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Director's Report to the National Advisory Council on Drug Abuse
February, 2002

Research Findings

Behavioral Research

Benzodiazepines Facilitate Heroin Reward

Few studies have been conducted on drug-interactions although polydrug use is common among drug abusers. Popular drug combinations are ethanol plus cocaine (cocaethylene), heroin plus cocaine (speedball), and heroin plus a benzodiazepine. Dr. Aaron Ettenberg completed a study of heroin plus alprazolam (a benzodiazepine) in which the conditioned place preference was used as a measure of drug reward. It was demonstrated that subcutaneously-applied alprazolam, at low doses, produced a leftward shift in the heroin dose-response curve. That is, small non-rewarding dose of benzodiazepine was seen to reliably increase the conditioned place preference produced by a non-rewarding dose of heroin. This confirms the clinical and case reports of human heroin users who pretreat themselves with benzodiazepines as a means of enhancing the rewarding effect of heroin and/or extending their supply of narcotic. Walker, B.M. and Ettenberg, A. Benzodiazepine Modulation of Opiate Reward. Experimental and Clinical Psychopharmacology, 9, pp. 191-197, 2001.

Beyond the Nucleus Accumbens: the Ventral Pallidum

Dopamine innervation of the nucleus accumbens is thought to have a major role in the biological processes underlying the self-administration of many drugs of abuse. Recent data has also suggested that the dopamine innervation of the ventral pallidum may also play an important role. A microdialysis study was done using rats self-administering cocaine. The animals had intravenous jugular catheters for drug self-administration and microdialysis probes aimed into the ventral pallidum. Controls were yoked; that is, they were surgically prepared in an identical fashion but received vehicle infusions when the experimental animals received cocaine. In the self-administering animals, extracellular fluid levels of dopamine and serotonin were elevated throughout the session and the increase was cocaine dose dependent. Extracellular fluid levels of other transmitters were only slightly increased or not at all (GABA, glutamate). The data and other studies from this laboratory indicate that the ventral pallidum plays an important role in psychomotor stimulant self-administration. Sizemore, G.M., Co, C., and Smith, J.E. Ventral Pallidal Extracellular Fluid Levels of Dopamine, Serotonin, Gamma Amino Butyric Acid, and Glutamate During Cocaine Self-Administration in Rats. Psychopharmacology, 150, pp. 391-398, 2000.

Inhalant Effects on Attention and Information Processing.

Epidemiologic tracking systems have detected alarming trends in the abuse of volatile inhalants, especially among adolescents and young adults. In light of this trend, there is increasing concern about the cognitive deficits that have been observed with chronic abuse of these substances. In particular, pronounced negative effects on attentional processes and short-term memory have been reported following repeated intoxication in human abusers and under conditions of occupational exposure. Dr. Jenny Wiley and colleagues at the Medical College of Virginia have been studying the behavioral, cognitive and neurotoxicologal effects of solvent exposure in preclinical models. Recently they exposed rats to vapors of toluene, 1,1,1-tricholorethane, methoxyflurane or flurothyl-m-xylene and measured their behavioral reactions in a pre-pulse inhibition procedure. Normally, animals react with a startle response to the presentation of a loud auditory stimulus. However, when preceded by an initial “pre-pulse”, this behavioral reaction is inhibited, or “gated”. In the pre-pulse inhibition paradigm, a low-intensity auditory stimulus is presented just prior to a second, higher intensity tone, and startle responses are measured to the second tone. The paradigm is routinely used as an assessment of pre-attentional processes in both human and animal studies. None of the vapors tested affected pre-pulse inhibition in this model. Thus, the findings suggest that these volatile solvents do not disrupt cognitive processes by virtue of interfering with attentional stages of information processing. Future studies using repeated exposures are needed to more closely model patterns of human abuse and identify the cognitive mechanisms that are disrupted by inhalants. Wiley J.L., Bowen, S.E., and Balster R.L. Effects of Volatile Inhalants on Sensorimotor Reactivity in Rats. Addiction Biol., 6, pp. 35-43, 2001.

