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Official websites use. Share sensitive information only on official, secure websites. Address for manuscript correspondence: Nancy K. Mello, Ph. Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels, and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid two min sampling procedure in nicotine-dependent volunteers or current cocaine users. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. Peak nicotine levels increased progressively after each of three successive cigarettes smoked at 60 min intervals, but the magnitude of the subjective effects ratings and peak ACTH and cortisol levels diminished. Only DHEA increased consistently after successive cigarettes. The possible influence of neuroactive hormones on nicotine dependence and cocaine abuse, and implications for treatment of these addictive disorders is discussed. The prevalence of numerous health hazards lung cancer, stroke, cardiovascular and respiratory disease, osteoporosis associated with cigarette smoking has been well documented CDC, a , , ; Pollock et al. There is now little question that cigarette smoking is an addictive disorder, characterized by tolerance and physical dependence APA, ; Benowitz, , ; Henningfield et al. Nicotine appears to be the primary addictive agent, and intravenous nicotine is self-administered by humans and experimental animals under a number of conditions Corrigall, ; Donny et al. Addiction to cigarette smoking is influenced by a myriad of social and contextual factors, as well as the pharmacology of tobacco. Although social sanctions and restrictions on public areas where smoking is permissible, combined with increasing costs for cigarettes, has resulted in decreases in cigarette sales and use estimated at two percent per year to , the use of alternative tobacco products has increased Connolly and Alpert, Nicotine replacement therapies have not been uniformly effective, and despite multimodal treatment efforts, relapse rates remain high Harvey et al. It is difficult to predict the eventual impact of legislation to regulate the tobacco industry by the Food and Drug Administration on cigarette smoking behavior. The development of more effective medication-based interventions to treat nicotine dependence is urgently needed. An improved understanding of the complex neurobiology underlying nicotine addiction is important for achieving this goal. The abuse-related effects of nicotine are mediated, in part, by stimulating nicotine acetylcholine receptors on mesolimbic dopamine neurons to release dopamine Corrigall et al. The importance of dopamine in the reinforcing effects of nicotine is suggested by the fact that dopamine D1—like and D2-like receptor antagonists, as well as nicotine receptor antagonists, reduce nicotine self-administration in preclinical studies Pierce and Kumaresan, ; Watkins et al. The neuroactive steroid hormones can also directly alter dopamine release under some conditions Becker et al. This issue is of interest because an emerging literature suggests that the neuroactive steroid hormones can enhance or diminish the reinforcing effects of another psychostimulant, cocaine Carroll et al. Although cocaine and nicotine have different molecular structures, and increase extracellular dopamine levels by different mechanisms, there are many similarities in their hormonal and behavioral effects Chausmer et al. Evidence that the hypothalamic-pituitary-adrenal HPA axis hormones are important in the addictive process has been shown for cocaine. Hypothalamic corticotropin-releasing hormone CRH stimulates anterior pituitary corticotrophs to secrete ACTH, which in turn stimulates cortisol or corticosterone release from the adrenal cortex. These data were consistent with our early hypothesis that the hormonal milieu may be one important modulator of the reinforcing effects of drugs Mendelson et al. To evaluate the generality of our findings in clinical studies of the hormonal and behavioral effects of cocaine, we have conducted a series of parallel clinical studies of nicotine that are summarized here. This review describes clinical laboratory studies of the hormonal and subjective effects of cigarette smoking conducted at the Alcohol and Drug Abuse Research Center, McLean Hospital. In each of our studies, subject met DSM-IV criteria for nicotine dependence or current cocaine abuse and provided written informed consent. One goal of these studies was to examine the temporal covariance between changes in hormone levels and subjective responses associated with cigarette smoking and IV cocaine administration. We used a rapid sampling procedure in which measures of each dependent variable were collected at 2 min intervals for 20 to 30 min after drug administration. This sampling frequency enabled us to measure HPA axis hormones, cardiovascular and subjective responses during the