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Director's Report to the National Advisory Council on Drug Abuse - February, 2004

Research Findings - Behavioral Research

The Role of Sensory Cues in Craving and Smoking

The relative contribution of sensory and pharmacological variables in regulating craving and smoking remains unclear. Rapid smoking procedures and denicotinized cigarettes can be used to further disentangle these factors, and to explore the relationship between craving and smoking. The present study examined the role of nicotine and sensory cues in mediating craving and smoking, and the relationship between craving and smoking. Participants (n=15) engaged in one session each of rapid smoking (up to nine cigarettes with puffs taken every 6 s) and normal paced smoking with nicotinized and denicotinized cigarettes (total of four sessions). During the next 3 h, craving and withdrawal assessments and smoking opportunities were scheduled every 15 min. Plasma nicotine levels were measured at baseline, immediately and 15 min after the smoking interventions, and subsequently at the time when the participant first chose to smoke. Results showed that craving ratings were equally suppressed immediately after all conditions. After self-paced conditions, both types of cigarettes produced equivalent effects on latency to smoke. Latency to smoke was significantly longer after rapid smoking of nicotinized cigarettes compared to all other conditions. Finally, changes in craving were associated with choices to smoke. The sensory cues associated with smoking suppressed craving ratings regardless of the smoking pace or nicotine content. Only at high doses did nicotine levels play an additional role in acutely suppressing smoking behavior. Small elevations in craving ratings were associated with choices to smoke. Dallery, J., Houtsmuller, E.J., Pickworth, W.B. and Stitzer, M.L. Effects of Cigarette Nicotine Content and Smoking Pace on Subsequent Craving and Smoking. Psychopharmacology, 165(2), pp. 172-180, 2003.

Nicotine-Dependence Symptoms In Adolescent Smokers

Although many factors have been identified as related to adolescent smoking, few studies have examined the role of nicotine-dependence (ND) symptoms. The purpose of this study was to investigate the association between ND symptoms and smoking status among adolescents in the early stages of the smoking onset process. The McGill University Study on the Natural History of Nicotine Dependence is an ongoing 6-year prospective investigation of the natural history of ND among 1267 grade 7 students in ten Montreal high schools. The baseline response was 55.4%. Subjects for this cross-sectional analysis of baseline data, collected in 1999, included 241 past 3-month smokers (mean age [SD] =13.0+/-0.7 years at baseline). ND symptoms were measured in five indicators, including a measure based on the criteria for tobacco dependence in the International Classification of Diseases-10th Revision (ICD-10), the Hooked on Nicotine Checklist, and three symptom clusters (withdrawal, self-medication, and ND/cravings symptoms). The association between ND symptom indicators and each of sporadic, monthly, weekly, and daily smoking relative to less frequent smoking was investigated in multiple logistic regression analysis. Dr. Difranza and colleagues found that low cigarette exposure, 16.6% of past 3-month smokers were tobacco dependent. The proportion increased from 0%, 3.1% and 4.6% among triers, sporadic smokers, and monthly smokers, respectively, to 19.4% and 65.9% among weekly and daily smokers, respectively. ND/cravings consistently distinguished each smoking category from less frequent smokers. These data challenge current smoking onset models, which suggest that ND develops only after several years of heavy or daily smoking. ND symptoms are associated, at least cross-sectionally, with increased smoking in adolescents. To increase the likelihood of being effective, tobacco-control programs for children and adolescents will need to take early ND symptoms into account. O'Loughlin, J., DiFranza, J., Tyndale, R.F., Meshefedjian, G., McMillan-Davey, E., Clarke, P.B.S., Hanley, J. and Paradis, G. Nicotine-Dependence Symptoms are Associated with Smoking Frequency in Adolescents. American Journal of Preventive Medicine, 25(3), pp. 219-225, 2003.

