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Director's Report to the National Advisory Council on Drug Abuse - September, 2003

Research Findings - Behavioral Research

Neurotoxicity Produced by High Dose METH may Enhance Subsequent Psychostimulant Reinforcement

NIDA-grantee, Dr. Michael Bardo, and colleagues at the University of Kentucky have followed up on earlier studies investigating the behavioral consequences of a neurotoxic regimen of methamphetamine (METH) treatment in the rat. They note that previous investigations showing decreases in central dopamine (DA) are paralleled by deficits in active avoidance, balance beam performance, and the Morris water maze task. Animals treated with such a dosing regimen also have decreased locomotor activity in response to acute METH. However, the functional consequences of high dose METH treatment in central transmitter systems that subserve drug reward are presently unknown. To address this question, the researchers treated rats with four injections of D-METH HCl (10 mg/kg each), separated by 2 hours between injections. In the first neurochemical study, rats were sacrificed 15 days later and it was determined that DA was significantly depleted in the nucleus accumbens (NAS) and striatum; and serotonin (5-HT) was significantly depleted in the NAS, striatum and prefrontal cortex. In the second study, locomotor response to challenge doses of 0.1, 0.3 or 1.0 mg/kg METH, and the development of a conditioned place preference (CPP) to this stimulant, was assessed at 5 days post high-dose treatment. Unlike previous reports in the literature, locomotor activity measured during four conditioning sessions in the CPP apparatus was no different for animals previously treated with neurotoxic doses of METH or with saline. Rats treated with saline before the CPP training was begun developed a preference for the side of the box paired with 1.0 mg/kg METH. However, rats that underwent a neurotoxic dosing schedule with high-dose METH prior to CPP also showed a significant place preference to the side paired with a lower METH dose (0.3 mg/kg). These findings suggest that the neurochemical alterations induced by neurotoxic doses of METH enhance sensitivity to the drug's rewarding properties, when assessed using responses to incentive motivational stimuli (i.e., the environmental cues previously paired with drug). The authors suggest that an upregulation of DA receptors (compensatory to DA terminal loss), or depletion in 5-HT systems that are inhibitory on central reward systems, may be responsible. Further investigation is needed to extend these findings to other models of drug reinforcement per se, and explore the underlying mechanism responsible for this behavioral effect. Gehrke, B.J., Harrod, S.B., Cass, W.A. and Bardo, M.T. The Effect of Neurotoxic Doses of METH on METH-Conditioned Place Preference in Rats. Psychopharmacology, 166, pp. 249-257, 2003.

Perinatal Lead Exposure and Relapse to Drug-Seeking Behavior in the Rat: A Cocaine Reinstatement Study

Prior work published by Dr. Jack Nation and his colleagues at Texas A&M University has shown that perinatal lead exposure enhances cocaine-induced locomotor sensitization. He now reports that perinatal lead exposure enhances cocaine reinstatement, measured in a paradigm that is regarded to be a preclinical model of drug-seeking and relapse. Female rats were gavaged with either 0 or 16 mg lead prior to mating and this exposure procedure was continued through gestation and postnatal day 21. At postnatal day 120, male offspring were trained to self-administer cocaine. Following acquisition of steady-state responding, cocaine restatement was assessed over a 5-hour session in which cocaine self-administration occurred during the first hour, extinction via replacement of cocaine with saline occurred in hours 2-4, followed by a priming i.p. injection of either 0.00, 5.00, 10.00, or 20.00 mg/kg cocaine with assessment of drug-induced reinstatement in hour 5. During hour 5, both the lead-exposed and non-lead-exposed rats exhibited a dose-related increase in saline responding, indicative of "drug-seeking" behavior elicited by environmental cues previously paired with drug reward. The lead-exposed group, however, exhibited more saline responding than the non-lead-exposed group following priming doses of 5.00 and 10.00 mg/kg. These results indicate that low levels of lead exposure during gestation and lactation are associated with enhanced vulnerability to cocaine relapse in response to reintroduction of the drug cue. In the same paper, Dr. Nation cites unpublished data from his research program showing that adult rats with a history of perinatal lead exposure self-administer more low-dose cocaine than non-lead-exposed rats. The mechanism underlying perinatal lead exposure's effects on cocaine sensitivity and vulnerability in adulthood is not known, but Dr. Nation suggests that it could be mediated by lead's direct effects on maternal behavior or by lead's direct effects on the pups which then modulate maternal behavior. Such early pup/dam behavioral interactions could alter motivational circuits expressed in adulthood as enhanced cocaine vulnerability. In view of human data indicating that lead exposure during pregnancy and lactation can produce significant developmental and neurological abnormalities, the present data are particularly important, especially given that 1999 survey data shows approximately 70% of inner-city children have "unsafe" blood lead levels and that this percentage is even higher for urban minority children. Nation, J.R., Cardon, A.L., Heard, H.M., Valles, R., and Bratton, G.R. Perinatal Lead Exposure and Relapse to Drug-Seeking Behavior in the Rat: A Cocaine Reinstatement Study. Psychopharmacology, 168, pp. 236-243, 2003.

