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Amphetamine Diverts the Brain’s Path to Maturity

July 26, 2018
By Stacey C. Tobin, Ph.D., ELS, NIDA Notes Contributing Writer

This research:

  • Sheds light on a key mechanism of adolescent brain development.
  • Shows how amphetamine disrupts this mechanism.
  • Links this disruption to animal behaviors that resemble human susceptibility to addiction.

During adolescence, the prefrontal cortex undergoes elaboration and refinement of the neural circuits that underpin adult self-control and mature judgment. Dr. Cecilia Flores’ team, with colleagues from McGill and Concordia Universities in Montreal, conducted experiments with mice to understand this process and how drugs affect it.

The researchers found that some dopamine axons that reach the midbrain early in life extend into the prefrontal cortex (PFC) during adolescence. Their experiments indicate that a protein called DCC controls this process. DCC resides in the tips of growing dopamine axons and uses molecular signals emitted by neurons as guideposts to pilot the axons to target sites. Upon reaching their target sites, the axons form synapses with neighboring neurons.

The researchers demonstrated that amphetamine alters the course of axon growth and synapse formation in adolescence. In these experiments, they exposed adolescent mice to amphetamine in amounts similar to those used in human amphetamine abuse, and examined the animals’ brain tissue at full maturity. Dopamine axons in the PFC of the exposed mice were spread out more diffusely and formed fewer synapses than axons in unexposed mice (see Figure 1). In behavioral tests, the mice exposed to amphetamine in adolescence exhibited enhanced sensitivity to the drug’s rewarding effects and potential for abuse.

See text description for a description of the graphic.Figure 1. Exposure to Amphetamine Alters Dopamine Axons and Reduces the Density of Dopamine Synapses in the Prefrontal Cortex In control mice, dopamine axons form a large number of closely spaced synapses (green circles) in the prefrontal cortex. In amphetamine-exposed mice, dopamine synapses are sparser and more widely dispersed (red circles).
Text Description of Graphic
See text description for a description of the graphic.Figure 2. Amphetamine Exposure Reduces DCC Production by Increasing miR-218 Levels In amphetamine-exposed mice, the levels of miR-218 increased almost two-fold compared with control mice. At the same time, the levels of Dcc mRNA and DCC protein showed a corresponding decline in the amphetamine-exposed animals.
Text Description of Graphic

Using a variety of genetic and molecular techniques, the Canadian researchers showed that amphetamine disrupts normal development and synapse formation of dopamine neurons by suppressing DCC production. The drug causes a very short strip of RNA (miR-218) to attach to Dcc messenger RNA and inhibit its translation into protein (see Figure 2). With less DCC to guide axons and facilitate synapse formation, the final organization and connectivity of the PFC are compromised.

The consequences of amphetamine-altered adolescent PFC development include deficits in cognition and heightened susceptibility to addiction phenotypes in adulthood. Dr. Flores suggests that because the causal sequence her group uncovered links alterations in miR-218 to susceptibility to these effects, it may be possible to use miR-218 levels to predict risk. She says, “We are now interested in determining whether changes in levels of miR-218 in specific brain regions can be detected in blood so as to be able to ask whether circulating levels of this microRNA in adolescence can predict differential vulnerability to enduring effects of drugs of abuse or stressors.”

Dr. Flores stresses that the amphetamine doses that altered brain development in this study were high, equivalent to those seen in illicit drug use. She and her colleagues are currently assessing whether low doses, such as those used to treat attention-deficit/hyperactivity disorder, might produce similar effects. Their preliminary results suggest that they do not.

This research was supported by NIH grant DA037911.


Cuesta, S., Restrepo-Lozano, L.M., Silvestrin, S., et al. Non-contingent exposure to amphetamine in adolescence recruits miR-218 to regulate Dcc expression in the VTA. Neuropsychopharmacology 43(4):900-911, 2018.

Reynolds, L.M., Makowski, C.S., Yogendran, S.V., et al. Amphetamine in adolescence disrupts the development of medial prefrontal cortex dopamine connectivity in a DCC-dependent manner. Neuropsychopharmacology 40(5):1101-12, 2015.

Reynolds, L.M., Pokinko, M., Torres-Barrío, A., et al. DCC Receptors Drive Prefrontal Cortex Maturation by Determining Dopamine Axon Targeting in Adolescence. Biol Psychiatry 83(2):181-192, 2018.

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This page was last updated July 2018

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NIDA. (2018, July 26). Amphetamine Diverts the Brain’s Path to Maturity . Retrieved from https://www.drugabuse.gov/news-events/nida-notes/2018/07/amphetamine-diverts-brains-path-to-maturity

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