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state reported by smokers during the first an d withdrawal, particularly within the 1. Epping-Jordan, M .P., Watkins, S.S., Koob, G. & Markou, A. Dramatic decreases in brain reward days of attempted abstinence. Indeed, the brain dopamine reward system 7• function during nicotine withdrawal. Nature 393, time course of altered activity in reward Nicotine has the potential to produce 76-79 (1998). circuits extended beyond the presence of such adaptations by virtue of the fact 2. Olds, J. & Milner, P. Positive reinforcement pro• duced by electrical stimulation of septa! area and somatic withdrawal symptoms. This sug­ that stimulation of nicotinic acetyl­ other regions of the brain. /. Comp. Physio/. Psycho/. gests that increased reward thresholds are choline receptors on both dopamine cell 47, 419-427 (1954). probably more important in relapse into bodies in the midbrain and their axon 3. Wise, R.A. Addictive drugs and brain stimulation re• ward. Annu. Rev. Neurosci. 19, 319-340 (1996). drug use. Perhaps that is why cocaine re­ terminals in the nucleus accumbens en­ 4. Markou, A. & Koob, G.F. Postcocaine anhedonia: lapse is so prevalent. Somatic withdrawal hance dopamine release8•9 • Chronic nico­ an animal model of cocaine withdrawal. signs are not obvious in cocaine with­ tine administration causes enigmatic Neuropsychopharmacology 4, 1 7-26 (1991 ). 5. Robinson, T.E. & Berridge, K.C. The neural basis of drawal but similar alterations in reward increases in nicotinic acetylcholine re­ drug craving: an incentive-sensitization theory of threshold are observed4. With these new ceptor expression apparently because the addiction. Brain Res. Re.v. 18, 247- 291 (1993). 6. Wise, R.A. lir Bozarth, M .A. A psychomotor stimu• 10 findings, we must accept that alterations receptors are dramatically desensitized • lant theory of addiction. Psycho/. Rev. 94, 469-492 in activity of the brain reward system are How are these adaptations then incor­ (1987). not tightly tied to the profound acute ef­ porated into reward behavior? Only time 7. Self, D.W. lir Nestler, E.J. Molecular mechanisms of drug reinforcement and addiction. Annu. Rev. fects of drugs on subjective experience or will tell. The important point for now is Neurosci. 18, 463-495 (1995). motor activation. Something more subtle that relatively weak psychoactive agents 8. Corrigall, W.A., Franklin, K.B ., Coen, K.M. & Clarke, must be taking place. such as nicotine, when used chronically, P.B.S. The mesolimbic dopaminergic system is im• plicated in the reinforcing effects of nicotine. Obvious questions raised by this im­ can change activity of brain reward path­ Psychopharmocology 107, 285- 289 (1992). portant discovery are: how does the ways in a manner that appears indistin­ 9. Wonnacott, S. Presynaptic nicotinic ACh receptors. Trends Neurosci. 20, 92- 98 (1997). dopamine reward pathway change to guishable from that of other major drugs 10. Marks, M.J., Burch, J.B. & Collins, A.C. Effects of produce nicotine withdrawal and, is it al­ of abuse. These provocative findings are chronic nicotine infusion on tolerance develop• tered in the same manner during opioid, certain to fuel the maelstrom of contro­ ment and cholinergic receptors. /. Pharmaco/. Exp. Ther. 226, 806-816 (1983). ethanol, and cocaine withdrawal? If it is, versy encircling issues of tobacco use. The ················································································ then we will have to reformulate basic publication of these results, 24 hours be­ Department ofC ellular and Molecular concepts regarding the neurobiology of fore the announcement of the US$6.6 bil­ Pharmacology addiction and withdrawal5·6• The last few lion out-of-court settlement between the Finch University ofHea lth Sciences/The Chicago years have seen the identification of sev­ U.S. tobacco industry and the State of Medical School eral important cellular and molecular al­ Minnesota, is more bad news for the to­ North Chicago, Illinois 60064-3095, USA terations in animal models of addiction bacco companies as they fight for survival. email: white(@mis.finchcms.edu Playing with dopamine release According to Paul Grasby and colleagues this task, then dopamine release might not ll: (Imperial College School of Medicine, Lon­ § correlate with performance if subjects are don) in their recent Nature paper, playing IMAGE j paid the same amount regardless of their a video game stimulates dopamine release ~ success at the game. in a brain region involved in reward path­ UNAVAILABLE [i~ Although there is an intriguing parallel ways and motor control. As subjects navi­ FOR COPYRIGHT 5 between video games and addictive drugs gated a tank through enemy bunkers, l in that both increase dopamine release in REASONS 'o positron emission tomography was used to j the ventral striatum (nucleus accumbens),

monitor displacement of a tracer from D2 ..______.... a: Grasby emphasizes that his subjects were dopamine receptors by newly released normal volunteers, not addicts, and that the dopamine (see figure). Neurotransmitter to bind the tracer. This technique has very study was not designed to address release correlated with success in the game slow time resolution, integrating dopamine dopamine's role in addiction (see above for individual subjects, who were paid seven release over tens of minutes. News & Views). Indeed striatal dopamine pro­ pounds (around ten dollars) for each level The researchers chose the video.game jections have also been implicated in the completed. This is the first measurement of task to maximize the odds of producing a motor disability characteristic of Parkinson's neurotransmitter release during a behavioral measurable signal, said Grasby. Although disease and in the positive symptoms of task in humans. raclopride had been used to measu re schizophrenia. Grasby, who is a psychiatrist, The tracer, (1 'C]raclopride, bound strongly dopamine release in response to ampheta­ next plans to turn this technique to explor­ in the striatum (left panel; scale goes from mine use in humans, no one knew whether ing how dopamine release correlates with blue, low binding, to red, high binding), behaviorally induced release would be particular symptoms of schizophrenia and which has a high concentration of D2 recep­ within the tracer's sensitivity. Playing the depression. Researchers are also seeki ng trac­ tors, as subjects watched a blank screen. Dur­ game combined several elements known to ers that can detect release of other neuro­ ing the video game, raclopride bi nding in produce striatal dopamine release in ani­ transmitters in humans, but visualizing neu­ this region was reduced significa ntly, par­ mals: novelty, sensorimotor learning and rotransmitter release seems to require a ticularly in the ventral striatum (right panel). anticipation of reward. Further experiments poorly understood combination of tracer Researchers infer that playing the game wi ll be needed to separate out these ele­ properties and synaptic properties, so this increased the release of synaptic dopamine, ments. For example, if anticipation of may prove difficult. reducing the number of receptors available reward is critical for activating neurons in Sandra Aamodt, Nature Neuroscience

660 NATURE MED ICINE • VOLUME 4 • NUMBER 6 • IUNE 1998