-dopa relating to plasticity in humans. To test this theory, researchers gathered 12 participants. The experimenters were interested in studying the effects of L-dopa on plasticity administered at different dosages. In the motor cortex, plasticity was induced using either inhibitory or facilitatory PAS. For each session, a low (25mg), medium (100mg), or high (200mg) dosage of placebo or L-dopa was given to each participant at random. Each dosage or placebo given to patients was accompanied with either excitability diminishing or enhancing PAS. The results of PAS-induced plasticity was seen in patients that received a low dosage of L-dopa.

Experimenters also observed facilitatory plasticity was sustained at a medium dosage of L-dopa. In addition, they observed an aversive effect with high dosage where PAS25- induced facilitation involved inhibition which was reversed by L-dopa. This current method effectively tested the hypothesis. The results demonstrated that at different dosages of L-dopa, it would yield a nonlinear effect on plasticity. researchers propose that the mechanisms in which this takes place be caused by enhancement of the D1 receptor activation. Activation of this receptor could be responsible for L-dopa being able to sustain facilitatory plasticity. Notably, if the D2 receptor is obstructed, facilitatory plasticity still occurs. It is theorized that the mechanisms in which facilitatory plasticity occurs is because of D1 receptor activation. Researchers know that PAS is responsible for causing NMDA receptor-dependent plasticity, so they further speculate that D1 receptor activation could mediate this function of enhancement. The authors do note that some limitations of this study are that they were not able to control for variance among the patients in the study because they were unable to acquire dopamine levels from the plasma levels of each participant. In addition, researchers in this study used healthy young participants, so the results for elderly patients may vary.

An alternative hypothesis that could help address the question of whether the activation of the D1 receptor has an impact on neuroplasticity is that the interaction of the D1 and D2 receptors is essential for facilitatory plasticity. this hypothesis could be tested in a similar way presented in this review. The D2 receptor would be blocked using sulpiride. This hypothesis would be an effective way to measure the interaction of these two receptors during the induction of plasticity. this alternative hypothesis would inform the current hypothesis that the interaction of these two receptors is needed to see the impact of dopamine in neuroplasticity. Based on the evidence presented in this review, enhancing cognition could be effective by eliciting D1 and D2 concurrent stimulation. To conclude, in regard to individuals with dopaminergic dysfunctions, stimulation of the D1 receptors could help shape future treatment. Further research should be done in this area because this could be effective in treating patients with disruptions in cognitive functions, which is seen in schizophrenia and Parkinson’s disease.

References

1. Abi-Dargham, A., Mawlawi, O., Lombardo, I., Gil, R., Martinez, D., Huang, Y., Hwang, D. R., Keilp, J., Kochan, L., Van Heertum, R., Gorman, J. M., & Laruelle, M. (2002). Prefrontal dopamine D1 receptors and working memory in schizophrenia. The Journal of neuroscience : the official journal of the Society for Neuroscience, 22(9), 3708–3719. https://doi.org/10.1523/JNEUROSCI.22-09-03708.2002
2. Cai, L., Chan, J. S., Yan, J. H., & Peng, K. (2014). Brain plasticity and motor practice in cognitive aging. Frontiers in aging neuroscience, 6, 31. https://doi.org/10.3389/fnagi.2014.00031
3. Fresnoza, S., Paulus, W., Nitsche, M. A., & Kuo, M. F. (2014). Nonlinear dose-dependent impact of D1 receptor activation on motor cortex plasticity in humans. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(7), 2744–2753. https://doi.org/10.1523/JNEUROSCI.3655-13.2014
4. Nitsche, M. A., Kuo, M. F., Grosch, J., Bergner, C., Monte-Silva, K., & Paulus, W. (2009). D1-receptor impact on neuroplasticity in humans. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29(8), 2648–2653. https://doi.org/10.1523/JNEUROSCI.5366-08.2009
5. Thirugnanasambandam, N., Grundey, J., Paulus, W., & Nitsche, M. A. (2011). Dose-dependent nonlinear effect of L-DOPA on paired associative stimulation-induced neuroplasticity in humans. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31(14), 5294–5299. https://doi.org/10.1523/JNEUROSCI.6258-10.2011