Altered Value of Carbohydrates for Females Withdrawn From Nicotine

Discontinuing nicotine intake usually results in weight gain partially due to heightened energy intake from between-meat snacks. This experiment tested the hypothesis that the reinforcing value of palatable carbohydrate-rich snacks increases for female smokers during nicotine deprivation. Eighteen smokers and 18 nonsmokers completed a concurrent-schedules operant computer task on two separate days. Smokers were bioverified abstinent at the second testing. The operant task allowed participants to earn points redeemable for either carbohydrate snacks or money on concurrent variable-ratio schedules of reinforcement. There were five different probabilities of earning points redeemable for snacks (8%, 16%, 25%, 50%, 75%), while the probability of earning points redeemable for money remained fixed at 25%. Reward value of snacks was measured by switch point: the reinforcement ratio at which the effort required to earn snacks exceeded their value to the respondent, as signified by a shift to working for money. Results showed that smokers undergoing nicotine deprivation persisted in working for snacks into leaner reinforcement schedules than nonsmokers (p=.026). Furthermore, nicotine deprivation increased smokers' allocation of effort to earn snack foods relative to their own behavior when smoking (p=.006). Variation in palatability or hunger did not explain these differences in snack reward value. Findings indicate that nicotine deprivation is associated with a heightened reward value of appealing snack foods for female smokers. Spring, B., Pagoto, S., McChargue, D., Hedeker, D. and Werth, J. Altered Reward Value of Carbohydrate Snacks for Female Smokers Withdrawn From Nicotine. Pharmacology, Biochemistry and Behavior, 76(2), pp. 351-360, 2003.

Reward Value of Cigarette Smoking Among Schizophrenic, Depressed, and Nonpatient Smokers

The study was designed to determine whether schizophrenic and depressed smokers perceive the reinforcement value of cigarette smoking differently from nonpsychiatric smokers who smoke as heavily. The authors assessed the preferences for smoking cigarettes versus engaging in other pleasant activities, the perceived advantages and disadvantages of smoking, and the amount of reinforcement that would be needed to attain smoking abstinence among 26 schizophrenic, 26 depressed, and 26 nonpsychiatric heavy smokers. Both schizophrenic and depressed participants chose smoking as their preferred activity more often than nonpsychiatric smokers, and they did not differ from each other. The patients also exceeded the comparison group in the benefits they ascribed to smoking and felt they would require more incentives to quit, but they attributed comparable drawbacks to smoking. Schizophrenic and depressed smokers recognize many drawbacks associated with smoking, but compared to nonpatients who smoke as heavily, they also perceive more benefits and find cigarettes more appealing than alternative rewards. Spring, B., Pingitore, R. and McChargue, D.E. Reward Value of Cigarette Smoking for Comparably Heavy Smoking Schizophrenic, Depressed, and Nonpatient Smokers. American Journal of Psychiatry, 160(2), pp. 316-322, 2003.

Separable Components of Satiation In Cigarette Smoking

To examine mechanisms underlying satiation in cigarette smoking, 18 smokers received intravenous (iv) nicotine, alone or in combination with denicotinized cigarette smoke. Nicotine was administered using programmed presentations of either pulsed injections or continuous infusions, with iv saline serving as a control. A high-nicotine cigarette smoke condition (usual brand) was also presented. During each of the six test sessions, subjects were allowed to puff on their usual brands of cigarette ad libitum while the programmed satiation conditions were in force. Administration of iv nicotine caused a small suppression of ad libitum smoking behavior; denicotinized smoke produced a significantly larger reduction, showing that short-term satiation is more dependent on the presentation of smoke than delivery of nicotine per se. However, denicotinized smoke alone did not have as much effect as puffs from the usual brands of cigarettes. The combination of iv nicotine and denicotinized smoke puffs produced equivalent satiation to that of the usual brand. Cigarette craving and negative affect were partially relieved by iv nicotine presentations as well as by denicotinized smoke, and again the combination of iv nicotine and denicotinized smoke approximated the effects of the usual brand. The results of this study underscore the importance of both sensorimotor aspects of smoking and the pharmacologic effects of nicotine in tobacco dependence. Rose, J.E., Behm, F.M., Westman, E.C., Bates, J.E. and Salley, A. Pharmacologic and Sensorimotor Components of Satiation in Cigarette Smoking. Pharmacology, Biochemistry and Behavior, 76(2), pp. 243-250, 2003.