The Effects of Alprazolam and Buspirone in Light and Moderate Female Social Drinkers

Benzodiazepines are prescribed to women almost twice as often as men. Additionally, women are more likely than men to become dependent on sedatives. Ongoing laboratory-based research by Dr. Suzette Evans and her colleagues at Columbia University is investigating sub-populations of women who may be at risk for anxiolytic abuse. One such population is moderate social drinkers. Several laboratory-based studies have shown a relationship between the positive reactions to the anxiolytic diazepam (a benzodiazepine) and degree of alcohol use. Those studies, however, did not examine data separately for females nor did they control for a family history of alcoholism. In the present study, Dr. Evans and her colleagues compared the subjective and cognitive/motor performance reactions to the anxiolytic benzodiazepine alprazolam (0.25, 0.50, 0.75 mg) in 14 female light social drinkers who consumed four drinks per month and 14 female moderate social drinkers who consumed 36 drinks per month. All subjects were non-drug abusing, without substance abuse problems, and had no first- or second-degree family history of alcoholism. Buspirone (5, 10, 15 mg), a non-benzodiazepine anxiolytic of low abuse liability and minimal performance effects, was studied as a comparison drug. The researchers found that the two anxiolytics produced similar cognitive/motor impairment. The impairment was dose-related for alprazolam, but not buspirone. Both anxiolytics produced greater "Drug Liking" and "Good Drug Effect" in moderate drinkers than in light drinkers. The moderate drinkers, but not the light drinkers, however, also reported more positive reactions to the placebo. These data suggest that female social drinkers may be more likely have enhanced psychoactive drug expectancies and to report positive subjective reactions that can contribute to vulnerability for addiction. Evans, S.M. and Levin, F.R. The Effects of Alprazolam and Buspirone in Light and Moderate Female Social Drinkers. Behavioural Pharmacology, 13, pp. 427-439, 2002.

Beta-Endorphin and Enkephalin Knock-Out Mice Show a Selective Reduction in Incentive Motivational Value of Food Rewards

Dr. Malcolm Low and colleagues have recently published an elaborate series of NIDA-funded investigations to determine how endogenous opioids modulate natural rewards. They tested groups of mice who were either B-end (beta-endorphin) deficient, met- and leu-enkephalin deficient, double knock-out, or male wild-type in progressive ratio (PR) procedures to obtain "normal", "sweet", or "fat" food pellets for bar press responses in an operant chamber. All three knock-out groups responded significantly less for food reward than their wild-type counterparts, when maintained on ad libitum feeding conditions. Thus, break-points (the number of operant responses an animal is "willing" to make to earn a food reward) were significantly less for these three knock-out groups. While there was a gradient for food preference of these three types of pellets, there was no difference in preference over the four groups. By contrast, when tested in PR procedures at 75-85% of their previous free-feeding body weights, all four groups responded for the three types of pellets with break-points that were not significantly different. The authors conclude that these endogenous opioid systems play a role in incentive motivational properties of food, or the hedonic quality of the food, rather than being important for caloric regulation or homeostatic balance. This was true even with three different food rewards that differ in palatability. In additional experiments, the Principal Investigator (PI) also was able to show that knock-out mice could work just as hard for food on a FR schedule (hence, were not motorically impaired), did not make more inappropriate responses on the inactive lever than their wild-type controls (thus, learned the operant task), and in a similar one-hour test session, all groups continued to bar press at an equivalent rate for food and consumed pellets throughout the session (suggesting that knock-out groups did not satiate sooner). Because PR schedules use an extinction criterion as an endpoint, the PI also conducted an independent assessment of resistance to extinction. In this study, he found that all four groups showed the same extinction curve when responding under a PR schedule. These separate control studies strengthen the investigators' interpretation of differences between knock-out and wild-type mice during PR operant testing under food satiation conditions. Thus, these endogenous opioid systems seem to be important for appetitive aspects of behavior directed toward food rewards, rather than for consummatory behaviors per se. Hayward, M.D., Pintar, J.E. and Low, M.J. Selective Reward Deficit in Mice Lacking B-Endorphin and Enkepahlin. J. Neurosci., 22, pp. 8251-8258, 2002.