Multi-Dimensional Analysis of Cue-Elicited Craving

Although “craving” is often considered to be a core component of drug addiction, its nature and assessment remain in dispute. The present study examined several new measures of craving, including a behavioral choice measure, a reaction time (RT) measure of cognitive resource allocation, two judgment measures and a novel measure of self-reported urge. Four groups of subjects, predicted to vary in the strength of their cravings, were assessed on these measures. Heavy smokers (HS: at least 21 or more cigarettes/day for 2 years, n=67) and tobacco chippers (TC: 1-5 cigarettes/day on at least 2 days/week for 2 years, n=60), who were either deprived (for at least 7 hours) or minimally deprived (20-25 min) of nicotine, were exposed to smoking cues and control cues. The smoking cue involved holding a lit cigarette. As expected, results indicated that both deprivation state and smoker type tended to affect responses across the multiple measurement domains. For example, deprived smokers reported higher urge scores than minimally deprived smokers, HSs reported higher scores than TCs and deprived HSs reported especially high urge scores relative to the other groups. In addition, TCs reported more positive mood than HSs and minimally deprived smokers reported more positive mood than did deprived smokers. On the choice measure, HSs demanded more money to delay smoking (for 5 min) than did TCs and deprived smokers demanded more money than did minimally deprived smokers. Moreover, deprived HSs demanded the most money, followed by minimally deprived HSs, deprived TCs and minimally deprived TCs. Both HSs and TCs responded slower in the presence of cigarette cues than in the presence of control cues. These findings support the use of several new measures for measuring craving-related processes. Behavioral choice was an especially sensitive measure in this study. Furthermore, magnitude estimation and a composite urge measure were found to be useful approaches when initial deprivation produces ceiling effects. Finally, judgment measures that are sensitive to assessing how craving alters reasoning provide promising tools for examining cognitive dimensions of craving. Sayette, M.A., Martin, C.S., Wertz, J.M., Shiffman, S., and Perrott, M.A. A Multi-dimensional Analysis of Cue-elicited Craving in Heavy Smokers and Tobacco Chippers. Addiction, 96, pp. 1419-1432, 2001.

Effects of d-Amphetamine and Alcohol on Behavioral Inhibition

Drs. Harriet de Wit, Jerry Richards and colleagues have been investigating the effects of drugs of abuse on cognitive inhibitory processes in parallel studies with human and animal subjects. These studies are of interest because drug abuse and addiction have long been associated with “impulsive” behavior patterns. Indeed, impulsive individuals are hypothesized to be predisposed to use drugs. Little is known, however, about the acute effects of psychoactive drugs on impulsive behavior. One factor that has hampered progress in this area is the lack of an agreed upon definition of impulsivity. These studies investigated the acute effects of drugs on one operationally defined measure of impulsivity in humans and the companion study investigated the effects of the same drugs in a parallel procedure in rats. Human subjects with a history of psychostimulant or alcohol abuse were treated with d-amphetamine (AMP: 10 and 20 mg, n=20) or ethanol (EtOH: 0.2, 0.4, and 0.8 g/kg, n=17) and assessed on a computerized “stop” task, a putative measure of behavioral inhibition and impulsivity. The stop task provides a measure of the reaction time (RT) needed to inhibit a response (Stop RT) relative to the time taken to execute a simple response (Go RT). Subjects performed the stop task before and after receiving one of the drugs. AMP decreased Stop RT (i.e., facilitated inhibition) but only among participants with relatively slow Stop RT baselines. EtOH increased Stop RT (i.e., impaired inhibition) at doses that did not affect Go RTs. These results suggest that AMP and EtOH have specific and opposite effects on the ability to inhibit responses. de Wit, H., Green, J., and Richards, J.B. Effects of d-Amphetamine and Ethanol on a Measure of Behavioral Inhibition in Humans. Behavioral Neuroscience, 114 (4), pp. 830-837, 2000.