Nicotine Self-Administration In Adolescent and Adult Female Rats

A rat model was used to determine the impact of the age of onset on nicotine self-administration. In Experiment 1, nicotine self-administration of female Sprague-Dawley rats over a range of acute doses (0.01-0.08 mg/kg per infusion) was determined in adolescent (beginning at 54-62 days) versus adult (beginning at 84-90 days). In Experiment 2, chronic nicotine self-administration over 4 weeks from adolescence into adulthood was compared with the chronic self-administration beginning in adulthood. In Experiment 3, adolescent-adult differences in nicotine effects on body temperature and locomotor responses were determined. Adolescent-onset rats showed increased nicotine intake compared with adult-onset rats in an eight-fold range of acute unit doses/infusion. Significant age differences were also seen in the chronic level of nicotine self-administration. Over 4 weeks, the adolescent-onset group had nearly double the rate of nicotine self-administration of the benchmark nicotine dose (0.03 mg/kg per infusion) compared to the adult-onset group. This increased nicotine intake persisted into adulthood. Adolescent rats had a significantly greater response than adults to the hypothermic effects of nicotine, but had significantly less response than adults to the reduction in locomotor activity seen after nicotine. Thus, adolescent-onset nicotine self-administration in female rats was associated with significantly higher levels of nicotine self-administration versus rats that began nicotine self-administration in adulthood. This greater self-administration persists into adulthood and may underlie greater propensity of adolescents to nicotine addiction. Levin, E.D., Rezvani, A.H., Montoya, D., Rose, J.E. and Swartzwelder, H.S. Adolescent-Onset Nicotine Self-Administration Modeled In Female Rats. Psychopharmacology, 169(2), pp.141-149, 2003.

Facial Coding Analysis of Smoking Opportunity on Cue-Elicited Urge

The authors analyzed smokers' facial expressions using the Facial Action Coding System (P. Ekman & W. V. Friesen, 1978) under varying smoking opportunity conditions. In Experiment 1, smokers first were told that they either could (told-yes) or could not (told-no) smoke during the study. Told-yes smokers reported higher urges than did told-no smokers. Unexpectedly, told-yes smokers became increasingly likely to manifest expressions related to negative affect and less likely to evince expressions related to positive affect, compared with told-no smokers. In Experiment 2, smokers were more likely to show positive affect-related expressions if the delay was 15 s than if it was 60 s. Craving may be related to both a desire to use and an impatient desire to use immediately. Sayette, M.A., Wertz, J.A., Martin, C.S., Cohn, J.F., Perrott, M.A. and Hobel, J. Effects of Smoking Opportunity On Cue-Elicited Urge: A Facial Coding Analysis. Experimental and Clinical Psychopharmacology, 11(3), pp. 218-227, 2003.

Attentional Bias Predicts Outcome In Smoking Cessation

Most attempts to quit smoking end in failure, with many quitters relapsing in the first few days. Responses to smoking-related cues may precipitate relapse. A modified emotional Stroop task-which measures the extent to which smoking-related words disrupt performance on a reaction time (RT) task-was used to index the distracting effects of smoking-related cues. Smokers (N = 158) randomized to a high-dose nicotine patch (35 mg) or placebo patch completed the Stroop task on the 1st day of a quit attempt. Smokers using an active patch exhibited less attentional bias, making fewer errors on smoking-related words. Smokers who showed greater attentional bias (slowed RT on the first block of smoking words) were significantly more likely to lapse in the short-term, even when controlling for self-reported urges at the test session. Attentional bias measures may tap an important component of dependence. Waters, A.J., Shiffman, S., Sayette, M.A., Paty, J.A., Gwaltney, C.J. and Balabanis, M.H. Attentional Bias Predicts Outcome In Smoking Cessation. Health Psychology, 22(4), pp. 378-387, 2003.

