Natl. Acad. Sci U.S.A. 79, 4714 (1982); B. G. Neel, S. C. Jhanwar, R. S. K. Chaganti, W. S. Hayward, ibid., p. 7842; N. Heisterkamp et al., Nature (London) 299, 747 (1982); 0. W. McBride, D. C. Swan, E. Santos, M. Barbacid, W. R. Tronick, S. A. Aaronson, ibid. 300, 773 (1982); B. de Martinville, J. Giacalone, C. Shih, R. A. Weinberg, U. Francke, Science 219, 498 (1983); A. Y. Sakaguchi, S. L. Naylor, T. B. Shows, J. J. Toole, M. McCoy, R. A. Weinberg, ibid., p. 1081. 10. R. F. Doolittle et al., Science 221, 275 (1983); M. D. Waterfield et al., Nature (London) 304, 35 (1983); C. D. Stiles, Cell 33, 653 (1983). 11. U. Francke, N. Busby, D. Shaw, S. Hansen, M. G. Brown, Somat. Cell Genet. 2, 27 (1976); U. Francke and B. Francke, ibid. 7, 171 (1981); see also (13). 12. E. Southern, J. Mol. Biol. 98, 503 (1975). 13. Hybrids with regions C, D, and E (Fig. 2) were derived from human donors with balanced trans- locations of chromosome I [U. Francke, Cyto- genet. Cell Genet. 14, 308 (1975); and M. A. Pellegrino, Proc. Natl. Acad. Sci. U.S.A. 74, 1147 (1978); ibid., p. 5776]. Hybrids with regions A, B, F, and G had acquired the rearrangements of chromosome I during evolution in vitro of the hybrid cell lines [D. L. George and U. Francke, Hum. Hered. 28, 161 (1978); S. Vora, S. Dur- ham, B. de Martinville, D. L. George, U. Francke, Somat. Cell Genet. 8, 95 (1982)]. 14. B. de Martinville, J. M. Cunningham, M. J. Murray, U. Francke, Nucleic Acids Res. 11, 5267 (1983); B. de Martinville, M. Muenke, J. M. Cunningham, M. J. Murray, U. Francke, Cytogenet. Cell Genet., in press. 15. M. J. Murray, J. M. Cunningham, L. F. Parada, Ettenberg et al. (1) reported that doses of the neuroleptic a-flupenthixol that spared nose poking for lateral hypotha- lamic self-stimulation markedly sup- pressed bar pressing for the same re- ward. Central to their interpretations of this apparently task-dependent drug ef- fect was the notion that the task used to earn brain stimulation somehow modu- lates the degree to which dopamine cells participate in reward. We do not consider the viability of their interpretations because the experi- ment itself suffers a serious design error. The drug effect on nose poking was assessed 2.5 hours after injection, and bar-pressing tests were held about 50 minutes afterward. The task order was not counterbalanced: "The effects of each dose were tested on nose poking for brain stimulation and then on lever pressing" (1, p. 358). If these tests were held over the rising phase of receptor concentration, then for any particular dose the effective antagonism would be consistently lower in the nose-poke trials than in the bar-press tests. It thus would come as no surprise that nose-poking behavior survived at a dose that com- pletely eliminated bar pressing. To see whether a-flupenthixol's be- havioral effect attains asymptote at 2 or even 3 hours after injection, we ran a time-course study of its action on lateral hypothalamic self-stimulation. Required 16 DECEMBER 1983 F. Dautry, P. Lebowitz, R. A. Weinberg, Cell 33, 749 (1983); K. Shimizu, M. Goldfarb, M. Perucho, M. Wigler, Proc. Natl. Acad. Sci. U.S.A. 80, 383 (1983). 16. X. 0. Breakefield, G. Orloff, C. M. Castiglione, in Biochemical and Clinical Aspects of Neu- ropeptides: Synthesis, Processing and Gene Structure. G. Koch and D. Richter, Eds. (Aca- demic Press, New York, in press). 17. "Human Gene Mapping 6," Cytogenet. Cell Genet. 32, 341 (1982). 18. V. B. Babapulle and N. B. Atkin, Cancer Genet. Cytogenet. 4, 215 (1981); M. M. Haag, S. W. Soukup, J. E. Neely, Cancer Res. 41, 2995 (1981); F. Gilbert, G. Balaban, P. Moorhead, D. Bianchi, H. Schlesinger, Cancer Genet. Cyto- genet. 