The new england journal of medicine special article shattuck lecture A Molecular Basis for Nicotine as a Gateway Drug Eric R. Kandel, M.D., and Denise B. Kandel, Ph.D. From the Howard Hughes Medical Insti- n the historic occasion of the 122nd Shattuck Lecture and tute (E.R.K.), Kavli Institute for Brain Sci- the 200th anniversary of the New England Journal of Medicine, we chose to ad- ence (E.R.K.), and the Departments of Neuroscience (E.R.K.) and Psychiatry Odress a topic that is at once scientific and personally historic. In recent (E.R.K., D.B.K.), College of Physicians debates over legalizing marijuana, from all-out acceptance in Colorado to narrow and Surgeons, and Mailman School of decriminalization in Maryland, the scientific question of the role of marijuana as a Public Health (D.B.K.), Columbia Univer- sity, and the New York State Psychiatric gateway drug (i.e., a drug that lowers the threshold for addiction to other agents) Institute (D.B.K.) — all in New York. Ad- has loomed large. Both opponents and proponents of legalization have distorted dress reprint requests to Dr. E. Kandel at what science does and does not tell us — and both sides have overlooked the im- the Department of Neuroscience, Col- lege of Physicians and Surgeons, Colum- portance of nicotine as a gateway drug. bia University, 1051 Riverside Dr., Unit Epidemiologic studies have shown that nicotine use is a gateway to the use of 87, New York, NY 10032, or at erk5@ marijuana and cocaine in human populations. What has not been clear is how columbia.edu. nicotine accomplishes this. In this article, we describe how our personal collabo- N Engl J Med 2014;371:932-43. ration allowed us to bring the techniques of molecular biology to bear on this DOI: 10.1056/NEJMsa1405092 Copyright © 2014 Massachusetts Medical Society. question and to reveal the action of nicotine in the brain of mice. We then apply our conclusions to the public health concerns that are being raised as the popularity of electronic cigarettes (e-cigarettes) has soared. In the process, we show the po- tential benefits to society of translating epidemiologic findings into public health policy. GATEWAY HYPOTHESIS AND THE COMMON LIABILITY MODEL The gateway hypothesis was developed by Denise Kandel, who observed that young people become involved in drugs in stages and sequences.1 She found that in the general population of the United States and other Western societies, a well-defined developmental sequence of drug use occurs that starts with a legal drug and pro- ceeds to illegal drugs. Specifically, the use of tobacco or alcohol precedes the use of marijuana, which in turn precedes the use of cocaine and other illicit drugs.1-6 Thus, in 2012, among U.S. adults 18 to 34 years of age who had ever used cocaine, 87.9% had smoked cigarettes before using cocaine, 5.7% began using cigarettes and cocaine at the same time, 3.5% used cocaine first, and 2.9% had never smoked cigarettes. An alternative to the gateway hypothesis has been proposed on the basis of the idea that the use of multiple drugs reflects a common liability for drug use and that addiction, rather than the use of a particular drug, increases the risk of pro- gressing to the use of another drug.2,7-10 Population studies have shown both gen- eralized risk across substances and substance-specific risk — in particular, risk attributable to tobacco use.11 Although epidemiologic studies can establish the sequence in which different sub- stances are used and can specify their associations, such studies cannot determine what causes the progression from one drug to the next, nor can they identify on 932 n engl j med 371;10 nejm.org september 4, 2014 The New England Journal of Medicine Downloaded from nejm.org on September 22, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. Shattuck Lecture a molecular level the mechanisms underlying ers of the priming effects of one drug on another the progression. Testing the validity of the gate- in the nucleus accumbens, a region of the stria- way hypothesis in biologic and molecular terms tum that is critical for reward and addiction.19 requires an animal model, in which investigators Locomotor sensitization showed that priming administer one drug and observe how it influ- mice with nicotine can enhance the effect of co- ences the reaction of the animal to a second drug. caine. Mice given nicotine in their drinking wa- Investigators can change the order of drug expo- ter were no more active than control mice given sures and observe the effect on outcomes. plain water. Mice given only cocaine were 58% more active than controls (Fig. 3A); mice given DRUG USE AND ADDICTION AS A nicotine