Effects of Nicotine Deprivation on Craving Response Covariation In Smokers

Most models of craving propose that when cravings are strong, diverse responses-thought to index an underlying craving state-covary. Previous studies provided weak support for this hypothesis. The authors tested whether nicotine deprivation affects degree of covariation across multiple measures related to craving. Heavy and light smokers (N = 127) were exposed to smoking cues while either nicotine deprived or nondeprived. Measures included urge ratings, affective valence, a behavioral choice task assessing perceived reinforcement value of smoking, and smoking-related judgment tasks. Results indicated higher correlations in the nicotine-deprived than in nondeprived group. The measures principally responsible for this effect loaded onto a single common Craving factor for nicotine-deprived but not nondeprived smokers. These findings suggest that, under certain conditions, measures of craving-related processes covary. Sayette, M.A., Martin, C.S., Hull, J.G., Wertz, J.M. and Perrott, M.A. Effects of Nicotine Deprivation On Craving Response Covariation In Smokers. Journal of Abnormal Psychology, 112(1), pp. 110-118, 2003.

Cigarette Smoking and Smoking-Related Beliefs After 2 Decades in a Community Sample

Rates of cigarette smoking and smoking-related beliefs in 1980 and 2001 among 7th-11th graders in a midwestern community were compared. Smoking was less prevalent in 2001 than in 1980, with the greatest declines in experimental smoking and a smaller drop in regular smoking. Beliefs about smoking generally became more negative. Adolescents (particularly nonsmokers) viewed smoking as more addictive and as having more negative social consequences in 2001 than in 1980 and had more negative attitudes toward smoking in 2001. These results were replicated among parent-child pairs in which parents were measured when they were adolescents between 1980 and 1983 and their children were measured in 2001. These beliefs and attitudes partially mediated the effects of time on smoking. Chassin, L., Presson, C.C., Sherman, S.J. and Kim, K. Historical Changes In Cigarette Smoking And Smoking-Related Beliefs After 2 Decades In A Midwestern Community. Health Psychology, 22(4), pp. 347-353, 2003.

Implicit and Explicit Attitudes Toward Cigarette Smoking

Two studies examined the effects of context and motivational state on two implicit measures of attitudes toward smoking (priming and the Implicit Association Test) as well as on explicit attitudes among nonsmokers and smokers. The priming measure was sensitive to changes in the salience of different aspects of smoking and to changes in motivational state (nicotine deprivation). There were only modest relations between explicit and implicit attitudes, and the two implicit measures were generally uncorrelated. These results have implications for the complexity and ambivalence of attitudes toward smoking held by smokers and for interventions that seek to change their attitudes and smoking behavior. Sherman, S.J., Rose, J.S. and Koch, K. Implicit and Explicit Attitudes Toward Cigarette Smoking: The Effects of Context and Motivation. Journal of Social and Clinical Psychology, 22(1), pp. 13-39, 2003.

Food Restriction Enhances Behavioral Sensitivity to Abused Drugs and Increases Dopamine Receptor Signaling

Chronic food restriction in rats is known to enhance sensitivity to the rewarding and motor-activating effects of abused drugs. Dr. Kenneth Carr and his colleagues have been investigating the neural mechanisms that account for this phenomenon. In the present study, they looked for evidence that food restriction produces increased dopamine (DA) receptor function in brain areas that are involved in the central substrates for reinforcement. In one experiment, they injected selective agonists for either the D1 or the D2/3 types of DA receptor and observed that both agonists produced greater motor activation in food-restricted animals. They also found higher levels of c-fos induction by these agonists in striatal (for the D1 agonist) and pallidal (for D2/3 agonist) areas. DA receptors are known to induce c-fos by activating cyclic AMP signaling. Therefore, in other experiments, they used neuronal membranes prepared from caudate-putamen and nucleus accumbens to investigate whether changes in signal transduction mechanisms downstream from DA receptors might be involved in the observed effects. Their results indicated that coupling between D2 receptors and the Gi protein was increased by food restriction. There was no change in adenylyl cyclase (AC) stimulation by the D1 agonist, but the results suggested a possible alteration in the AC isoform. The findings of these studies suggest that food restriction produces neuroadaptations in D1 and D2 receptor-bearing cells that, in turn, mediate augmented behavioral and transcriptional responses to DA agonists. These changes are therefore also likely to mediate an increased sensitivity to drugs of abuse seen under conditions of food deprivation. The exact nature of these neuroadaptations, however, remains to be fully elucidated. Carr, K.D., Tsimberg, Y., Berman, Y., and Yamamoto, N. Evidence of Increased Dopamine Receptor Signaling in Food-Restricted Rats. Neuroscience, 119, pp. 1157-1167, 2003.