ascending limb of the plasma nicotine or cocaine curve. A second goal was to compare the effects of cocaine and nicotine studied under these conditions. The first section of this review describes the effects of smoking a single cigarette on HPA axis hormones and subjective effects in men. The second section describes the effects of smoking three successive cigarettes studied under the same conditions. In each study, the effects of low and high nicotine cigarettes are compared, and the temporal concordance between plasma nicotine levels, HPA axis hormones and subjective reactions to nicotine is described. The third section describes preliminary data on the subjective effects of smoking a single high nicotine cigarette during the follicular and luteal phase of the menstrual cycle. The fourth section compares the subjective and hormonal effects of cigarette smoking and IV cocaine administration. The concluding section discusses some implications of the several similarities between the hormonal and abuse-related effects of nicotine and cocaine for understanding the neurobiology of these drugs as well as possible approaches to medication-based treatment. Studies to explore the interactions between HPA axis hormones and the abuse-related effects of cigarette smoking were conducted in ten nicotine-dependent men average age Men had smoked for at least 5 years and smoked 15 or more cigarettes each day. CO levels were below 4 ppm in all subjects on the study day. Each subject smoked a high nicotine cigarette Marlboro Red; We used a rapid sampling procedure to examine the temporal covariance between plasma nicotine levels, changes in HPA axis hormones, cardiovascular measures, and reports of subjective effects during as well as after cigarette smoking. All dependent variables were measured at 2 min intervals during and for 20 min following cigarette smoking. Then, samples were collected at 25, 30, 40, 50, 60, 80, and min. Cigarette smoking produced nicotine dose-dependent increases in anterior pituitary and adrenal hormones as well as cardiovascular and subjective responses in nicotine-dependent men. Nicotine plasma levels were significantly higher after smoking a high nicotine cigarette than after smoking a low nicotine cigarette. The low nicotine cigarette did not increase pituitary or adrenal hormones, and although there were increases in heart rate and VAS ratings of positive subjective effects, these were significantly lower than after smoking a high nicotine cigarette. Smoking behavior, defined in terms of duration of cigarette exposure and number and duration of puffs, was equivalent for high and low nicotine cigarettes. Thus, it is likely that the significant differences in hormonal and subjective effects were attributable to the relative dose of nicotine. Plasma nicotine levels after smoking a high nicotine cigarette filled circles and a low nicotine cigarette open circles are shown on the left ordinates. Time min is shown on the abscissae. Points above BL were collected 10 min before cigarette smoking began at time 0. The 12 min cigarette smoking period is indicated by a grey rectangle. Reprinted with permission from Mendelson, J. Neuropsychopharmacology —, Figure 1 shows that nicotine plasma levels increased significantly above baseline within 2 min 4 puffs and reached peak levels within 12 to 14 min after cigarette smoking began. Nicotine plasma levels and pharmacokinetic profiles in the present study also were similar to those we previously reported under similar smoking conditions Mendelson et al. Moreover, the small but significant increase in plasma nicotine occurred later after 6 min or 12 puffs after smoking a low than a high nicotine cigarette and remained at relatively stable, low levels for min. Hormone levels after smoking a high nicotine cigarette filled circles and a low nicotine cigarette open circles are shown on the left ordinates. The min cigarette-smoking period is indicated by a grey rectangle. Increases in ACTH after cigarette smoking have been reported under conditions where samples for analysis were collected once a day or at relatively infrequent intervals, often without concurrent plasma nicotine measurement Baron et al. Carefully controlled preclinical studies have consistently shown that nicotine rapidly stimulates the HPA axis Matta et al. Figure 2 shows that when samples were collected every 2 min, ACTH and epinephrine began to increase within 6 min after high nicotine cigarette smoking began and reached peak levels within 4 to 6 min after peak nicotine plasma levels were detected Fig. This time course was similar to our previous report of the temporal covariance between ACTH, epinephrine and plasma cocaine levels, after IV cocaine administration in men Mendelson et al. We interpreted those data to suggest that the HPA hormone increases may be significant concomitants of the abuse-related effects