In a parallel preclinical study, the researchers developed a stop task procedure for use in rats and assessed the effects of AMP and EtOH on behavioral inhibition. This task provides a quantitative index of the ability to inhibit a response that has been initiated. Rats were tested after intraperitoneal injections of AMP (0.125, 0.25, 0.5, 1.0 mg/kg) and EtOH (250, 500, 750 mg/kg). As in humans, AMP improved the ability to inhibit responses only in rats with relatively poor inhibitory performance at baseline, whereas EtOH impaired inhibition at doses that did not affect simple RT. These results support the sensitivity, reliability, and validity of the procedure as a measure of behavioral inhibition in rats and they are highly concordant with the parallel study conducted with humans. The establishment of the stop task in rats provides an important approach for studying neurobiological processes that mediate behavioral inhibition and substrate changes responsible for drug effects on these cognitive mechanisms. Feola, T.W., de Wit, H., and Richards, J.B. Effects of d-Amphetamine and Alcohol on a Measure of Behavioral Inhibition in Rats. Behavioral Neuroscience, 114 (4), pp. 838-848, 2000.

Triazolam Improves Memory Through Effects on Automatic Processes

In addition to their well-known amnestic effects, benzodiazepines (BZPs) have been shown to improve memory. Thus, memory enhancement might contribute to the motivation for BZP abuse. It is important, therefore, to understand the mechanisms responsible for these BZP effects. If subjects receive a BZP immediately after studying to-be-remembered material, memory for the information is improved (retrograde facilitation) when tested in the drug state. This is an important finding because it demonstrates, (contrary to so-called ‘state-dependent’ learning), that a drug can be used after the fact to enhance memory even when the original learning occurred in the drug-free state. Previous research has shown that this retrograde facilitation of memory is not due to suppression of new learning that might interfere retroactively with recall. Rather the facilitation affects some aspect of memory retrieval. The present study tested the degree to which BZP-induced retrograde facilitation of recall is due to enhancement of an automatic (nonconscious, unintentional), as opposed to a controlled (conscious, intentional), retrieval processes. Forty healthy adults were randomly assigned to one of three dose conditions (double-blind), under which they received 0 mg (placebo), 0.125 mg, or 0.25 mg of the short-acting BZP, triazolam. Subjects studied a list of words just prior to drug administration. One hour later, subjects were tested using a word-stem completion task. This commonly used test of implicit memory involves studying a list of nouns (e.g., motel), followed by a test in which the subjects are cued with a word stem (e.g. mot--) which can be completed in one of several ways (e.g., motel, motor, motif or motto). Automatic influences on memory are inferred when there is a greater probability of completing a stem with a previously studied word than with an unstudied word. In this study, the investigators estimated the degree to which retrieval was under the influence of memory processes that were automatic versus controlled. Results revealed that those who received active doses of triazolam had a higher probability of using studied words as stem completions, implicating greater use of automatic influences during memory retrieval under triazolam. These findings indicate that retrograde facilitation of memory following BZP administration does not necessarily reflect an improved ability to intentionally retrieve information but could instead reflect increased responsiveness to cues that automatically elicit retrieval of pre-drug information. Fillmore, M.T., Kelly, T.H., Rush, C.R., and Hays, L. Retrograde Facilitation of Memory by Triazolam: Effects on Automatic Processes. Psychopharmacology, 158, pp. 314-321, 2001.