Genetically Altered Mice with Higher Dopamine Levels "Want" but do not "Like" Sweet Reward More than Normal Mice

The mesolimbic dopamine system plays an important role in natural reward and drug addiction, but the exact contribution of DA to reward is controversial. One hypothesis suggests that DA mediates the sensory pleasure, or hedonic value (the "liking") of rewards such as food and drugs. Under this hypothesis, addiction results from withdrawal-induced anhedonia caused by DA downregulation. A second hypothesis is that DA is primarily involved in reward learning, and that drug addiction results from aberrant neural learning processes, which cause exaggerated reward predictions or excessive drug-taking habits. Dr. Kent Berridge (with his colleague Dr. Terry Robinson) has been developing a third idea, the incentive salience hypothesis, which posits that DA systems modulate the perceived incentive value of reward stimuli so that rewards become more "wanted" without necessarily being more "liked." Their hypothesis suggests that addiction results from sensitization of mesolimbic systems, causing an excessive "wanting" to take drugs. In the current study, Berridge and colleagues used a genetic mutant approach to examine the consequences of elevated synaptic dopamine. The mutant mice have genetic knockdown of the dopamine transporter (DAT), which preserves only 10% of normal DAT and results in a 70% elevated level of synaptic dopamine. Behavioral observations were made on: (1) spontaneous food and water intake, (2) incentive motivation and learning to obtain a palatable sweet reward in a runway task, and (3) affective "liking" reactions (i.e., facial expressions) elicited by the taste of sucrose. The hyperdopaminergic DAT knockdown mice had higher food and water intake and maintained higher body weight, consistent with the obverse effect of DA deficiency (observed in other experiments), which reduces eating. In the runway task, the hyperdopaminergic mutant mice showed enhanced acquisition and greater incentive performance for a sweet reward compared to wild-type animals. Mutant mice left the start box more quickly, required fewer trials to learn, paused less often in the runway, resisted distractions better, and proceeded more directly to the goal. Those observations suggest that the hyperdopaminergic mice attribute greater incentive salience ("wanting") to a sweet reward, although they do not rule out the possibility that the mutant animals also have enhanced reward learning. In a third experimental procedure, the affective taste reactivity test, sucrose taste did not elicit higher orofacial "liking" reactions from mutant mice, and in fact, produced somewhat reduced "liking" at the highest concentrations. These results indicate that chronically elevated extracellular dopamine facilitates "wanting" and learning of an incentive motivation task for a sweet reward, but does not increase "liking" reactions to the hedonic impact of sweet tastes. Pecina, S., Cagniard, B., Berridge, K.C., Aldridge, J.W., and Zhuang, X. Hyperdopaminergic Mutant Mice have Higher "Wanting" but not "Liking" for Sweet Rewards. Journal of Neuroscience, 23, pp. 9395-9402, 2003.

Chronic Stress and Obesity: A New View of "Comfort Food"