for 1 day, followed by 4 days of nicotine FORM OF MEMORY and cocaine, showed no increase in locomotor response, but mice given nicotine for 7 days, Early psychological studies involving humans followed by 4 days of nicotine and cocaine, were suggested that addiction is a form of learning significantly (98%) more active than controls and that relapse is a persistent memory of the (Fig. 3A and 3B). Activity did not increase when drug experience.12 To test this idea, investigators the protocol was reversed (7 days of cocaine, fol- needed some insight into the cell-biologic nature lowed by 4 days of concurrent cocaine and nico- of memory in general and of addiction in partic- tine) (Fig. 3C). ular. Initial insights into the nature of memory Conditioned place preference is a more natu- were provided by Eric Kandel and colleagues, ralistic model of addictive behavior than sensiti- who found that the gene transcription factor cy- zation. It measures the preference of an animal clic AMP response-element–binding protein (CREB) for a particular place in its environment as that acts as a switch, converting short-term memory place becomes associated with a reward and as- to long-term memory (Fig. 1). This conversion sumes some of the pleasurable effects of the involves a CREB-mediated modification in chro- reward. As with sensitization, mice primed with matin (Fig. 2).13 7 days of nicotine and then given both nicotine Hyma, Malenka, and Nestler14-16 explored the and cocaine for 4 days had a 78% greater prefer- learning mechanisms underlying addiction in ence for the chamber associated with cocaine the striatum, a critical brain area that is targeted than were mice given only water and then co- by drugs of abuse. They found that the same mo- caine (Fig. 3D). lecular steps Kandel had delineated as underly- We next examined synaptic plasticity, as mea- ing memory also play a major role in addiction17: sured by changes in long-term potentiation, in activation of CREB and the transcription of the core of the nucleus accumbens, a region of the downstream target genes such as FOSB and its ventral striatum that integrates rewarding input isoform ΔFosB. The accumulation of ΔFosB in from dopamine-producing neurons in the ventral the striatum is a crucial step in establishing ad- tegmental area with excitatory input from gluta- diction to most drugs of abuse and has been mate-producing neurons in the amygdala and used as a molecular marker for these processes. the prefrontal cortex. Reducing excitatory input Levine et al.17 and Alibhai et al.18 found that to the nucleus accumbens is thought to decrease structural changes occur in the chromatin of inhibitory output from the nucleus accumbens FosB in response also to cocaine. to the ventral tegmental area and thereby to con- tribute, by means of disinhibition, to enhanced TEST OF THE GATEWAY HYPOTHESIS reward with drugs of abuse. This disinhibition IN MICE results in the production of more dopamine and contributes to an enhanced rewarding effect of In collaboration with Amir Levine, we developed drugs of abuse. a mouse model that would enable us to explore Since we knew that the repeated administra- the behavioral, electrophysiological, and molecu- tion of cocaine resulted in reduced long-term po- lar genetic effects of particular drug-use sequenc- tentiation in the excitatory synapses of the nucle- es. We examined two addiction-related behaviors, us accumbens in the mouse, we stimulated those locomotor sensitization and conditioned place pref- synapses and measured long-term potentiation erence, and the physiological and molecular mark- (Fig. 4A). We found that just one injection of n engl j med 371;10 nejm.org september 4, 2014 933 The New England Journal of Medicine Downloaded from nejm.org on September 22, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Long-term Stimulus CREB-2 (gene repressor) Marine snail (aplysia) CREB-1 (gene activator) Nucleus P P Tail CBP Tail sensory neuron 5-HT Adenylyl CRE Early and late genes receptor cyclase MAPK Stimulus 5-HT G protein Sensory neuron Interneuron cAMP Growth of new synapses PKA Short-term K+ channel Ca2+ channel Activation AMPA NMDA AMPA NMDA Glutamate receptors Glutamate receptors Motor neuron Motor neuron Figure 1. Cellular and Molecular Mechanisms Underlying the Switch from Short-Term to Long-Term Memory in a Simple Animal Model. The sensitization of the gill-withdrawal reflex is shown in the marine snail aplysia. In short-term memory, an external stimulus, such as an electric shock to the tail of the animal, causes the sensory neuron to send information in the form of chemical signals across the synapse to a motor neuron.