Effects of THC on Behavioral Measures of Impulsivity in Humans

Drugs of abuse have been associated with poorly controlled, maladaptive behaviors that have been described as impulsive. Research on the effects of drugs of abuse on impulsive behavior has been hampered, in part, because there is no universally accepted measure of impulsivity. The purpose of the present study was to examine the effects of THC on four behavioral measures of impulsivity in male and female recreational marijuana users. The four tasks were: The Stop task, which measures the ability to inhibit a prepotent motor response; a Go/No-Go task, which involves reward/punishment conflict and the ability to inhibit a punished response; a Delay Discounting task, which measure the value of delayed or uncertain reinforcers; and a Time Estimation task, which measures alterations in time perception. Subjects also completed mood questionnaires and general measures of performance. Results indicated that THC produced increases in euphoria and responses on the marijuana scales of the ARCI (Addiction Research Center Inventory). In addition, THC increased impulsive responding on the Stop task, but had no effect on the Go/No-Go task or the Delay Discounting task. THC decreased patterns of impulsive responding on the Time Estimation task. There were no effects of gender alone or in interaction with the four tasks. There were no significant correlations among the four measures of impulsivity, suggesting that multiple processes underlie impulsive behavior, and that THC affects some, but not all, of these processes. These findings emphasize the importance of using multiple measures when investigating impulsive behavior. To say that drugs of abuse affect impulsivity, without specifying how impulsivity is measured, may not give an accurate or meaningful description of the drug's effects. Mcdonald, J., Schleifer, L., Richards, J.B., and deWit, H. Effects of THC on Behavioral Measures of Impulsivity in Humans. Neuropsychopharmacology, 28, pp. 1356-1365, 2003.

Repeated Exposure to Nicotine Facilitates Reward-Related Learning

Repeated exposure to drugs of abuse causes neuroadaptive changes in brain circuits that may comprise the neurobiological substrate for incentive-motivational processes and reward-related learning. Drug-induced alterations may contribute to the process of drug addiction because the combination of enhanced incentive motivation (i.e., increased salience of drug-associated cues), and increased stimulus control over behavior by drug-associated cues, can drive compulsive drug-seeking and drug-taking. The present study investigated the effects of repeated exposure to nicotine on the acquisition and performance of a Pavlovian discrimination task. Water deprived rats were trained to associate a light/tone CS (conditioned stimulus) with the presentation of a water reward in 15 consecutive sessions. Approach to the CS and the water served as the measure of learning. Separate groups of rats were repeatedly treated with nicotine (0.35 mg/kg, s.c.) either (1) prior to the onset of training, (2) after each daily training session, or (3) both prior to onset of training and after each daily training session. Results indicated that all nicotine treatment schedules increased discriminative approach behavior. This work demonstrates that systemic nicotine administration facilitates appetitively motivated stimulus-reward learning in the rat, and suggests that nicotine augments the control over behavior by reward-associated stimuli. These results contribute to understanding nicotine abuse and addiction since smoking-related cues elicit craving and can trigger relapse during nicotine abstinence. Olausson, P., Jentsch, J.D., and Taylor, J.R. Repeated Nicotine Exposure Enhances Reward-Related Learning in the Rat. Neuropsychopharmacology, 28, pp. 1264-1271, 2003.

Prolonged Deficits in Associative Learning for Natural Rewards Following Opiate Withdrawal

Opiate abuse has been associated with cognitive deficits in human addicts. To determine if prior opiate exposure alters the ability to learn, Dr. Glenda Harris and Dr. Gary Aston-Jones tested animals during morphine withdrawal in several learning tasks for food reward. The first experiment involved learning to press a bar for food. During a 2-week period after withdrawal, morphine-abstinent rats were significantly slower at learning an escalating fixed-ratio response for food reward compared to placebo-treated animals. In another experiment, morphine-abstinent rats withdrawn 2 or 5 weeks were tested for their ability to associate a highly palatable food reward with a specific environment using a place-conditioning paradigm. At 2 weeks post-withdrawal, morphine-abstinent rats did not show any significant place preference for a food they readily consumed, while placebo-treated rats readily learned to prefer the food-paired environment. At 5 weeks post-withdrawal, abstinent rats developed significantly less preference for food-associated cues, but more preference for morphine-associated cues, compared to placebo-treated animals. The results of these two experiments indicate that, during protracted abstinence, animals are slower to learn to respond for food reward, and slower to learn about environmental cues that predict food reinforcement, while at the same time they readily learn about cues that are predictive of morphine reward. To determine whether the learning deficits of withdrawn animals was limited to the positive reinforcement of natural rewards, animals from the first experiment were also trained in a conditioned suppression paradigm (two tone-shock pairings given in the operant box). Morphine-withdrawn animals were not impaired in this aversive conditioning, and in fact showed greater retention than control animals. The results of these experiments are consistent with hypotheses implicating post-withdrawal dysregulation of hedonic processing as a factor that may compromise the ability of former addicts to overcome their addictions. Harris, G.C. and Aston-Jones, G. Altered Motivation and Learning Following Opiate Withdrawal: Evidence for Prolonged Dysregulation of Reward Processing. Neuropsychopharmacology, 28, pp. 865-871, 2003.