Dr. Mary Dallman and her colleagues have, over many years, carried out studies in a rat model to understand the relationship between acute and chronic stress, feeding, and the hormones, neurotransmitters, and neural circuits that underlie behavior. In a recent paper, they proposed a new working model of the chronic effects of glucocorticoid (GC) function in the central nervous system that can help explain the altered eating patterns by humans who are chronically stressed, depressed, drug-addicted, or have eating disorders. The effects of adrenal corticosteroids on subsequent adrenocorticotropin secretion, and feedback regulation of these effects, are complex. Acutely (within hours), glucocorticoids (GCs) directly inhibit further activity in the hypothalamo-pituitary-adrenal axis, but the chronic actions (across days) of these steroids on brain are directly excitatory. Chronically high concentrations of GCs act in three ways that are functionally congruent: (i) GCs increase the expression of corticotropin-releasing factor (CRF) mRNA in the central nucleus of the amygdala, a critical node in the emotional brain. CRF enables recruitment of a chronic stress-response network. (ii) GCs increase the salience of pleasurable or compulsive activities (e.g. ingesting sucrose, fat, and drugs, or wheel running), which, in turn can motivate the ingestion of "comfort food." (iii) GCs act systemically to increase abdominal fat depots, which provide a negative feedback signal to inhibit catecholamines in the brainstem and CRF expression in hypothalamic neurons that regulate adrenocorticotropin. Chronic stress, together with high GC concentrations, usually decreases body weight gain in rats; by contrast, in stressed or depressed humans chronic stress induces either increased comfort food intake and body weight gain or decreased intake and body weight loss. Comfort food ingestion that specifically produces abdominal obesity also decreases CRF mRNA in the hypothalamus of rats. Depressed people who overeat have decreased cerebrospinal CRF, catecholamine concentrations, and hypothalamo-pituitary-adrenal activity. Integrating these observations into the model, Dr. Dallman proposes that people eat comfort food in an attempt to reduce activity in the chronic stress-response network and its attendant anxiety. These mechanisms, identified from research in animals, may help explain the obesity epidemic in our society. Dr. Dallman is currently using this model in her research funded by NIDA to investigate whether chronic stress enhances the process whereby normally rewarding activities become "devalued" relative to supernormal drug rewards by drug abuse and addiction. Dallman, M.F., Pecoraro, N., Akana, S.F., La Fleur, S.E., Gomez, F., Houshyar, H., Bell, M.E., Bhatnagar, S., Laugero, K.D., and Manalo, S. Chronic Stress and Obesity: A New View of "Comfort Food." Proceedings of the National Academy of Sciences, USA 100, pp. 11696-11701, 2003.

Neurons in Nucleus Accumbens Remain Responsive to Drug-associated Cues after Prolonged Abstinence from Cocaine Self-administration

For abstinent drug users, exposure to stimuli associated with prior drug use can provoke craving and increase the risk of relapse. Thus, the neural representation of drug-predictive environmental stimuli is likely to be persistently salient. Dr. Mark West and his colleagues tested this hypothesis using single-unit recording in rats, to determine whether nucleus accumbens (NAcc) neurons exhibit responses to a discriminative stimulus (SD,) tone previously paired with cocaine availability during cocaine self-administration. In behavioral testing, presentation of the tone after 3-4 weeks of abstinence resulted in cue-induced relapse of drug seeking under extinction conditions - i.e., with no cocaine provided for the animal's operant responses. NAcc neurons did not exhibit any tone-evoked activity before cocaine self-administration training, but during extinction, they showed significant SD tone-evoked activity. The researchers further examined whether the NAcc subdivisions, shell and core, had differential responses. Under extinction conditions, shell neurons exhibited significantly greater activity evoked by the SD tone than by a neutral tone that had never been paired with cocaine. In contrast, core neurons responded indiscriminately to the SD and neutral tones. The onset of SD tone-evoked activity occurred well before the earliest movements began (150 msec), although it often persisted beyond the onset of tone-evoked movements. Thus, the firing of these neurons appears to be most clearly related to the motivational significance of the tone, rather than to subsequent movements. These results indicate that NAcc shell neurons exhibit persistent processing of information about reward-related stimuli after prolonged drug abstinence. While the NAcc shell appears to be involved in discriminating the motivational value of such stimuli, the NAcc core does not. The results are also consistent with a growing body of experimental evidence indicating that stimulus-reward associations are not unlearned or forgotten during extinction. Rather, via an active process, animals and humans learn not to respond to certain cues under circumstances where the cue no longer predicts reward, but may relapse to cue-induced responding in environments that differ from the extinction context. Ghitza, U.E., Fabbricatore, A.T., Prokopenko, V., Pawlak, A.P., and West, M.O. Persistent Cue-evoked Activity of Accumbens Neurons after Prolonged Abstinence from Self-administered Cocaine. Journal of Neuroscience, 23, pp. 7239-7245, 2003.