of cocaine in humans Mendelson et al. The possible influence of HPA axis activation, as indicated by ACTH and cortisol increases, on the abuse-related effects of cocaine has been discussed in several reviews Goeders, , a , b ; Mello and Mendelson, , a. The similar patterns of HPA axis activation and subjective responses after IV cocaine and smoked nicotine are provocative. It is also interesting to consider the possible contribution of cortisol and DHEA to the abuse-related effects of cigarette smoking. Figure 2 shows that cortisol began to increase significantly when ACTH levels were highest, and reached peak levels between 30 and 60 min after smoking began, when ACTH levels were decreasing. This time course is consistent with established feedback relationships between ACTH and cortisol Yen et al. The increases in cortisol and DHEA were significantly correlated, and each hormone had a similar half-life after high nicotine cigarette smoking. Cigarette smoking usually induces an increase in plasma cortisol levels Cryer et al. It has also been suggested that nicotine may inhibit the diurnal decrease in plasma cortisol levels Pomerleau et al. DHEA is an adrenal androgen precursor of testosterone Yen et al. DHEA is believed to improve feelings of wellbeing and sexuality in the elderly, although the evidence is conflicting see for review, Nair et al. Two placebo-controlled clinical trials support the notion that DHEA treatment improves mood and alleviates depression Morales et al. In a 6 month, placebo-controlled, cross-over trial, DHEA administration at physiological levels 50 mg, P. In the present study, peak levels of DHEA after smoking a high nicotine cigarette It is interesting to speculate that increases in DHEA levels may contribute to the mood elevating effects reported after cigarette smoking, as well as to the alleviation of anxiety and depression Picciotto et al. Subjective ratings on a Visual Analogue Scale VAS 0— are shown on the left ordinates and time min is shown on the abscissae. Points above BL were collected 10 min before smoking began at time 0. The 12 min cigarette-smoking period is indicated by a grey rectangle. Significant increases in ratings of positive subjective effects occurred within 4 puffs over 2 min after initiation of smoking both a low and a high nicotine cigarette Figure 3. However, Visual Analog Scale VAS ratings were significantly higher during high than low nicotine cigarette smoking, and this suggests that subjects could detect the relative nicotine levels within 4 puffs. Low nicotine cigarettes usually fail to reduce smoking behavior because smokers adjust their smoking topography and smoke more cigarettes to try to compensate for a low nicotine yield Benowitz, This dose of nicotine nasal spray produced nicotine plasma levels of 2. Despite differences in routes of nicotine administration nasal spray and smoking , these data converge to suggest that experienced smokers can discriminate very low doses of nicotine. During high nicotine cigarette smoking, the highest positive VAS ratings were reported during the initial ascending limb of the plasma nicotine curve, then gradually diminished during the smoking period as plasma nicotine approached peak levels. During low nicotine cigarette smoking, positive VAS ratings remained relatively stable across the 12 min smoking period. Interestingly, the time course of increases in VAS ratings of positive subjective effects was similar during smoking a high nicotine cigarette and after intravenous nicotine administration. When intravenous nicotine was infused over 10 sec. A similar rapid decrease in positive subjective reports was also observed after intravenous nicotine administration, although plasma nicotine levels were not measured Jones et al. Smoking a high nicotine cigarette reduced ratings of craving significantly more than smoking a low nicotine cigarette, and craving scores remained significantly below baseline for much longer min vs 30 min. Plasma nicotine levels after smoking a high-nicotine cigarette filled circles and a low-nicotine cigarette open circles are shown on the left ordinates. Points above baseline were collected 10 min before smoking the first cigarette began at time 0. A vertical line and an arrow indicate each 4-min cigarette-smoking period. In a subsequent study, we examined the effects of smoking three successive cigarettes on nicotine levels, HPA axis hormones, heart rate and subjective effects measures using rapid 4 min sampling procedures Mendelson et al. Figure 4 shows that plasma nicotine levels increased significantly from baseline after smoking each of three high-nicotine cigarettes at 1 hr intervals. Moreover, nicotine levels were significantly higher after the third cigarette than after the first cigarette. The progressive increase in peak nicotine levels after smoking three successive high-nicotine cigarettes