Orexin, Grelin, Epigenetics, and ?FosB Transcription Factor
Just a few years ago, a sense of tremendous excitement was generated by the annual announcements of discoveries which helped us begin to unlock the human brain’s secrets. Now, exciting developments seem to occur on a monthly basis and many seeming “breakthroughs” disappeared over time because they did not contribute to improved treatment outcomes for addictions. However, some discoveries did provide a better understanding of the neurochemistry of craving and led to the development of anti-craving medications, which have made huge contributions to treatment outcomes. Recent discoveries of brain neuropeptides, immediate alterations in neuronal genetic expression and brain proteins that bind to DNA and control their transfer of genetic information to produce drug craving have immense potential to improve treatment outcomes. These also hold the promise of better explaining differences between “normies” and those susceptible to Substance Use Disorders.
Orexin is a neuropeptide, neurotransmitter that regulates wakefulness and appetite. Orexin (also called hypocretin) was first discovered in 1998 by Dr. Masashi Yanagisawa at the University of Texas, Dallas. It was researched for appetite suppression leading to the development of an antagonist, SB334867. Narcolepsy is a disorder characterized by excessive daytime sleepiness. Narcoleptics suddenly fall asleep often at inappropriate times, situations and places. This condition has recently been attributed to a lack of orexin producing neurons in the lateral hypothalamus that also regulates thirst and hunger. Treatment of narcolepsy employs the use of stimulant drugs like methamphetamine and methylphenidate. During the 1970s, narcoleptics treated with potent stimulants rarely became addicted to those medications. National Institute on Drug Abuse scientists now speculate that orexin may be another key neurotransmitter (like dopamine, GABA and endorphins) involved in the development of addiction and craving. Animal research at the University of California and the University of Pennsylvania found that orexin stimulates a rat’s preference for morphine, cocaine and sweet food. Rats injected with SB334867, the orexin antagonist, had a 58% decrease in preference for those substances. Morphine and cocaine was found to stimulate the production of orexin causing the brain’s normal feeding and craving mechanisms to be hijacked. Animal research demonstrates that drugs like morphine and cocaine cause an increase production of orexin, which increases the ventral tegmental area (VTA) sensitivity for neural excitation for dopamine release by stimulating an increase in VTA receptors. Orexin antagonists were seen to block this effect and decrease drug craving, which may promote sustained recovery in humans. (SL Borgland, et al. (2006). Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49(4): 589-601; GC Harris, et al. (2005). A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437(7058): 556-559)
A year after orexin’s discovery, Masayasu Kojima and his Japanese colleagues discovered ghrelin, a hormone produced by cells lining the stomach. Like orexin, ghrelin also activates appetite and drug cravings in the brain’s mesolimbic reward reinforcement circuitry. (E Jerlhag, et al. (2007). Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens. Addiction Biology, 12(1): 6-16.) Confusingly, lack of sleep not excessive sleepiness stimulates ghrelin production, which increases appetite. This indicates that there are separate orexin mesolimbic mechanisms: one for arousal and another for feeding, reward and drug craving.
Epigenetics refers to heritable, long-term alterations in gene function that occur without changes to the underlying DNA sequence. A good analogy for the relationship of genetics and epigenetics can be found in the computer relationship of software to hardware. Genes are the hardware and epigenetics is the software that instruct genes what, where and when they are to be expressed. Once dismissed as a pseudo-science, epigenetics is now part of the powerful science of “cell memory”. Epigenetics helps explain the occasional incongruity of substance use disorder or the occurrence of schizophrenia in just one homozygotic (identical) twin. Epigenetics has drawn renewed attention to the importance of environmental factors in the development such disorders. Genes rely on random mutations and recombinations to pass on phenotypic traits from one generation to another. Epigenetics consist of several mechanisms that induce immediate and often long-term alterations in gene function within an individual. DNA methylation, imprinting, paramutation, chromatin remodeling, histone modification, RNA transcripts and prions are just some of the epigenetic processes. All are sensitive to environmental toxins and affect the long-term health of an individual. For example, chronic exposure to cocaine activates the genes in neurons to create proteins like ?FosB Transcription Factor by the chromatin remodeling process. ?FosB correlates with craving and cocaine self-administration in animals, and may contribute to long-lasting structural changes in cocaine abusers’ mesolimbic reward reinforcement circuitry. A unit of chromatin consists of DNA wrapped around complexes of histone proteins. This unit is also known as a nucleosome and chemical processes determine how tightly the DNA is wrapped around the histones. Chromatin remodeling occurs when the nucleosome is more or less compact, changing the DNA’s ability to interact with RNA polymerase and produce proteins. Chronic exposure to drugs like amphetamine, morphine, nicotine, phencyclidine and cocaine activates genes for the production of ?FosB transcription factor in the nucleus accumbens by spreading out nucleosomes in those neurons to make them more available to RNA polymerase (MB Kelz, et al. (1999). Expression of the transcription factor ?FosB in the brain controls sensitivity to cocaine. Nature 401(6750): 272-276). This results in more ?FosB being produced, which generates an increase in cravings and drug self-administration. Scientists are now developing chemical compounds to reverse chromatin remodeling, this is a promising new strategy to treat substance use disorders. (L Whitten (2007). Gene experiment confirms a suspected cocaine action. NIDA Notes, 21(4): 8-10; A Kumar, et al. (2005). Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48(2): 303-314.)
A Transcription Factor is a protein that binds to a specific part of the DNA double helix to control the transfer genetic information to RNA for the neuron’s synthesis of other proteins. In addition to addictive drugs, compulsive running and other compulsive behaviors increase ?FosB Transcription Factor in the nucleus accumbens and the dorsal striatum. ?FosB alters gene expression in these areas which results in an increased sensitivity to addictive drugs and behaviors. This triggers the initiation of and then sustains changes in gene expression that persists long after drug exposure ceases to create craving and increase drug-seeking behaviors. This type of molecular switch gradually converts acute drug responses into relatively stable adaptations, which contribute to the long-term neuronal and behavioral processes that underlie addiction. Reversal or blockage of ?FosB production may also result in an effective treatment of substance use disorders. (EJ Nestler, et al. (2001). ?FosB: A sustained molecular switch for addiction. Proc. Nat. Acad. Sci. (PNAS), 98(20): 11042-11046.
Orexin, Grelin, Epigenetics, and ?FosB Transcription Factor are just a few of the many exciting developments in the expanding science of addiction. The more we learn about the root causes of behaviors associated with substance use disorders, the more questions we have. The answers seem to be getting more and more complex. In the mid 1950’s, Bill and Bob described alcoholism as, “cunning, baffling and powerful”. The 12-Step recovery process begins with Step 1: We have admitted that we are powerless over alcohol that our lives have become unmanageable. The current science of addiction better explains and profoundly validates Bill and Bob’s early conjecture about chemical dependence.
Darryl S. Inaba, PharmD., CADC III