Methylphenidate Treatment of Adolescent Rats Enhances Behavioral Reactivity and Vulnerability to Self-Administer Cocaine as Adults

The recent dramatic increase in the use of methylphenidate (MP; Ritalin‘) to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents has raised the question of whether long-term exposure to this psychostimulant might lead to increased vulnerability for drug abuse disorders. Epidemiological studies have yielded conflicting answers to this important question, and previous studies in animal models have also been inconclusive, in part because of controversy about whether the MP dosages tested in rats have replicated therapeutic levels in humans. In a recent study, Dr. Cindy Brandon, a NIDA NRSA postdoctoral fellow in Dr. Frank White’s laboratory, developed an animal model to assess whether repeated exposure to MP during adolescence enhances locomotor stimulant effects of cocaine and increases vulnerability to self administer this drug in adulthood. Adolescent rats (5-weeks old – age equivalent to the beginning of adolescence) received seven daily injections of moderate doses (10 mg/kg or 5 mg/kg) of MP and were then tested as adults (8-weeks old) for their response to a single dose of cocaine. The pre-exposure to MP significantly increased sensitivity to the locomotor activating effects of the cocaine, a phenomenon known as cross sensitization. In a separate experiment intended to emulate more closely dosing regimens in humans and associated plasma drug concentrations, the investigators pretreated adolescent rats with a low dose of MP (2 mg/kg) and challenged them with various doses of cocaine. The rats showed no cross sensitization at any of the cocaine doses, but when they were tested in a self-administration (SA) protocol, they acquired SA at the low cocaine dose of 75 mg/kg and showed enhanced intake of cocaine compared to control animals pretreated with saline. Thus, animals exposed to the low dose of MP during adolescence appeared considerably more vulnerable to the reinforcing effects of cocaine as adults even though they did not show locomotor cross sensitization. The results of this study suggest that known neuroadaptations produced by therapeutic treatment with MP, such as decreased dopamine transporter binding, may increase drug abuse vulnerability. Brandon, C.L., Marinelli, M., Baker, L.K. and White, F.J. Enhanced Reactivity and Vulnerability to Cocaine following Methylphenidate Treatment in Adolescent Rats. Neuropsychopharmacology, 25, pp. 651-661, 2001.

Sexual Experience Activates Neurons in the Nucleus Accumbens and Cross Sensitizes Female Hamsters to the Behavioral Effects of Amphetamine

Dopamine transmission in the nucleus accumbens from neurons originating in the midbrain ventral tegmental area is important both for the regulation of appetitive behaviors and for self-administration of drugs of abuse. Dr. Robert Meisel and his graduate student Katherine Bradley recently carried out a study to examine the effects of female sexual experience on cellular activity in the nucleus accumbens and to determine whether previous sexual experience could sensitize animals to the behavioral effects of amphetamine. They found that sexual activity elevated c-Fos induction (a measure of neuronal activity) in the core, but not the shell, of nucleus accumbens. Drugs of abuse have most often been observed to activate neurons in the shell of nucleus accumbens. Nevertheless, the investigators were able to demonstrate that prior sexual activity made female hamsters more sensitive to the locomotor effects of amphetamine. These experiments in female animals join a growing list of studies indicating that the prior experiences of an animal -- such as exposure to mild stress, environmental novelty, or highly palatable food, and male sexual behavior -- can sensitize the responsiveness of the mesolimbic dopamine pathway to the effects of drugs of abuse. Research on cross-sensitization between experience and drug effects may shed light on the neural mechanisms underlying individual vulnerability to the effects of drugs. Bradley, K.C. and Meisel, R.L. Sexual Behavior Induction of c-Fos in the Nucleus Accumbens and Amphetamine-stimulated Locomotor Activity are Sensitized by Previous Sexual Experience in Female Syrian Hamsters. Journal of Neuroscience, 21, pp. 2123-2130, 2001.