presumably reflects some accumulation of nicotine. A similar pattern of increases in nicotine levels was reported when subjects smoked five cigarettes at min intervals Isaac and Rand, and seven cigarettes at 1 hr intervals Russell, However, subjective effects and cardiovascular measures were not reported in those studies. Progressive increases in nicotine levels were also reported after successive IV nicotine injections Rosenberg et al. In contrast, smoking three low-nicotine cigarettes did not result in cumulative increases in nicotine levels Fig. Hormone levels after smoking a high-nicotine cigarette filled circles or a low nicotine cigarette open circles are shown on the left ordinates. Points above baseline were collected 10 min before cigarette smoking began at time 0. The cumulative increases in peak nicotine levels shown in Figure 4 were not accompanied by progressive increases in peak levels of ACTH, cortisol and DHEA Figure 5 or peak positive subjective effects ratings Figure 6 or in peak heart rate data not shown. Rather, these measures gradually decreased or remained the same after smoking each successive cigarette. Although the magnitude of changes in VAS ratings and heart rate were nicotine-dose related, the pattern of changes in these measures was similar after low- and high-nicotine cigarette smoking. HPA axis hormone levels increased after smoking high-nicotine cigarettes, but no changes or a significant decrease occurred after smoking low-nicotine cigarettes. Subjective ratings on a Visual Analogue Scale VAS 0— after smoking a high nicotine cigarette filled circles or a low-nicotine cigarette open circles are shown on the left ordinates. Points above baseline were collected 10 min before smoking began at time 0. ACTH increased significantly after smoking the first high-nicotine cigarette, and the time course was similar to that shown earlier in Figure 2 Mendelson et al. ACTH levels did not increase significantly after the second cigarette, and this may have reflected negative feedback from the sustained elevation in cortisol at the time of smoking. The plausibility of this explanation is strengthened by the fact that when the third cigarette was smoked, cortisol levels were much lower and ACTH increased significantly. Interpretation of these data is complicated by the feedback relationships between ACTH and cortisol see for review Yen et al. Peak levels of cortisol occur between 8 and 9 a. The high craving scores reported by the low-nicotine group suggests that subjects remained in a state of relative nicotine deprivation throughout the study. These data are consistent with DHEA levels after smoking a single high nicotine cigarette. Interestingly, IV cocaine also stimulated significant increases in DHEA and cortisol that were similar in time course and magnitude to smoking a high-nicotine cigarette Mendelson et al. The significant increases in cortisol and DHEA induced by both IV cocaine and smoked nicotine suggest that these hormones may contribute to the abuse-related effects of both drugs Mendelson et al. DHEA has been suggested as a potential medication for smoking cessation Marx et al. Heart rate also increased significantly after smoking each high-nicotine cigarette, but the greatest increase occurred after the first high-nicotine cigarette. Tolerance to the acute cardiovascular stimulating effects of nicotine has also been observed after repeated injections of the same dose of intravenous nicotine Benowitz et al. Peak VAS ratings after the first cigarette were similar in time course and magnitude to ratings shown earlier after a single cigarette Figure 3. Although VAS ratings of positive subjective effects were significantly higher after high- than low-nicotine cigarette smoking, nicotine levels did not appear to be the sole determinant. In contrast to the progressive increases in peak plasma nicotine levels shown in Figure 4 , peak ratings of positive subjective effects were progressively lower after smoking each successive cigarette. The successive decrease in peak positive VAS ratings after repeated cigarette smoking is consistent with decreases in subjective responses after repeated nicotine nasal spray administration Perkins et al. The decrease in peak positive VAS ratings after successive cigarettes appeared to be unrelated to changes in the aversive properties of smoking. Nicotine-dependent smokers appear to be quite sensitive to relative nicotine levels Mendelson et al. In other naturalistic smoking conditions, inter-cigarette intervals of 30 - 35 min are often reported Hatsukami et al. The progressive diminution in peak hormone levels and VAS ratings after smoking successive cigarettes suggests that tolerance may have developed to these effects Figures 5 and 6. Acute tolerance develops to some effects of nicotine under a number of conditions, and chronic tolerance may persist for weeks or even