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Director's Report to the National Advisory Council on Drug Abuse
February, 2001

Research Findings

Behavioral Research

Economic Trade-Offs for Cigarette Puffs versus Nicotine Gum

Researchers from the University of Vermont compared smokers' preferences for cigarette puffs and nicotine gum at varying "prices" for these commodities. As expected, the researchers found that when only cigarette puffs were available, participants decreased smoking as the price per puff increased. In a second phase of the experiment, when participants were offered a choice between chewing nicotine gum at a low price, or purchasing cigarette puffs at different prices, they continued to purchase the same number of cigarette puffs at each price as in the previous experiment (i.e., when gum was previously unavailable). At higher prices for cigarette puffs however, nicotine gum chewing increased modestly. These data suggest that nicotine gum is a weak substitute for cigarettes in smokers unprepared to quit. Given that the gum was selected when the price of puffs was very high, and no puffs were purchased under these experimental conditions, the data suggest that under some economic situations nicotine gum is a weak substitute for cigarettes. Future experiments using this methodology may lead to the development and testing of pharmacotherapies that may better compete and substitute for cigarettes. Shahan, T.A. et al., Nicotine Gum as a Substitute for Cigarettes: A Behavioral Economic Analysis. Behavioural Pharmacology, 11, pp.71-79, 2000.

Postpartum Separation from Offspring Produces Long-Lasting Effects in Mother Rats

Prior research has shown that neonatal rat pups exposed to periodic separation from their mothers show an elevated stress-reactivity in adulthood that is manifest on both behavioral and physiologic indices. Researchers at the Emory University School of Medicine now show that this separation also produces long-lasting changes in the dams. Dams separated from their neonatal pups for 3 hours daily on postpartum days 2-14 and tested four to six weeks post-weaning, exhibited anxiety-like behaviors measured via (a) both entries and time spent in the open arms of an elevated plus-maze, (b) time spent in the center of a novel locomotor arena, and (c) ultrasonic vocalizations. The separation also resulted in reduced sensitivity to morphine as measured by tail-flick and hot-plate tests of analgesia. Kalinichev, M., Easterling, K.W., and Holtzman, S.G. Periodic Postpartum Separation from the Offspring Results in Long-Lasting Changes in Anxiety-Related Behaviors and Sensitivity to Morphine in Long-Evans Mother Rats. Pharmacology, 152, pp. 431-439, 2000.

Sex Differences, Estrus Cycle, and Regulation of Self-Administered Cocaine in Rats

Drs. Wendy Lynch and Marilyn Carroll of the University of Minnesota previously demonstrated that female rats acquire cocaine self-administration faster than male rats and that a larger percentage of female than male rats acquire cocaine self-administration. Using a choice procedure, these researchers now find that the mean infusion dose is lowest during metestrus/diestrus and highest during estrus and proestrus. The regulation of cocaine intake was measured by the correlation between the mean interdose interval and the preceding dose. Self-administration regulation was significantly more precise in males and in metestrus/diestrus females as compared to estrus and in proestrus females. Furthermore, there was no difference in regulation between males and metestrus/diestrus females. Lynch, W.J., Arizzi, M.N., and Carroll, M.E. Effects of Sex and the Estrous Cycle on Regulation of Intravenously Self-Administered Cocaine in Rats. Psychopharmacology, 152, pp. 132-139, 2000.

Sex Differences in Nicotine Self-Administration in Rats

Evidence has accumulated that there are sex differences in nicotine use and dependency in humans. However, until now there has been no corroborating evidence in animals. Drs. Eric Donny and Anthony Caggiula at the University of Pittsburgh found that at the lowest dose female rats acquired nicotine self-administration faster than males. Female rats reached higher break points on a progressive ratio schedule of self-administration, and therefore took more nicotine infusions. Female rats displayed a shorter latency before self-administering the first nicotine infusion in a session. No reasons for these differences were found. Self-administration in female rats did not vary with the estrus cycle. Nor were there sex differences in either up-regulation of nicotinic receptor binding sites or in brain or plasma nicotine levels. Donny, E.C., Caggiula, A.R., Rowell, P.P., Gharib, M.A., Maldovan, V., Booth, S., Mielke, M.M., Hoffman, A., McCallum, S. Nicotine Self-Administration in Rats: Estrous Cycle Effects, Sex Differences and Nicotine Receptor Binding. Psychopharmacology, 151, pp. 392-405, 2000.

Opiate Pharmacology and Gender Difference

Dr. Theodore Cicero and his associates demonstrated that morphine served as a positive reinforcer in a place-conditioning paradigm in both male and female rats. However, the dose response curves displayed marked differences by sex. In male rats, morphine at doses above 10 mg/kg ceased to act as a positive reinforcer. Since no gender differences were observed in the blood and brain levels of morphine during the conditioning phase, the investigators suggest that these results may demonstrate intrinsic sex-linked differences in the sensitivity of the CNS to morphine's reinforcing properties. Cicero, T.J., Ennis, T., Ogden, J., and Meyer, E.R. Pharmacology Biochemistry and Behavior, 65, pp. 91-96, 2000.