7, 33 (1982); G. M. Brodeur, A. A. Green, F. A. Hayes, K. J. Williams, D. L. Williams, A. A. Tsiatis, Cancer Res. 41, 4678 (1981). 19. T. Waris, L. Rechardt, P. Waris, Experientia 29, 1128 (1973); A. R. Kolber, M. N. Goldstein, B. W. Moore, Proc. Natl. Acad. Sci. U.S.A. 71, 4203 (1974); C. P. Reynolds and J. R. Perez- Polo, Neurosci. Lett. 1, 91 (1975). 20. U. Francke, in Chromosomes and Cancer: From Molecules to Man, J. D. Rowley and J. E. Ultmann, Eds. (Academic Press New York 1983), p. 99. 21. J. M. Taylor, R. Illmensee, J. Summers, Nucleic Acids Res. 9, 2313 (1981). 22. U. Francke, Cytogenet. Cell Genet. 31, 24 (1981). 23. Supported by NIH research grant GM 26105 (to U.F.) and Genentech Inc. * Address correspondence to U.F. 31 August 1983; accepted 6 October 1983 frequencies (2) needed to sustain criteri- on bar-press rates were determined at hourly intervals beginning immediately after injection. This measure is equiva- lent to "threshold" determination; the sole difference is that reward summation functions (3) are cut at moderate levels UF 0 0 .. . . 407 N I - CT S 120 60 30 U 120 60 30 U 120 60 30 U of performance instead of at just notice- able departures from zero responding. Often, high doses suppressed responding altogether. Required frequencies could not be measured and these undetermined points are shown as unconnected dots against "U" of Fig. 1. Lower doses caused required frequencies to climb, on average, through to the 4-hour test. The implication is that Ettenberg et al. con- ducted their tests too soon after drug administration; by failing to counterbal- ance task order, they effectively as- sessed the two tasks with different phar- macological populations. We then attempted to replicate their result with tests that (i) began after a longer postinjection interval (3 hours, 45 minutes) and (ii) included both orders of task presentation. Each behavior was tested daily for 20 minutes and the two sessions were separated by 20 minutes. Doses of a-flupenthixol were given ev- ery other day (4). The dose of 0.4 mg/kg completely abolished bar pressing and nose poking (Fig. 2), a result that is at odds with the spared nose poking report- ed at this dose and twice this dose by Ettenberg et al. Our failure to replicate fits with a report (5) that haloperidol reduces performance of these two oper- ants to the same degree. Bar-pressing performance was more reduced than nose poking at our lower doses; we agree with Ettenberg et al. that this latter re- sult cannot be taken as a task-dependent difference in substrate sensitivity. Our first experiment demonstrates 80 _0 00 0 0 0 0 408 - .4 * @00- E-26 - S0 0 0 0 0 E-33 5 0 6co 0 0 CL co 0 40 0 0.1 0.2 0.4 Dose (mg/kg) 120 0/ /2 Fig. 1 (left). Time-course data. Frequency of : 0) , * _ 0.1 stimulation pulses required to obtain criterion eo- '_ responding after administration of a-flupen- 30 __ a thixol. Open circles represent saline tests and , , , , , , closed circles depict drug tests. Doses, in 0 2 4 6 24 milligrams per kilogram, are shown beside the Time after injection (hours) curves. Each symbol indicates the geometric mean and standard error of four measure- ments. Points at the "U" level are undetermined. Fig. 2 (right). Effects of ox-flupenthixol on lever pressing (closed bar) and nose poking (open bar) for lateral hypothalamic stimulation. The mean response rate is expressed as a percentage of the saline control. These data illustrate that a-flupenthixol has equally disruptive effects on both tasks. 1251 Time Course of a-Flupenthixol Action Explains "Response Artifacts" of Neuroleptic Action on Brain Stimulation Reward on June 1, 2020 http://science.sciencemag.org/ Downloaded from