Cocaine produces genetic changes in zebrafish embryos
José Pichel Andrés/DICYT The Instituto de Neurociencias de Castilla y León (Incyl) from the Universidad de Salamanca has published two articles in PLOS ONE, a prestigious journal, on the impact cocaine has on zebrafish embryos (Danio rerio). Although this research model is evolutionarily remote from human beings, molecular results may be easily extrapolated to humans and suggest that children from mothers consuming cocaine may have a greater predisposition to addiction in case of trying this substance; they may also be hyposensitive to certain opioid analgesics.
Raquel Rodriguez’s laboratory (Incyl director), has been focusing for years on two research areas: pain and addiction. Both areas join together in the study of some analgesics such as morphine, that could eventually cause addiction. According to these research areas, besides morphine, “we consider cocaine as a potential addictive agent”, as the researcher explains to DiCYT.
Thanks to this study, one of the main results helps to clarify cocaine addictiveness mechanism. “Cocaine reduces microRNA 133b, increasing the role of Pitx3 transcription factor and this, in turn, increases dopamine levels and dopamine receptors activity”, researcher Roger López Bellido, one of the responsibles for the study, accounts.
Dopamine is a multi-function neurotransmitter, primarily associated with pleasure. If cocaine increases dopamine levels and the number of its receptors, its use produces a great pleasure through increased activity of dopaminergic system in the nucleus accumbens, “a pleasure center in the brain”. Therefore, “if you like chocolate, dopamine is released in this nucleus when you eat it”, the scientific points out; but cocaine’s effect is stronger. “The brain calls for more cocaine and that makes it more tolerant, so you need increasing amounts to obtain the same effects and people eventually become drug dependent”, he states.
This relationship between cocaine and dopamine levels increase was already known, but discovering that a microRNA is involved suggests genetic changes. “If a pregnant woman consumes cocaine, the amount arriving to the embryo produces a change in de dopaminergic system and there is a potential risk of the child being prone to cocaine or more easily developing addiction to the substance”, Roger López explains.
All in all, results presented in the PLOS ONE article suggest that cocaine may change gene expression. “From gestation, certain genes that could overdevelop the dopaminergic system can be changed”, and, in this way, in front of a cocaine exposure, the temptation to take another dose may increase.
These effects have been demonstrated in zebrafish embryos at a molecular level. Next step would be to determine whether these changes are reflected in animal’s behavior, which is more difficult to analyze, although some tests could be designed in order to ascertain it, such as those used on other animals, mice, for instance.
Changes in Opioid Receptors
In addition, cocaine affects dopaminergic receptors, those related to pleasure, but also affects opioid receptors, those related to pain. This aspect has also been part of the study and results point one more time to some changes depicted in another recent article published in the same journal.
“We already knew cocaine changed opioid receptors expression, those associated with analgesia and now, when exposing zebrafish embryos to cocaine, we found opioid receptors decreasing their expression”, this happens through other microRNA alteration called let7d.
Specifically, cocaine increases the activity of enzymes involved in let7d microRNA formation and this increase leads to an opioid receptors lowering, so opioid analgesics are much less efficient. Regarding human beings, this means that “if a mother consumes cocaine, some opioid receptors formation would be decreased and both mothers and embryos would need al larger amount of analgesic for pain relief”.
For instance, morphine is a potent analgesic drug that is used in cases of painful severe diseases, especially in some types of cancer. In this case, opioid receptors allowing its action would be diminished, so, its analgesic effect would be lower due to the genetic changes caused by cocaine.
Advantages of using zebrafish
All these studies must be verified on human beings, but in general terms, results on zebrafish have their correspondence in all mammals, because even if organisms differ, molecular mechanisms have remained the same through evolution. The advantage of carrying out experiments on this animal lies on its fast development: brain is almost formed in a 24 hour period and it needs 48 hours for the rest of the organs. Three days amount to the human nine months gestation period.
Katherine Barreto-Valer, Roger López-Bellido, Fátima Macho Sánchez-Simón, and Raquel E. Rodríguez. Modulation by Cocaine of Dopamine Receptors through miRNA-133b in Zebrafish Embryos. PLoS One, 2012. doi: 10.1371/journal.pone.0052701
Roger López-Bellido, Katherine Barreto-Valer, Fátima Macho Sánchez-Simón, and Raquel E. Rodríguez. Cocaine Modulates the Expression of Opioid Receptors and miR-let-7d in Zebrafish Embryos. PLoS One, 2012. doi: 10.1371/journal.pone.0050885