The Effects of Pain on Morphine Tolerance, Withdrawal and Reward

Although opiates are used primarily for analgesia in the clinical setting, most prior preclinical research on the tolerance, withdrawal and reinforcing effects of these drugs has been conducted in pain-free animals. Recently, Dr. Shepard Siegel and his colleagues from McMaster University in Hamilton, Ontario used a standardized pain-induction procedure in rats. To compare the effect of pain on tolerance, withdrawal and the reinforcing effects of drugs. Tolerance to morphine developed only when it was administered in the absence of pain. After a three-week wash-out period, the rats were again given three days of morphine treatment, with or without pain present, and then challenged with a narcotic antagonist to test for precipitated withdrawal. The rats administered morphine in the presence of pain showed an attenuated withdrawal response. When morphine was paired with a distinct set of environmental cues in the conditioned place preference procedure, both drug groups showed an increase in time spent on the drug-paired side of the chamber in comparison to controls, but this preference was greater for rats administered morphine in the presence of pain. Thus, Dr. Siegel and his colleagues found that pain reduced tolerance to, and withdrawal from, morphine. However, pain enhanced reinforcement as measured by conditioned place preference. While conditioned place preference is not a direct measure of opiate reward, the present observation suggests that pain may enhance the reinforcing effects of morphine. However, the consequences for continued drug-seeking and drug-taking behavior (i.e., abuse liability) remain to be determined. Bardin, L., Kim, J.A. and Siegel, S. The Role of Formalin-Induced Pain in Morphine Tolerance, Withdrawal, and Reward. Experimental and Clinical Psychopharmacology, 8, pp. 61-67, 2000.

Exaggerated Corticosterone Response in Animals More Reactive to Morphine-Conditioned Taste Aversions

Dr. Felipe Gomez and colleagues at Penn State College of Medicine examined parallels between self-administration of reinforcing drugs and the ability of these drugs to condition a taste aversion when paired with distinctive gustatory cues (a "conditioned taste aversion", CTA). Senior author Dr. Patricia Sue Grigson has previously argued that these parallels, among other sources of evidence, suggest that the CTA phenomenon may be attributed to anticipatory contrast (thus reflecting the drug's rewarding properties) rather than to drug aversion. For example, activation of the hypothalamic-pituitary axis (HPA) enhances both self-administration and the development of a CTA. In a recent study these investigators took plasma corticosterone (CORT) samples from rats prior to CTA conditioning with morphine. They found that while some animals more readily acquired a CTA to a saccharin ‘cue' paired with morphine, basal CORT was no different between this group and those acquiring a weaker CTA. However, when rats developing a strong CTA were compared with those who showed a weaker CTA, (i.e., less aversion for morphine, as evidence for more acceptability of the paired gustatory cue), the large suppressers had significantly higher plasma CORT levels following the last morphine-saccharin pairing. This observation is interesting in that basal CORT was not an indicator for which rats would be more likely to develop this classically conditioned association, but those who did acquire a strong CTA also appear to have a stronger conditioned activation of the HPA axis. These results provide further support for a role of endogenous stress systems in reinforcing the effects of this opiate. Gomez, F., Leo, N.A. and Grigson, P.S. Morphine-Induced Suppression of Saccharin Intake is Correlated with Elevated Corticosterone Levels. Brain Research, 863, pp. 52-58, 2000.

Caffeine May Not Contribute to the Flavor of Caffeinated Soft Drinks

Dr. Roland Griffiths at the Johns Hopkins University School of Medicine in Baltimore, Maryland is studying the stimulant, caffeine, as a potential model of drug reinforcement and dependence. He recently examined the concentration of caffeine in cola soft drinks using a sensitive flavor detection procedure, with 25 adult volunteers who were frequent cola drinkers. Commercially available cola drinks were adulterated with additional caffeine in order to test caffeine concentrations from 0.05 to 1.6 mg/mL. The procedure was essentially a forced-choice test with trial-by-trial feedback to compare all of the concentrations versus a caffeine-free cola. The investigators found that at the concentration typically found in commercial colas, 0.1 mg/mL, only 2 of the 25 subjects (8%) could detect a flavor difference. Overall, percent mean trials correct in detecting a flavor difference was at chance (53%) for the 25 subjects. However, at 0.4 mg/mL, subjects correctly detected a difference on 96% of the trials conducted, most often reporting the caffeine-adulterated choice to be extremely unpleasant. Based on observations from these 25 volunteers, the authors suggest that the concentration of caffeine typically found in commercial colas may contribute little to the taste of the beverage and that regular cola consumption in adults may be driven in part by pharmacological properties of the drug caffeine. Griffiths, R.R. and Vernotica, E.M. Is Caffeine a Flavoring Agent in Cola Soft Drinks? Archives of Family Medicine, 9, pp. 727-734, 2000.

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