years after cessation of smoking Benowitz et al. There was a clear dissociation between the monotonic increases in peak nicotine levels, and the progressive decreases in peak VAS ratings of positive subjective effects and peak heart rate. The robust subjective, cardiovascular and hormonal response to the first cigarette is consistent with the usual observation that after a period of nicotine abstinence, the first cigarette of the day is the most reinforcing Fant et al. However, it is not clear if the subsequent decreases in peak subjective and cardiovascular effects primarily reflect acute tolerance to these effects of nicotine or relief of nicotine withdrawal symptoms after overnight abstinence from smoking. Pillitteri et al. It is interesting to compare these effects of repeated cigarette smoking with previous clinical laboratory studies of cocaine, where drug abstinence symptoms were not an issue. As in the cigarette smoking study, repeated administration of cocaine did not result in cumulative increases in ratings of positive subjective effects or heart rate Dudish et al. Only ratings of negative subjective effects increased after repeated doses of IV cocaine Foltin and Fischman, whereas, peak ratings of negative effects after cigarette smoking tended to decrease or stay about the same. The 12 min cigarette-smoking period is indicated by a gray rectangle. Each data point is the average of three nicotine-dependent women studied during the follicular closed circles and the luteal open circles phase of successive menstrual cycles. Preliminary data from N. Mello, ongoing studies. Both sex and phase of the menstrual cycle appear to influence the biologic effects and subjective responses to cocaine Evans, ; Mello and Mendelson, , a , b in press ; Newman and Mello, In clinical laboratory studies, cocaine produced higher ratings of positive subjective effects in women studied during the mid-follicular phase than during the luteal phase of the menstrual cycle Evans et al. This hypothesis was confirmed in subsequent clinical studies where progesterone, at doses that mimicked luteal phase progesterone levels, was administered during the follicular phase. Under these conditions, women reported lower ratings of positive subjective responses to cocaine in comparison to their responses during a normal follicular phase without progesterone treatment Evans and Foltin, ; Sofuoglu et al. In preclinical studies, progesterone treatment reduced the facilitory effect of estradiol on acquisition of cocaine self-administration in ovariectomized rats Jackson et al. Progesterone also decreased cocaine self- administration and shifted the cocaine dose-effect curve to the right in rhesus monkeys Mello et al. Similarly, in a cocaine-primed reinstatement paradigm, progesterone treatment attenuated responding during estrus, but not during proestrus or diestrus phases of the estrous cycle in gonadally intact female rats Feltenstein and See, Progesterone treatment also reduced cocaine-primed reinstatement in ovariectomized rats Anker et al. There has been considerably less research on the interactions between progesterone and nicotine. In rats, it has been difficult to detect an effect of estrous cycle phase on patterns of nicotine self-administration Donny et al. Studies of the effects of menstrual cycle phase on cigarette smoking behavior or responses to acute nicotine administration have often yielded inconsistent results Perkins et al. Menstrual cycle phase appears to be more important in modulating nicotine withdrawal symptoms than ongoing patterns of smoking behavior Allen et al. We are currently examining the subjective and hormonal effects of cigarette smoking in nicotine-dependent women during the follicular and luteal phases of the menstrual cycle. The experimental procedures were identical to those described earlier for studies of cigarette smoking in men and presented in Figures 1 , 2 and 3. Women were studied during the mid-follicular and mid-luteal phases of successive menstrual cycles. Menstrual cycle phase was verified by analysis of progesterone levels within 24 hours of the study day. Progesterone levels averaged 0. Preliminary data on three women are shown in Figure 7. Peak plasma nicotine levels after smoking a high nicotine cigarette Marlboro Red, Phillip Morris Brand were equivalent in the follicular and luteal phase women Plasma nicotine levels increased rapidly within two minutes, or four puffs on a high nicotine cigarette and peak levels were detected within 12—14 minutes. The small number of subjects precludes statistical analysis, but the overall time course and shape of the nicotine curve is similar to that measured in men shown earlier in Figure 1. Although these observations of the effects of spontaneous increases in endogenous progesterone levels during the luteal phase is a less powerful experimental design than administration