Common Areas of Prefrontal Cortex are Activated by Environments Associated with Either Nicotine or Chocolate

In humans, a specific environment or the sight of objects associated with prior drug use can trigger craving and relapse. Corollary responses to drug-associated cues have also been demonstrated in animals. Such reactions to drug-associated environments may be maladaptive, but the general phenomenon of learning about environmental cues that predict the availability of, for example, a food source, and the activation of appetitive behaviors in the presence of such cues, has an obvious adaptive value for an organism. In a recent study, Dr. Anne Kelley and her colleagues sought to determine whether similar neural circuits would be activated by cues associated with nicotine and a naturally rewarding palatable food, chocolate. In the first experiment, rats were treated with either nicotine (0.4 mg/ml/kg) or saline once per day for 10 days in a test environment distinct from their home cages. In the second experiment rats were given access to either a bowl of chocolate chips or an empty bowl in the distinct environment for 10 days. After a 4-day interval, rats were re-introduced to the environment where they previously received either nicotine treatment or chocolate access. Nicotine-associated sensory cues elicited marked and specific activation of Fos (an “immediate early gene” that serves as a marker for neural activation) expression in prefrontal cortical and limbic regions. Exposure to cues associated with the chocolate induced a pattern of gene expression that showed similarities with that elicited by the drug cues, particularly in the ventrolateral orbital area, and other areas, of the prefrontal cortex. Previous experiments have shown an overlapping pattern of neural activation in morphine- and cocaine-associated environments. Taken together, the previous results and those of the current experiment, in which nicotine and chocolate were explicitly compared, support the hypothesis that addictive drugs induce long-term changes in brain regions that subserve normal learning and memory for motivationally salient stimuli, especially within the prefrontal cortex. Schroeder, B.E., Binzak, J.M., and Kelley, A.E. A Common Profile of Prefrontal Cortical Activation following Exposure to Nicotine- or Chocolate-associated Contextual Cues. Neuroscience, 105, pp. 535-545, 2001.

Selective Disruptions of Serotonergic (5-HT) Function May Produce Mood Disruptions seen During Abstinence from Chronic Cocaine

Abstinence from chronic cocaine abuse in human addicts has been associated with a range of mood disturbances, including increased depression, anxiety and irritability. While cocaine induces its subjective and behavioral effects via inhibition of monoamine reuptake in central dopaminergic (DA) and serotonergic (5-HT) systems, little is known about the neurochemical changes in abstinence giving rise to these mood disturbances. Preclinical studies have revealed reductions in central DA and 5-HT levels following chronic cocaine exposure in the rat. Dr. M. Haney and her colleagues recently used an indirect measure of central 5-HT and DA activity to study neurochemical perturbations during abstinence from cocaine in human addicts. These researchers assessed prolactin and cortisol release in response to challenge with the 5-HT releaser and reuptake inhibitor, d-fenfluramine (d-FEN). Previous research has demonstrated that neuroendocrine response to 5-HT agonists such as d-FEN are blunted in clinically depressed populations, suggesting that this challenge is potentially useful for assessing the neurochemical substrate changes giving rise to mood disturbances during abstinence. In this study, cocaine-dependent subjects who were not seeking drug abuse treatment were allowed to self-administer “crack” cocaine in an inpatient setting over a three day bout. Neuroendocrine challenges with d-FEN were performed during 2-weeks of abstinence following this three day bout. A separate group of addicts was challenged with the DA agonist, bromocriptine, to assess sensitivity of the central DA system (which regulates prolactin release), during abstinence. Results show that abstinent cocaine addicts had a similar stimulation of prolactin upon DA stimulation as non-addicted control subjects. However, while d-FEN administration to non-addicts induced profound increases in both prolactin and cortisol, abstinent addicts showed a blunted response to 5-HT agonist challenge on both neuroendocrine measures. These observations suggest that central DA systems in cocaine addicts appear normal over 2 weeks following cessation of a cocaine binge. However, the central 5-HT systems regulating neuroendocrine activity appear to be suppressed for at least 14 days after drug cessation. The authors conclude that hypoactivity of central 5-HT systems may underlie the mood disturbances seen in abstinent cocaine addicts. Haney, M., Ward, A.S., Gerra, G. and Foltin, R.W. Neuroendocrine Effects of d-fenfluramine and bromocriptine following Repeated Smoked Cocaine in Humans. Drug and Alcohol Dep., 64, pp. 63-73, 2001.

