Blocking Dopamine Receptor Could Enhance Memory Formation

Researchers have found that blocking a specific dopamine receptor may enhance memory formation in older individuals, according to a study published in Aging Cell. This discovery adds to our understanding of the brain's aging process and potential treatments for memory decline.

Dopamine and Memory

As humans age, changes occur in the way the brain processes dopamine, a neurotransmitter associated with reward and motivation.[^1] The study focuses on the D3 dopamine receptor (D3R), which binds to dopamine more strongly than its more common counterpart, D2R.[^2] While D3Rs have been targeted for treating conditions like schizophrenia and depression, their role in memory and cognition has been under-explored until now.[^3]

The Hippocampus and Memory Formation

The hippocampus, a key brain region responsible for memory formation, contains D3Rs.[^4] In studies with rodents, blocking D3Rs improved memory and cognitive performance.[^5][6] Similarly, early research in humans suggests that blocking D3Rs may lead to cognitive benefits.[^7] However, the exact mechanisms behind these effects remained unclear, prompting further investigation.

Experiment: CA3-CA1 Synapses and Memory

The researchers began their investigation by studying CA3-CA1 synapses, a common target in neuroscience research, taken from the hippocampi of mice. When these synapses received light stimulation without a D3R blocker, they formed weak long-term connections that needed further reinforcement to become permanent.

When a D3R blocker was administered, even light stimulation created permanent connections much faster than normal. Stronger stimulation also resulted in enhanced connections when combined with D3R blockers. These results were confirmed with genetically engineered mice lacking D3Rs. Further research showed that these improvements occurred post-synaptically, meaning that D3R blocking did not affect how neurons worked before the stimulation.

Turning Short-Term Memory Into Long-Term Memory

The researchers next tested D3R blockers in living mice. Mice typically remember familiar and unfamiliar objects for about six to eight hours, but they forget after that time period. After administering D3R blockers, however, the mice retained memory of the objects for 24 hours, as if they had undergone a more rigorous training regimen. D3R knockout mice exhibited similar results, forming long-term memories more quickly than their wild-type counterparts.

Age-Related Memory Decline

Although memory formation becomes more challenging with age, the number of D3Rs decreases over time, particularly in pre-synaptic sites. However, the number of post-synaptic D3R sites remained largely similar between adult and aged mice. When comparing the hippocampal neurons of D3R knockout mice with those of wild-type mice, the researchers found that age-related memory decline was significantly reduced.

These findings suggest that blocking D3Rs may prevent age-related memory loss, with no sex-based differences observed in the study. Mice with genetic or chemical D3R inhibition showed preserved memory function even in older age.

Implications for Human Memory

Blocking D3 receptors may present a potential treatment for improving memory in humans, particularly for age-related memory loss. However, the researchers caution that turning more short-term memories into long-term memories could have unintended side effects, as some information is naturally forgotten to avoid cognitive overload. Further studies are needed to determine the safety and effectiveness of D3R blockers in humans.

[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.

More Information:

• Title: Blocking Dopamine Receptors and Memory Formation in Aging
• Published By: Neurological researchers in Aging Cell
• Journal: Aging Cell (2024)
• Acknowledgements: Lifespanio news, Aging Cell, Josh Conway