There were no significant differences between measures taken during placebo and doxazosin treatment. Change in heart rate and blood pressure following study medication dosing on the first day of treatment with each dose of study medication, when the largest effects would be expected, are shown in Table 3. Doxazosin and placebo both produced minimal changes in blood pressure measured following study medication dosing on the first day of treatment with each dose of study medication. Doxazosin had trend-level effects on systolic blood pressure following cocaine dosing but did not significantly affect diasystolic blood pressure or heart rate and there were no statistically significant interactions between cocaine dose and cardiovascular measures. Doxazosin treatment was well tolerated, as was expected from earlier studies in other normotensive populations. Doxazosin treatment had very modest effects on heart rate and blood pressure. The blood pressure effects of cocaine are likely mediated by sympathetic outflow and by effects of epinephrine and NE on peripheral vasculature and the observed effects of doxazosin on the cardiovascular effects of cocaine are consistent with this. Doxazosin treatment significantly attenuated several of the positive subjective effects produced by cocaine, including ratings of ‘‘stimulated’’ and ‘‘like cocaine’’,Neferine though the results for like should be interpreted with caution due to statistical limitations. Doxazosin also attenuated ratings of ‘‘likely to use’’ an index of craving. The magnitude of the effect was substantial for some of the variables. The usual dose of doxazosin for the treatment of hypertension is 8–16 mg/d, which is several-fold higher than the dose we tested in this study, 4 mg/d. Further, though doxazosin 4 mg substantially attenuated many of the effects produced by 20 mg cocaine, this dose of doxazosin reduced the effects produced by 40 mg cocaine to a more modest extent. Higher doses of doxazosin would be expected to have a greater impact on the effects produced by a wider range of cocaine doses, including perhaps doses abused by cocaine users. These doses are thought to be in the 50 to 100 mg range, though there are no good data to base this estimate on. Nevertheless, that doxazosin antagonism of cocaine’s was surmounted by the higher cocaine dose suggests a pharmacological dose-effect function and likely higher doses of doxazosin are needed for more complete antagonism. These data are very much in keeping with Timsaponin-C reported in rats by Zhang and colleagues, who found that prazosin pretreatment dose-dependently attenuated cocaine-induced reinstatement of extinguished cocaine-seeking behavior. The ‘‘reinstatement model’’ is frequently put forward as a model for craving induced by drug, stress, or other factors. The report by Zhang and colleagues is somewhat at odds with older data reported by Woolverton who found that prazosin did not alter responding maintained by cocaine. Prazosin treatment thus produced differential effects on cocaine reinstatement compared to reinforcing effects of cocaine. Consistent with this dissociation, we found that doxazosin treatment reduced indices reflecting desirability of cocaine, such as ‘‘like’’ and ‘‘likely to use cocaine with access’’, without affecting indices reflecting euphoria, such as ‘‘high’’. Euphoric effects are thought to relate to reinforcing effects, though they need not necessarily do so. The dampening effects of doxazosin on ratings of ‘‘stimulated’’ that we observed may reflect doxazosin’s specific effects on noradrenergic neurotransmission. Cocaine inhibits the reuptake of NE with nearly the same potency that it inhibits the reuptake of DA. The present data complement earlier preclinical research, and underscore the importance of noradrenergic mechanisms in mediating many of cocaine’s effects.