Repeated Maternal Separation in Neonatal Rats Alters Sensitivity to Chronic Morphine in a Sex-Dependent Manner

Research has shown that neonatal rat pups separated from their mothers for several hours each day, during the first few weeks of life, subsequently exhibit elevated stress-reactivity during adulthood. Exaggerated responsivity is evident from both behavioral and physiological indices. Moreover, animals exposed to early separation distress with this paradigm are also more sensitive to the locomotor activating effects of acute psychostimulant drugs and are more vulnerable to acquire psychostimulant self-administration. Dr. Steve Holtzman and his colleagues at Emory University School of Medicine have been examining the behavioral and physiological effects of opiates in animals exposed to the early separation procedure, and using this paradigm to uncover influences of early post-natal stress on neuroadaptations to chronic drug administration. These investigators report that 3 hours of separation from the dam, in comparison to handled and nonhandled controls, alters subsequent sensitivity to morphine’s antinociceptive effects. Notably, after this extended period of early separation, male but not female offspring were less sensitive to the antinociceptive effects of morphine. Also, the development of tolerance to antinociceptive effects was enhanced in males exposed to early maternal separation, but not in females. In both male and female rats, daily 3 hour maternal separations over 12 days was also associated with an increase in the severity of withdrawal from chronic morphine, suggesting the development of a greater degree of opiate dependence in animals exposed to early maternal separation. The authors speculate that maternal separation alters morphine sensitivity via stress-induced stimulation of opioid peptides in separated pups, providing additional evidence that early deleterious environmental influences may have an impact on subsequent response to drugs of abuse. Kalinichev, M., Easterling, K.W. and Holtzman, S.G. Early Neonatal Experience of Long-Evans Rats Results in Long-Lasting Changes in Morphine Tolerance and Dependence. Psychopharmacology, 157, pp. 305-312, 2001.

Progesterone Effects in Healthy Postmenopausal Women and Normally-Cycling Women

There is accumulating evidence that the stage of the menstrual cycle influences subjective responses to abused drugs. Certain neurosteroid metabolites of progesterone, e.g. allopregnanolone, are known to bind to the GABA-A receptor and there has been some evidence that they produce sedative-like effects, suggesting that progesterone may have behavioral and subjective effects in women and could perhaps influence responses to abused drugs in women. Dr. Harriet de Wit and her colleagues at the University of Chicago examined the behavioral and subjective effects of acute injections of progesterone in two groups of women, healthy normally cycling women and postmenopausal women. Normally cycling women (n=10) who were not on hormone replacement received a single injection of progesterone (100 mg im) or placebo in two sessions conducted a month apart during the follicular phase when endogenous progesterone and estrogen are low. Postmenopausal women (n=10) received progesterone (25, 50, 100 mg im) or placebo at four one-week intervals. Extensive behavioral assessments (including measures of motor, cognitive, and memory impairment) and evaluations of subjective effects (including mood and physiological states) were conducted following each injection. The progesterone injections produced time and dose-related increases in plasma concentrations of progesterone and allopregnanolone that were similar in the two groups. Yet, the behavioral and subjective effects were only modest. In cycling women there were mild sedative effects consisting of a decrease in ratings of “vigor,” “friendliness,” and “arousal,” and paradoxically, there was a small improvement on the motor task (digit-symbol substitution test). In post-menopausal women, only the highest dose (100 mg) slightly increased ratings of feeling “sluggish” and in “positive mood.” These modest sedative-effects occurred at plasma concentrations well beyond those attained during normal menstrual cycles and suggest that brief increases (i.e., several hours) in plasma levels of allopregnanolone produce only marginal sedative-like effects. The authors suggest that the allopregnanolone may produce stronger sedative-like effects only in other phases of the menstrual cycle or when estrogen is present, or alternatively, only in certain vulnerable populations, such as women with anxiety disorders. These results indicate that allopregnanolone can affect subjective states in women, albeit weakly, and could play a role in the changes in the response to abuse drugs across the menstrual cycle. de Wit, H., Schmitt, L., Purdy, R. and Hauger, R. Effects of Acute Progesterone Administration In Healthy Postmenopausal Women and Normally-Cycling Women. Psychoneuroendocrinology, 26, pp. 697-710, 2001.

