Molecular evidence for marijuana as a gateway drug?

Posted: October 25, 2012 in Science

We have probably all heard people refer to marijuana as a “gateway drug,” now a recent study from Mount Sinai School of Medicine published in the journal Biological Psychiatry provides evidence for the biological basis of this gateway effect. Specifically, the authors demonstrate that early marijuana administration increases later heroin intake and leads to changes in gene expression in a brain region implicated in drug reward.

Previous long-term studies using human adolescent volunteers have suggested that marijuana use is a necessary step in the transition from casual drinking to illicit drug use. Although it should be noted that this is still a controversial subject, based on these studies, marijuana, like alcohol, has been termed a “gateway drug”.  Additionally, studies have also shown that the earlier an adolescent begins their marijuana use, the higher their risk for subsequent illicit drug use. Due to the complex nature of the human adolescent experience, it has remained difficult to determine the basis for the “gateway” association of marijuana.  Do a subset of adolescents experience marijuana as a gateway drug based on genetic makeup? Does social pressure and drug availability play a role? Does marijuana use during adolescence lead to changes in the brain that result in further and more illicit drug use later in life?

The recent study titled “Proenkephalin Mediates the Enduring Effects of Adolescent Cannabis Exposure Associated with Adult Opiate Vulnerability” aimed to address this final question. Does early marijuana use change brain chemistry to subsequently drive a person to later drug taking and increase their risk for drug addiction? The lead author is Hilarie C. Tomasiewicz and the work was conduced in the laboratory of Dr. Yasmin L. Hurd. Dr. Hurd is a Professor in the Departments of Psychiatry, Pharmacology and Systems Therapeutics, and Neuroscience at Mount Sinai School of Medicine in New York, New York.

In the study, the authors treated male rats with Δ9-tetrahydrocannabinol (THC; the primary psychoactive component of marijuana) during the adolescent phase of rat development. Then, during adulthood, the rats were tested for the amount of heroin they would self-administer and for biochemical and molecular changes in the nucleus accumbens, a major brain region implicated in reward and decision making processes. The researchers found that THC treatment during adolescence increased the amount of heroin the animals would self-administer and increased nucleus accumbens mRNA levels of proenkephalin, a precursor to enkephalin, the natural neuropeptide that activates the mu opioid receptor. The mu opioid receptor is also activated by heroin and morphine. These initial results were a replication of previously published data, but raise the question of whether this increase in heroin intake was a result of increased proenkephalin mRNA levels in the nucleus accumbens.

In order to address this question, the authors used molecular biology techniques to either increase or decrease the levels of proenkephalin in the nucleus accumbens. They found that if they increased the levels of proenkephalin in non-marijuana exposed rats, these rats demonstrated the same increase in heroin self-administration seen in rats that had been exposed to marijuana as adolescents. Likewise, when the authors decreased the levels of proenkephalin in adult rats that were previously treated with marijuana as adolescents, these rats did not show the increase in heroin self-administration, suggesting that regulation of proenkephalin underlies this increased heroin intake.

Finally the authors investigated if adolescent marijuana exposure leads to altered levels of histone methylation in the nucleus accumbens. Methylation of certain parts and types of histones results in either repression or activation of genes and thus regulates protein levels within cells. The authors found that there was decreased methylation of several repressive histones that regulate the proenkephalin gene in adult rats that had been previously exposed to marijuana as adolescents. These results suggest that adolescent marijuana exposure leads to increased proenkephalin levels and subsequent increases in heroin self-administration by relieving suppression of proenkephalin gene expression.

Adolescence is a period of profound neuronal development and maturation. The nucleus accumbens is one of the main brain regions to go through such development during adolescence. Due to the major role the nucleus accumbens plays in reward and drug abuse, drug use during this time could potentially disrupt normal developmental processes in a maladaptive manner, resulting in the increased heroin intake seen in the present study. Epigenetics, changes in gene expression that do not result from changes to the DNA sequence, has increasingly been gaining recognition for playing a role in the long lasting effects of drug abuse and subsequent addiction risk. Dr. Eric Nestler, a coauthor of the paper and also at Mount Sinai, and his laboratory are at the forefront of epigenetic research involving cocaine use and depression. For example, previous studies have shown that cocaine administration also results in epigenetic changes in gene expression in brain regions involved in reward and drug addiction.

Thus, early drug use by adolescents may lead to altered levels of critical genes for drug reward in these brain regions, leading to enduring behavioral changes such as increased drug use and addiction risk. While much additional work remains to be done, these results raise the possibility of designing therapeutic drugs that work to reverse these changes in gene expression and thus decrease the risk of drug addiction in adulthood.

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