Free The Addicted Brain by Michael Kuhar

night, and in his dreamy state he wrote it down on a scrap of paper on his nightstand. In the morning, much to his horror, hecouldn’t read his writing, nor could he remember the dream! Luckily, the next night he had the same dream, and this time he got out of bed and immediately went to the laboratory and did this definitive experiment. Thirteen years later, he was awarded the Nobel Prize for his “dream experiment!”
    2 The following is a brief summary of the history of the dopamine story and drug addiction. It is a personal communication from Dr. Roy Wise, a longtime, productive researcher in this field.
    The earliest work was by Olds (a) who showed that nonselective drugs like chlorpromazine and reserpine (whose effects included a blunting of dopamine’s effects) antagonized electrical brain stimulation reward. Stein generated a theory of reward that proposed that norepinephrine was the key neurotransmitter, but this was not supported by subsequent data (b, c). When selective dopamine antagonists became available, they, and selective destruction of dopamine-containing neurons showed effects on reward. This implicated dopamine and not norepinephrine or other neurotransmitters in brain stimulation reward (d, e). Pickens and Harris were the first to suggest that the substrates of brain stimulation reward and psychostimulant reward were perhaps the same (f).
Yokel and I (g) and Davis and Smith (h) were the first to show that amphetamine lost its rewarding action if the dopamine system was selectively blocked, and de Wit and I (i) and Risner and Jones (j) showed the same result with cocaine. Roberts showed that selective dopamine (but not norepinephrine) lesions disrupted cocaine reward (k). These were the first studies to show that dopamine function was necessary for cocaine and amphetamine reward. Yokel and I then showed that a dopamine agonist, apomorphine, (a compound that directly stimulated dopamine receptors) was self-administered (g, l), which confirmed that dopamine activation was also sufficient for drug-related reward. Ritz et al., (m) took the story further by showing that the initial site of action of cocaine and the psychostimulants—specifically for their rewarding and reinforcing actions—was the dopamine transporter rather than some other site. Initial work in knockout mice suggested that cocaine might still be rewarding in animals lacking the dopamine transporter (n), but more recent work questions this finding and shows, rather, the opposite (o).
(a) J. Olds, K. F. Killam, P. Bach y Rita,
Science,
124, 265 (1956). (b) L. Stein,
J Psychiat Res
8, 345 (1971). (c) S. K. Roll,
Science,
168, 1370 (1970). (d) A. S. Lippa, S. M. Antelman, A. E. Fisher, D. R. Canfield,
Pharmacology Biochemistry and Behavior,
1, 23 (1973). (e) G. Fouriezos, R. A. Wise,
Brain Research,
103, 377 (1976). (f) R. Pickens, W. C. Harris,
Psychopharmacologia
12, 158 (1968). (g) R. A. Yokel, R. A. Wise,
Science
187, 547 (1975). (h) W. M. Davis, S. G. Smith,
Journal of Pharmacy and Pharmacology,
27, 540 (1975). (i) H. de Wit, R. A. Wise,
Can J Psychol,
31, 195 (1977). (j) M. E. Risner, B. E. Jones,
Psychopharmacology,
71, 83 (1980). (k) D. C. S. Roberts, M. E. Corcoran, H. C. Fibiger,
Pharmacology Biochemistry and Behavior,
6, 615 (1977). (l) R. A. Yokel, R. A. Wise,
Psychopharmacology
(Berl),
58, 289 (1978). (m) M.C. Ritz et al., 1987. Science 237: 1219–1223. (n) B. A. Rocha et al.,
Nature Neuroscience,
1, 132 (1998). (o) M. Thomsen, D. D. Han, H. H. Gu, S. B. Caine,
J Pharmacol Exp,
Ther 331, 204 (2009).
    3 The dopamine transporter (DAT) is known as the initial site of action of cocaine that produces the addicting properties of the drug. This was shown more or less definitely in a paper in 1987 using “receptor binding,” a technique that reveals the initial site of action of drugs. The problem before that was that cocaine has many actions. It not only inhibits the uptake of dopamine, but it also inhibits the uptake of serotonin and