of exogenous progesterone during the follicular phase, these findings on nicotine are consistent with previous clinical reports on the effects of exogenous progesterone administration on subjective reactions to cocaine in women Evans, ; Evans and Foltin, ; Sofuoglu et al. Thus far, progesterone appears to be less effective in reducing positive responses to cocaine in men Evans and Foltin, ; Sofuoglu et al. In our ongoing preclinical studies on the effects of progesterone administration on nicotine self-administration in nonhuman primates, we also found that progesterone decreased nicotine self-administration. Monkeys were trained to self-administer nicotine on a progressive ratio schedule in which the number of responses required for each successive nicotine injection i. Administration of progesterone 0. The decrease in nicotine self-administration did not appear to be related to the sedative effects of progesterone because, at the end of each session, monkeys were alert, took treats, and scored zero on a sedation scale completed by trained observers. Taken together, these clinical and preclinical data suggest that synthetic derivatives of the neuroactive gonadal steroid hormones may offer a novel approach to the medication-based treatment of cigarette smoking in women. Some similarities between the abuse-related effects of cocaine and nicotine have been noted throughout this review. Clinical studies have shown that the positive subjective and physiological effects of nicotine are very similar to the effects of IV cocaine in cocaine abusers who smoke cigarettes Chausmer et al. Nicotine and cocaine also have similar pharmacokinetic profiles after both inhalation and intravenous administration Evans et al. The rapid distribution of both nicotine and cocaine, combined with the relatively brief duration of positive subjective effects, is characteristic of drugs with high abuse liability Balster and Schuster, As described earlier, nicotine, like cocaine, activates the mesolimbic dopamine system, and the resulting increases in extracellular dopamine levels appear to mediate the abuse-related effects of both drugs Corrigall et al. However, cocaine and nicotine increase extracellular dopamine levels by different mechanisms. Nicotine stimulates dopamine release in the nucleus accumbens by stimulating nicotinic acetylcholine receptors on the cell bodies of mesolimbic dopamine neurons Watkins et al. Interestingly, microdialysis studies indicate that administration of equipotent doses of nicotine and cocaine, given in combination, produce additive effects on nucleus accumbens dopamine release Gerasimov et al. In addition to dopaminergic effects, cocaine and nicotine both stimulate release of hypothalamic-anterior pituitary-gonadal and-adrenal hormones. Preclinical studies suggest that these rapid hormonal changes may contribute to the abuse-related effects of cocaine Goeders, , a , b ; Mello and Mendelson, , a. Cocaine 0. Because stimulation of LH release is a robust effect of cocaine administration in humans and in non-human primates Mello and Mendelson, , we compared the effects of IV cocaine and cigarette smoking on LH and T in men to determine the generality of these findings Mendelson et al. These data are shown in Figures 8 , 9 , and We found that IV cocaine and high nicotine cigarette smoking each stimulated a significant increase in LH release that was temporally correlated with increases in plasma levels of cocaine and nicotine. Moreover, high nicotine cigarette smoking produced significantly greater stimulation of LH than IV cocaine. Pharmacokinetic analyses showed that the Tmax and Cmax for LH were significantly higher after cigarette smoking than after IV cocaine. Testosterone levels did not change significantly after cocaine or nicotine administration. Placebo-cocaine and low nicotine cigarettes had no effect on any endocrine or subjective report measures. Points above BL were collected 10 min before drug administration at time 0. The top panel shows plasma nicotine levels after smoking a high nicotine yield cigarette filled circles and a placebo cigarette open circles. The 12 min cigarette smoking period is indicated by the grey rectangle. The bottom panel shows plasma cocaine levels after administration of 0. The vertical line indicates when cocaine was administered. The top panel shows LH levels after smoking a high nicotine yield cigarette filled circles and a placebo cigarette open circles. The 12 min cigarette-smoking period is indicated by the grey rectangle. The bottom panel shows LH levels after administration of 0. The vertical line indicates when cocaine or placebo-cocaine was administered. Figure 8 top panel shows plasma nicotine levels before, during and after low and high dose nicotine cigarette smoking. Before cigarette smoking, low levels of nicotine that averaged 1. Baseline CO levels averaged 3. Nicotine