(Please see Point article by Jeffrey A. Schaler, Ph.D.)
The practice of medicine obligates physicians to accept the responsibility of promoting the overall health of their patients. When dealing with patients who abuse substances, we can find direct and indirect adverse consequences from such use. Lung cancer, although rare in the general population, is linked to chronic tobacco smoking, for example. Cigarette smokers who begin this addiction in their teen years appear to have a higher incidence of adult depression (Goodman and Capitman, 2000); so, either early tobacco use is a marker for later mental illness or, more ominously, this legal drug of abuse may promote the development of mental illness. Multiple warning labels describing tobacco's toxicity and other risks to health have been printed for decades on each pack of cigarettes sold, yet more than 20% of Americans continue to "choose" to smoke (Centers for Disease Control and Prevention [CDC], 2001). Despite the hundreds of millions of dollars spent in anti-tobacco messages and education, the ever-increasing state and federal "sin" taxes collected on every pack of tobacco product sold, the harsh restrictions on tobacco advertisements by legislative mandate, and the high-profile lawsuits and settlements, the median prevalence figures of current tobacco use in the United States have held steady for the last five years.
Perhaps, then, "choice" has little to do with the decision to continue tobacco use. Cigarette smokers are so concerned about their drug use that each year some 1 million of them attempt to quit; but, sadly, less than 15% succeed in abstinence for a full year (Rose, 1996). Despite understanding that risks outweigh perceived benefits, addicted individuals compulsively continue their drug use in a chronic, relapsing fashion. It is not that these individuals are devoid of any choice when engaging in behaviors that support and reinforce continued drug use; rather, we must accept that not all choices are equally easy to make, especially when there exists a host of genetic, environmental and non-environmental factors supporting continued drug use.
Clinical research reveals that some individuals may be more vulnerable to drug dependence than others due to genetic and developmental risk factors. The best-validated risks are family history and male gender (Hyman, 2001). Studies of separated, adopted twins, for example, have found the risk for alcoholism and other addictive drugs is greater for those twins whose biological parents also had drug dependence, regardless of drug use status in the adoptive parents (Cadoret et al., 1995; Kendler et al., 2000; Tsuang et al., 1996). Drug craving and relapse are triggered by exposure to drug-related cues (e.g., photos of drugs and paraphernalia), as well as stress. Neuroimaging studies of former cocaine-dependent individuals have, for example, identified neural correlates of cue-induced craving for cocaine (Childress et al., 1999; Wexler et al., 2001).
Preclinical studies also indicate that repeated exposure to highly addictive substances alters, perhaps permanently, a number of molecular and neurochemical indices, thereby changing physiologic homeostasis. In other words, even after detoxification, an individual may be sensitized to relapse because of changes in the brain from prior repeated use. We know the molecular targets in the central nervous system for most of the addictive drugs. As examples, opioids are agonists at µ opioid receptors; alcohol is an agonist at g-alphabutyric acid-A (GABA-A) receptors and an antagonist at -methyl-D-aspartate (NMDA) glutamate receptors; and tobacco's nicotine is an agonist at nicotinic acetylcholine receptors (Hyman, 2001). We also know that the principal CNS pathway for processing reward, punishment and reinforcement extends from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), mediated, in particular, by the release of the neurotransmitter dopamine (Spanagel and Weiss, 1999). Preclinical evidence supports the "final common pathway" theory that addictive drugs, despite discordant molecular targets, all result in an increased release and dysregulation of synaptic dopamine in this region of the brain (Nestler, 2001). For example, the same dose of cocaine administered weekly to monkeys results in increased extracellular release of dopamine in the CNS, a phenomenon called neurochemical sensitization. When a second dose of cocaine is administered after the first dose is wearing off, a decreased release of extracellular dopamine is found in the CNS, a phenomenon called acute tolerance (Bradberry, 2000). As tolerance builds, increased amounts of the drug are ingested in an attempt to achieve the same rewards, which, in turn, will also further drive molecular changes in the brain. Drug dependence, then, is reinforced at the cellular level as the CNS adjusts to continued drug exposure. Such conditioning may be unmasked by abrupt cessation of drug use, resulting in a period of observable and reproducible symptoms of withdrawal.
Chronic exposure to addictive substances also shifts signal transduction pathways within neurons, thereby altering gene expression (Matsumoto et al., 2001; Walton et al., 2001). New or different concentrations of regulatory proteins, in turn, are synthesized, directing neurons to form new synaptic branches and altered concentrations of cellular receptor density. Cocaine, for example, has been found to increase spine density and dendritic branching of neurons in the NAc and prefrontal cortex of rats (Robinson and Kolb, 1999). The remodeling of neurons involved with the maintenance of the brain's reward center also may continue long after drug use has ceased (Hyman and Malenka, 2001; Ungless et al., 2001). There are probably hundreds of transcription factors involved in gene regulation; already the cyclic-AMP response-element-binding protein (CREB) and FosB are implicated in addiction (Nestler, 2001). Interestingly, biochemically modified isoforms of FosB appear only slightly after acute drug exposure, but they accumulate over time with repeated drug administration. Other regulatory proteins of the Fos family rapidly break down after synthesis, but FosB is highly stable, persisting for months after drug withdrawal. Here, then, is one example of a molecular mechanism for drug-induced changes in gene expression persisting long after last use. Preclinical models reveal that chronic, but not acute, administration of cocaine, amphetamine, phencyclidine, alcohol, nicotine and opiates induces FosB release in the NAc and dorsal striatum (Kelz and Nestler, 2000).
In short, both human and preclinical data converge to suggest that addiction is associated with frank biological abnormalities that cannot be easily explained by a simple hypothesis of "choice." It is a strange set of societal circumstances that people may still consider the ingestion of some drugs as outside the purview of physicians, when clearly the practice of medicine deals with the impact of exogenous substances upon the human body and mind. Those individuals who abuse drugs do so absent the legal mechanisms for which society provides, i.e., a prescription or recommendation from a physician. Whether legal or not, all addictive substances should be carefully reviewed with our patients precisely because physicians must obtain all information that may assist in the diagnosis and treatment of disease and in the improved preventive health of patients.
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