Rats in Withdrawal from Amphetamine Show Increased Impulsivity and Impaired Inhibitory Control

Impulsivity is thought to contribute to relapse to drug abuse. The prefrontal cortex (PFC) is involved in the inhibitory control of impulsive behavior, and the dopaminergic input to PFC is critical for this function. A previous collaborative electrophysiological study from the laboratories of Drs. Frank White and Marina Wolf at the Chicago Medical School showed that the inhibitory effect of dopamine on the firing rate of medial PFC neurons was reduced in rats following repeated amphetamine treatment. They have followed up with a behavioral study to determine if impulsivity is increased after amphetamine treatment. They used a behavioral task called differential reinforcement for low rates of responding (DRL30), in which rats are trained to inhibit a nose poke response for 30 seconds, after which a nose poke results in food reward. An inactive hole was also provided to assess non-specific effects on overall nose poking behavior. After training, the rats received 5 days of daily saline or amphetamine injections. Following 3 days of withdrawal, performance on the DRL30 task was tested for 9 days. Throughout the 9 days, nose poking by amphetamine-withdrawn animals was elevated compared to saline controls, significantly so on withdrawal days 3, 6, and 7. On the first day of post-withdrawal testing, but not on subsequent days, previously amphetamine- treated animals also nose poked more often in the inactive hole. Amphetamine pretreatment also increased the number of times rats nose poked before the 30 seconds were up; that is, made a greater number of responses that were not reinforced in this paradigm. Therefore, previous drug treatment significantly reduced "training efficiency," defined as the percent of nose pokes that result in reward. The DRL task has been used in a wide variety of studies and is thought to reveal a specific aspect of impulsiveness, termed inhibitory control -- the ability to inhibit or delay a voluntary behavior. The results of this experiment, combined with the previous results, suggest that this aspect of impulsivity is increased during amphetamine withdrawal as a result of disruption of dopamine function in the medial PFC. Peterson J.D., Wolf M.E., and White F.J. Impaired DRL 30 Performance During Amphetamine Withdrawal. Behavioural Brain Research 143, pp. 101-108, 2003.

Cannabinoid Exposure Alters Vocal-Motor Learning in a Songbird

Song learning in birds is an established model system that has been used to study the neurobiology of critical period learning and sensori-motor development. Song is learned in two stages: first, a young bird memorizes the song of an adult "tutor" and then later, during a period equivalent to adolescence, it begins to vocalize and practices its song until it is a near match to the tutor song. At that point, the song becomes "crystallized" and is usually produced in a highly stereotyped manner for the rest of the bird's life. Dr. Ken Soderstrom has been exploiting this system to investigate the role of endocannabinoids and the effects of exogenous cannabinoids in this well-defined type of learning. Previously, Dr. Soderstrom and his co-investigator, Dr. Frank Johnson found that the CB1 cannabinoid receptor is densely expressed in areas of the songbird brain known to be involved in song learning and production. Now they have shown that daily cannabinoid exposure at modest doses during the adolescent period alters song learning, while the same treatment has no effect on already-learned song in the adult. They compared the songs of pairs of birds that had been exposed to the same tutor and then either injected with the cannabinoid agonist WIN55212-2 or vehicle for 50 days. Vehicle-treated birds developed a normal song with, on average, about 8 different syllable types sung in stereotyped motifs. In contrast, the adult songs of birds treated with WIN55212-2 had an average of only about 6 song syllables, contained abnormally repeated notes, and were less stereotyped than the songs of vehicle-treated birds, even though they were no longer being exposed to cannabinoid agonist. The altered vocal learning in the cannabinoid-treated animals may be the result of effects on neural development, mechanisms of learning, or both. These effects of cannabinoids on coordinated perceptual-motor learning may be parallel to their effects on striatal processes in mammals. The songbird model, for which the brain structures and behavioral contingencies of song learning are well-characterized, may provide insight into the neural mechanisms of endocannabinioids and the disruptive effects of marijuana on specific types of learning. Soderstrom, K. and Johnson, F. Cannabinoid Exposure Alters Learning of Zebra Finch Vocal Patterns. Developmental Brain Research, 142, pp. 215-217, 2003.


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