plasma levels increased significantly within 2 min or 4 puffs after smoking a high nicotine cigarette and remained significantly above baseline throughout the min sampling period. Peak plasma nicotine levels of Plasma nicotine levels also increased significantly above pre-smoking baseline levels after smoking the low nicotine cigarette. Peak plasma nicotine levels of 3. Cocaine plasma levels were maximal within 8 min after 0. Plasma cocaine levels gradually decreased over the remainder of the sampling period and averaged No cocaine was detected after placebo-cocaine injection. Cocaine and high nicotine cigarette smoking each stimulated rapid increases in LH Figure 9. LH levels increased significantly from baseline within 14 min after high nicotine cigarette smoking and reached peak levels of 8. After low nicotine cigarette smoking, LH levels did not change significantly from baseline. After administration of 0. LH reached peak levels of 5. The increase in LH was significantly correlated with the increase in plasma cocaine levels shown in Figure 8. After placebo-cocaine administration, LH levels did not change significantly from baseline. The time course and duration of LH increases after cocaine are consistent with previous clinical reports Mendelson et al. Moreover, cigarette smoking produced significantly greater and more sustained increases in LH than IV cocaine. These findings disagree with earlier clinical studies where no effect of cigarette smoking on LH was detected Seyler et al. Differences in the frequency and duration of sample collection after cigarette smoking could account for these discrepant findings. For example, no changes in LH were detected when a single sample was collected after each cigarette Winternitz and Quillen, or at 5 min intervals for 25 min after smoking Seyler et al. In the present study, significant increases in LH were not detected until 18 min after smoking began. The behavioral implications of rapid increases in LH release after IV cocaine and cigarette smoking are unclear. The significant correlations between increases in LH and plasma nicotine and plasma cocaine levels suggest that LH may contribute to the abuse-related effects of both drugs for review see Mello and Mendelson, , a. High LH levels are often associated with enhanced sexual feelings. For example, in young men, increases in LH were temporally related to behavioral and physiological measures of sexual arousal in response to sexual stimuli La Ferla et al. LH is essential for normal reproductive function Yen et al. The significant increases in LH after IV cocaine and high nicotine cigarette smoking were not followed by changes in T levels. Previous clinical studies also reported no changes in T in men who smoked 6 cigarettes over 2 hr Winternitz and Quillen, or who were given intranasal cocaine Heesch et al. For example, in rhesus monkeys, when LH was stimulated by an opioid antagonist, nalmefene, T increased significantly within 40 to 50 min after significant increases in LH Mello et al. It may be that the magnitude of LH increases in the present study was not sufficient to stimulate T. LH increased by 80 percent from baseline after IV cocaine and by percent after smoking a high nicotine cigarette. Whereas in rhesus monkey, nalmefene stimulated LH increases of and percent from baseline were followed by significant increases in T Mello et al. Differences in LH assay procedures, as well as species differences limit these comparisons. Subjective ratings on a Visual Analogue Scale 0— are shown on the left ordinates and time min is shown on the abscissae. All other details are as described in the legend for Figure 8. Moreover, the highest IV nicotine dose produced higher ratings on most of the subjective effects measures than IV cocaine Jones et al. It is possible that IV nicotine has more potent subjective effects than smoked nicotine and is more comparable to IV cocaine. Drug plasma levels were not reported by Jones and co-workers, so nicotine dose levels cannot be directly compared with the present study. It is unlikely that differences in the time course of IV and smoked nicotine can account for these different findings. Smoked nicotine is estimated to reach the brain within 10 to 20 sec and is faster than IV nicotine Benowitz et al. One limitation of these cigarette-smoking studies is that nicotine and hormone levels were measured in venous rather than arterial blood. Arterial nicotine levels are 2 to 3 or 6 to 10 fold higher than venous nicotine levels Benowitz, ; Rose et al. After the first 5 sec puff, nicotine from cigarette smoke reached peak levels in the arterial circulation within 15 to 20 sec and continued to increase after the second and third puff Rose et al. We detected significant increases in subjective ratings and plasma nicotine within 2—4 min Mendelson et al. Although the time course of the rapid increases