Exposure to Amphetamine or Cocaine Limits the Ability of Later Environmental Enrichment to Promote Structural Plasticity in the Brain

Drugs of abuse and many other kinds of experiences share the ability to alter the morphology of neuronal dendrites and spines, the primary site of excitatory synapses in the brain. Dr. Terry Robinson, Dr. Brian Kolb and colleagues hypothesized that exposure to psychostimulant drugs might influence later experience-dependent structural plasticity. They treated rats repeatedly with amphetamine or cocaine and then housed them in either a complex environment or standard laboratory cages for 3-3_ mo. The brains were processed for Golgi-Cox staining, and the number of dendritic branches and density of dendritic spines on medium spiny neurons in the nucleus accumbens and pyramidal cells in the parietal cortex were quantified. On most measures, prior treatment with amphetamine or cocaine interfered with the ability of experience in a complex environment to increase dendritic arborization and spine density, which occurred in the untreated controls. Studies of humans who have used psychostimulants for long periods indicate that they have neuropsychological deficits that persist during abstinence. These deficits are usually attributed to either neurotoxic effects of the drugs or their ability to render specific brain areas dysfunctional. However, the data from the current study suggest an alternative way in which drug use might produce persistent behavioral and cognitive deficits, by impairing the ability of specific neural circuits to change as a result of experience. On a more positive note, if exposure to psychostimulant drugs can alter the effects of subsequent experience, then experience may be able to influence the later effects of drugs. In fact, there is evidence from animal studies that early environmental enrichment can be protective against the effects of psychostimulant drugs in adulthood. Kolb, B., Gorny, G., Li, Y., Samaha, A.N., and Robinson, T.E. Amphetamine or Cocaine Limits the Ability of Later Experience to Promote Structural Plasticity in the Neocortex and Nucleus Accumbens. Proceedings of the National Academy of Sciences, USA, 100, pp. 10523-10528, 2003.

Activity in the Ventral Subiculum is Necessary for Reinstatement of Cocaine- or Cue-Induced Cocaine Seeking

Exposure to a drug-associated environment can provoke relapse to drug seeking in both humans and animals, even after prolonged periods of abstinence. For this to occur, information about the environment must have access to motivational circuitry in the brain. One likely route for such information is via the ventral subiculum (vSUB), an extension of ventral hippocampus known to play a role in goal-directed behavior. In this study, Dr. George Rebec and his associate Dr. WenLin Sun investigated the role of the ventral subiculum in cocaine- or cue-induced cocaine-seeking behavior in rats tested on a between-session reinstatement model. Rats were trained to self-administer cocaine in a lever-pressing operant task in a daily 2 hr session. Responding was reinforced contingent on a modified fixed-ratio 5 schedule. Reinstatement tests began after the lever-pressing behavior was extinguished in the absence of cocaine and conditioned cues (light and tone). Bilateral microinjections of lidocaine to transiently inactivate the vSUB decreased cocaine- or cue-induced reinstatement of cocaine-seeking behavior compared with saline microinjections into the same area in another group of rats. Lidocaine microinjections, however, had no effect on cocaine self-administration behavior or food-maintained or food-reinstated responding. Collectively, these results suggest that the vSUB plays an important role in cocaine-seeking behavior. Considering the role of this structure in context learning, these data suggest that the full expression of cocaine- or cue-induced reinstatement may depend on the context in which the cocaine experience occurs. Sun, W. and Rebec, G.V. Lidocaine Inactivation of Ventral Subiculum Attenuates Cocaine-Seeking Behavior in Rats. Journal of Neuroscience, 23, pp. 10258-10264, 2003.