Triazolam Impairs Inhibitory Control of Behavior in Humans

Benzodiazepines (BZPs) are prescribed widely in the treatment of anxiety and insomnia, but they have high potential for abuse and dependence. In addition, they are hypothesized to produce adverse behavioral outcomes (e.g., aggressiveness) by causing a loss of control over behavior. This loss of control is manifested as an inability to inhibit responding, called disinhibition. Triazolam (TZM) is a short-acting BZP that has received considerable publicity for its association with aggressive, criminal and other socially inappropriate acts. To date, however, there have been few controlled laboratory studies of triazolam on behavioral control in humans. The present study used the stop-signal paradigm to directly measure the ability of triazolam to disinhibit responding (i.e., activate a suppressed response), without increasing behavioral arousal (i.e., non-specifically activating all responses). The stop-signal paradigm engages individuals in responding to “go” signals and occasionally requires them to inhibit the response when a “stop” signal occurs. The present study was designed to test the hypothesis that triazolam impairs the ability to inhibit responding. The effects of two doses of triazolam (0.125 mg and 0.25 mg) were tested in a double blind, placebo-controlled design. During the stop-signal task, subjects were instructed to press one of two keys on the keyboard as quickly and as accurately as possible to the presentation of the letters on a computer monitor (a “go” response), but to withhold a response when a tone sounded (a “stop” response). Subjects were tested on this task 70 min, 120 min and 180 min after drug ingestion. The results showed that compared with placebo, triazolam reduced the number of inhibitions to stop signals and increased the RT to inhibit a response on each of the three tests. The results also indicated that triazolam increased go RT after the highest dose (0.25 mg), but that this effect only emerged 3 hr after TZM administration. These findings indicate that triazolam can impair the ability to inhibit behavioral responses and the ability to execute responses. The impairing effects of triazolam on inhibitory control of behavior resemble those observed after a moderate dose of alcohol. Fillmore, M.T., Rush, C.R., Kelly, T.H., and Hays, L. Triazolam Impairs Inhibitory Control of Behavior in Humans. Experimental and Clinical Psychopharmacology, 9, pp. 363-371, 2001.

Behavioral Economics of Human Drug Self-administration: Progressive Ratio versus Random Sequences of Response Requirements

Progressive-ratio (PR) schedules have been used widely to examine the relationship between drug consumption and drug price (i.e. demand curves) in the study of the behavioral economics of drug abuse. Sequential effects produced by the increasing response requirements of progressive-ratio schedules might influence the shape of demand curves for drug reinforcers. This study compared progressive, ratio schedule and random sequences of ratio requirements, each incremented across sessions in a within-subject design, to determine if they produced similar behavioral economic and traditional measures of reinforcer efficacy. Self-administration of standardized cigarette puffs (70 cc each) was studied with eight smokers. Puffs were available at nine ratio requirements (e.g. 3, 100, 300, 600, 1500, 3000, 6000, 12,000, 24,000 responses/three puffs), presented in ascending (progressive-ratio schedule) or random sequence across daily sessions. The parameter estimates obtained on measures of reinforcing efficacy (e.g. breakpoint, peak response rates, elasticity of demand) were similar for both methods of incrementing prices. The authors found no evidence the PR and random sequences of fixed-ratio (FR) schedules, incremented across daily sessions, resulted in difference demand curves. Giordano, L.A., Bickel, W.K., Shahan, T.A., and Badger, G.J. Behavioral Economics of Human Drug Self-administration: Progressive Ratio Verses Random Sequences of Response Requirements. Behavioral Pharmacology, 12 (5), pp. 343-347, 2001.

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