after cocaine and cigarette smoking were similar, but it is not clear if these drugs stimulate LH release by similar mechanisms. However, LHRH may be stimulated by norepinephrine, epinephrine and neuropeptide y, either stimulated or inhibited by dopamine and gonadal steroid hormones, and inhibited by endogenous opioid peptides Yen et al. The relative contribution of these complex and inter-related systems to the acute effects of cocaine and nicotine on LH are unknown. Smoking a high-nicotine cigarette significantly increased plasma nicotine levels, HPA axis hormones, heart rate and VAS reports of positive subjective effects Mendelson et al. Smoking three successive high nicotine cigarettes at 1-hr intervals resulted in progressive increases in peak nicotine levels that probably reflected an accumulation of nicotine over time. However, peak VAS ratings and heart rate gradually diminished after each successive cigarette suggesting that tolerance developed to these effects of nicotine Mendelson et al. It is often postulated that behavioral and biologic indicators of tolerance reflect desensitization of nicotinic acetylcholine receptors nAChRs , and this concept is supported by a number of preclinical studies of endocrine Sharp and Beyer, ; Sharp and Matta, and behavioral endpoints James et al. Speculation about receptor mechanisms of acute nicotine tolerance is beyond the scope of this review. Peak levels of ACTH and cortisol also were lower after the second and third cigarette than after the first cigarette. These changes probably reflected alterations in the direct effects of nicotine as well as the feedback relationships between ACTH and cortisol. The exception was DHEA. It is interesting to speculate that the antidepressant effects of cigarette smoking Breslau et al. It was surprising to find that DHEA levels measured after smoking a single cigarette were over twice as high as levels measured after 6 weeks of high dose DHEA treatment for depression Mendelson et al. The sustained increases in DHEA after repeated cigarette smoking are consistent with the hypothesis that DHEA may contribute to the abuse-related effects of cigarette smoking Mendelson et al. Relatively, little is known about the interactions between DHEA and cocaine. Preclinical studies have shown that DHEA can reduce cocaine self-administration and reinstatement of cocaine seeking in rats Doron et al. Taken together, these clinical findings suggest that neuroactive steroid-based medications that are effective for nicotine treatment might also be effective for cocaine. Unfortunately, no uniformly effective medications to treat either cocaine or nicotine are available as yet, although there are many promising candidates Henningfield et al. The neuroactive steroid hormones may offer a novel approach to modifying the abuse-related effects of nicotine and cocaine. There is considerable interest in using neuroactive steroid hormones to treat depression, anxiety and panic disorder Eser et al. There were no benzodiazepine-like adverse side effects, possibly due to the fact that neuro steroids and benzodiazepines modulate GABA A receptors at different allosteric sites Rupprecht et al. The neuroactive gonadal steroid hormones, progesterone and estradiol, have opposite effects on the abuse-related effects of cocaine Mello and Mendelson, b in press. Progesterone usually decreases the abuse-related effects of cocaine and nicotine in women but not in men Evans, ; Evans and Foltin, ; Sofuoglu et al. A better understanding of the interactions between the hormonal milieu and the abuse-related effects of nicotine and cocaine may provide a novel perspective on the neurobiology of these drugs and eventually lead to the development of more effective medication-based treatments. This review summarizes some findings from a program of clinical research on the hormonal and behavioral concomitants of cigarette smoking and IV cocaine led by my late husband, Jack H. Mendelson, M. August 30, — August 15, After pioneering research on alcoholism, opioid addiction and marihuana abuse, he became interested in studying cigarette smoking and cocaine abuse during the last decades of his life. I am grateful to Murty Pharmaceuticals Inc. I thank the clinical research team, and especially Drs. Siegel, N. Goletiani and M. Sholar for their many contributions to these studies and Alicja Skupny for excellent technical assistance in conducting the hormone and cocaine analyses. I also thank Dr. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. As a library, NLM provides access to scientific literature. Horm Behav. Published in final edited form as: Horm Behav. Find articles by Nancy K Mello. Issue date Jun. PMC Copyright notice. The publisher's version of this article is available at Horm Behav. Open in a new tab. Similar articles. Add to Collections. 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