Not all drugs can completely change who we are. Cocaine is one of the few with this power. Like many other psychoactive drugs, cocaine was first used as an anesthetic, but its potential effect on one’s mind and will was soon discovered and overshadowed its original usage. Cocaine’s power does not lie within the molecule itself, but rather in its interaction with the brain’s reward system (see a previous TBT post for the discovery of this system).
Cocaine’s port of entrance into the reward system is the transporter of the neurotransmitter dopamine, the brain’s major signaling molecule for reward. When a reward comes, such as when an animal consumes a delicious meal, a plume of dopamine is released in reward centers such as the nucleus accumbens. The dopamine transporter’s job is to take up the dopamine from the synapses, just like a vacuum cleaner sucking in litter from the floor. In this way, it prevents dopamine from binding to its receptors for too long and therefore limits the amount of reward that the animal feels (Figure 1). Cocaine inactivates these dopamine vacuum cleaners in the brain, thereby leaving dopamine in the synapses for much longer and causing a long period of hedonic sensation. Animals lacking this dopamine vacuum cleaner in their genome are completely indifferent to cocaine1.
Cocaine’s true destructive power lies not in its ability to bring intense reward but rather in its aftermath. The brain is evolutionarily tuned to work with a range of dopamine dosages. Cocaine administration can overshoot this range by as much as 800%2, and this shocks the reward system like overstretching a piece of clothing. As a result, normal amounts of reward/dopamine are simply not enough anymore (just like a normal amount of stretch is not enough for overstretched clothes), and the subject will seek means to obtain the abnormal dopamine rush again (i.e. addiction) (Figure 2). The biological basis of this “overstretching” phenomenon is quite complex. This is because dopamine belongs to a group of special neurotransmitters named neuromodulators (other famous members include serotonin and adrenaline), which can not only transmit their own signals across the brain but also influence how other neurotransmitters (e.g. glutamate) work. Consequently, after as few as one single administration of cocaine, the reward system starts to make changes in all these facets of dopamine signaling, including downregulating the expression of dopamine receptors (presumably to compensate for the large increase in dopamine dosage)1, changing the expression and composition of glutamate receptors3,4, remodeling the reward circuit configuration5,6, etc. The brain will never be the same.
It is no simple task to reverse these biological effects of cocaine administration and relieve the subject from addiction. The therapeutic target is likely not the dopamine transporter, on which cocaine directly acts, but instead the downstream physiological changes (e.g. the receptor expression changes). The state-of-art methods of reversing cocaine’s effects on animal models involve precisely stimulating neurons in which the changes take place, with the goal of using the neuron’s own plasticity to recalibrate and reconstitute receptor expressions back to their normal levels4,7,8. These techniques are currently not available to human subjects, but they can point in the direction towards which clinical therapies are headed7.
Author’s disclaimer (3/9/2016): It was pointed to me that, in the original version, statements such as “Don’t do cocaine, seriously.” can be interpreted as an official stance of the Harvard Neuroscience Blog. This writing only reflects the opinion of me (SXZ) and my effort to synthesize recent discoveries in cocaine research, which I find fascinating. Numerous sources have stated that not everyone who uses cocaine will become addicted, which I agree with. To avoid further confusion between results and opinions, I have modified the first and last paragraphs to remove statements that are closer to my opinion than to results. I apologize for the confusion resulted from my writing, and wish our readers knowledge and rationality.
- Giros, B., Jaber, M., Jones, S. R., Wightman, R. M. & Caron, M. G. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379, 606–12 (1996).
- Wise, R. A. et al. Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology (Berl). 120, 10–20 (1995).
- Ungless, M. a, Whistler, J. L., Malenka, R. C. & Bonci, a. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583–7 (2001).
- Pascoli, V. et al. Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature 509, 459–64 (2014).
- MacAskill, A. F., Cassel, J. M. & Carter, A. G. Cocaine exposure reorganizes cell type– and input-specific connectivity in the nucleus accumbens. Nat. Neurosci. 17, 1198–1207 (2014).
- Cahill, M. E. et al. Bidirectional Synaptic Structural Plasticity after Chronic Cocaine Administration Occurs through Rap1 Small GTPase Signaling. Neuron 89, 566–582 (2016).
- Meaghan, C., Pascoli, V. J. & Lüscher, C. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science. 347, 659–664 (2015).
- Ma, Y.-Y. et al. Bidirectional Modulation of Incubation of Cocaine Craving by Silent Synapse-Based Remodeling of Prefrontal Cortex to Accumbens Projections. Neuron 83, 1453–1467 (2014).