Neurological researchers, in Aging Cell, have deepened our understanding of the brain, explaining how turning off a dopamine receptor may lead to better memory in older people.
Sometimes it’s better for the dopamine not to hit
With aging comes changes in how the brain processes dopamine [1]. This work focuses on specific dopamine receptors called D3Rs, which are less common than related D2Rs although much stronger in binding dopamine [2]. This potency has made them attractive targets in drug discovery, and prior work has focused on D3Rs for the treatment of such disorders as schizophrenia and depression [3].
One of the brain regions that contains D3Rs is the hippocampus [4], which is responsible for the formation of memories. Rodent studies have found that, unlike D2Rs, blocking D3Rs improves memory [5] and cognition [6], and the same appears to be true for people [7]. However, the reasons why blocking a receptor would lead to cognitive benefits are not clear, which is why these researchers took a closer look.
Cells and mice agree
This work began with an examination of CA3-CA1 synapses, which are very common targets in brain research, derived from the hippocampi of mice. Without a D3R blocker, giving light stimulation to these synapses creates a weak long-term connection, which takes time and reinforcement to become a more permanent one.
However, administering a D3R blocker makes even this light stimulation form a permanent connection much more quickly. Strong stimulation does normally cause these synapses to form a permanent connection, but even this was enhanced with a D3R blocker. These findings were confirmed with a strain of mice that has the genes for D3 reception knocked out. Further work found that these behavioral changes were post-synaptic: they did not affect how the neurons worked before the stimulation.
Turning to living animals, the researchers found that D3R blocking turned short-term memory into long-term memory much more readily. Normally, a light training regimen allows mice to distinguish between familiar and unfamiliar objects for six to eight hours [8], after which they forget about it. However, administering D3R blockers to the mice allowed them to distinguish between the objects 24 hours later, as if they had gone through a heavier training regimen. The same was true of D3R knockout mice: they gained long-term memories much more quickly.
Although memories are harder to form with age, D3R numbers were found to be decreased with age, but mostly in the pre-synaptic sites. Post-synaptic D3R sites were largely similar between adult and aged mice. Comparing the hippocampal neurons of D3R knockout mice and wild-type mice, the researchers found that the age-related loss of memory formation did not occur: these neurons’ ability did not seem to have diminished. These findings were confirmed in mice that had their D3R receptors blocked through genetics or chemical intervention. No sex differences were found.
These findings are impressive, and it may be that D3 receptor blockers might become an effective “memory pill” for people seeking to learn information quickly or people suffering from age-related memory problems. However, there may be significant neurological side effects to engraving more things in long-term memory that would normally be lost. Further work needs to be done to judge the effectiveness and safety of blocking D3 in animals and, ultimately, in people.
Literature
[1] Shohamy, D., & Wimmer, G. E. (2013). Dopamine and the cost of aging. Nature Neuroscience, 16(5), 519-521.
[2] Maramai, S., Gemma, S., Brogi, S., Campiani, G., Butini, S., Stark, H., & Brindisi, M. (2016). Dopamine D3 receptor antagonists as potential therapeutics for the treatment of neurological diseases. Frontiers in neuroscience, 10, 451.
[3] Kiss, B., Laszlovszky, I., Krámos, B., Visegrády, A., Bobok, A., Lévay, G., … & Román, V. (2021). Neuronal dopamine D3 receptors: translational implications for preclinical research and CNS disorders. Biomolecules, 11(1), 104.
[4] Li, Y., & Kuzhikandathil, E. V. (2012). Molecular characterization of individual D 3 dopamine receptor-expressing cells isolated from multiple brain regions of a novel mouse model. Brain Structure and Function, 217, 809-833.
[5] Watson, D. J., Loiseau, F., Ingallinesi, M., Millan, M. J., Marsden, C. A., & Fone, K. C. (2012). Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex. Neuropsychopharmacology, 37(3), 770-786.
[6] Xing, B., Meng, X., Wei, S., & Li, S. (2010). Influence of dopamine D3 receptor knockout on age-related decline of spatial memory. Neuroscience letters, 481(3), 149-153.
[7] Gross, G., Wicke, K., & Drescher, K. U. (2013). Dopamine D 3 receptor antagonism—still a therapeutic option for the treatment of schizophrenia. Naunyn-Schmiedeberg’s archives of pharmacology, 386, 155-166.
[8] Blokland, A., & Sesia, T. (2023). Delay-dependent forgetting in object recognition and object location test is dependent on strain and test. Behavioural Brain Research, 437, 114161.