Furthering Our Understanding of the Role of Dorsomedial Prefrontal Cortex in Conditioned-cue-induced Cocaine-seeking Behavior in Rats

It is well known that environmental cues (i.e., people, places and situations) previously paired with cocaine can induce craving in humans. Similarly, using an animal model of drug abuse relapse, environmental cues can reinstate cocaine-seeking behavior in laboratory rats. Over the past several years, neuroscientists have implicated several brain regions as possible substrates involved in environmental-cue associated drug craving and relapse, and two in particular: the amygdala and the prefrontal cortex (PFC). Dr. Ron See and his colleagues at the University of South Carolina explored in detail the role of PFC in an animal model of conditioned-cued-induced cocaine relapse. The PFC comprises several subdivisions in the brain including the: anterior cingulate (ACing), the prelimbic cortex (PL), and the infralimbic cortex (IL). Dr. See temporarily, and in-turn, systematically inactivated each of these brain regions and determined their role in conditioned-cued-induced cocaine-seeking behavior. From these inactivation studies, he and his colleagues determined that inactivation of the ACing, or the PL impaired the ability of environmental cues to induce cocaine seeking. In contrast, inactivation of the IL had no effect on conditioned-cued cocaine seeking. These results support a role for the involvement of some of the subdivisions of the dorsomedial PFC as part of the brain's circuitry involved in conditioned-cued-induced drug-seeking behavior. McLaughlin, J. and See R.E. Psychopharmacology, pp. 168, pp. 57-65, 2003.

Adolescent Sensitivity to Nicotine and Cross-sensitization to Cocaine Effects in Adulthood

In 2002, Dr. Sari Izenwasser reported that peri-adolescent rats were less sensitive to the development of behavioral sensitization with repeated cocaine administration than their adult counterparts. This was an important observation, as sensitization is believed to reflect an underlying change in the neurobiological substrate for reinforcing effects of drugs of abuse, and therefore may be involved in the addiction process. More recently, she has examined the behavioral and neurochemical effects of repeated nicotine treatments in this model. The study of nicotine mechanisms in adolescence is also an important area of investigation, since it has been reported that adolescents show a more rapid progression to dependence on smoking than do adults. Moreover, girls may show an even more precipitous course. In this study, adult and peri-adolescent rats (postnatal day 28 to 40) received 0.4mg/kg of nicotine/day via intra-peritoneal administration for 7 days. Matched age and sex control groups received vehicle instead. After each injection, locomotor activity was measured for one hour. On day 8, all rats were challenged with a cumulative dosing regimen of i.p. cocaine and their locomotor activity tested for 10-min after each injection to probe for cross-sensitization. This portion of the study design addresses concerns that smoking or nicotine exposure may "prime" subsequent illicit drug abuse. Both developmental and gender differences were observed in acute effects of nicotine and in the development of sensitization to locomotor stimulation: The young male group had a higher activity count (and greater stereotypy) after the first nicotine injection than all other groups, and did not show a behavioral sensitization. All other groups (female adolescent, and both adult groups) sensitized to nicotine's behavioral activating and stereotypy effects. However, female adolescents showed a significant sensitized response after only one nicotine exposure (versus adults, who showed significant sensitization on day five for both behavioral measures). Unlike their response on locomotor measures, male adolescents did show a sensitized stereotypy that emerged on the fourth nicotine injection. When all groups were challenged with cocaine on day 8, adolescent males - who had not shown locomotor sensitization to repeated nicotine - were sensitized to all doses of cocaine tested (i.e., had higher activity counts than males treated with vehicle) and, in fact, showed greater cross-sensitization than their adult counterparts. By contrast, neither female group showed any greater response than their chronic vehicle controls after cocaine. These findings, in conjunction with previous reports of gender differences in rats treated acutely, or chronically, with behaviorally active doses of nicotine, highlight potential neurobiological differences in the substrates for addictive processes in adolescence. Thus, although methodological differences between these various studies must be considered (e.g., varied routes of administration and schedules), male adolescents may be initially more behaviorally responsive to nicotine, whereas females may show a more rapid neuroadaptation that gives rise to changing behavioral profiles. Collins, S.L. and Izenwasser, S. Chronic Nicotine Differentially Alters Cocaine-induced Locomotor Activity in Adolescent vs. Adult Male and Female Rats. Neuropharmacology, Available online December 10, 2003.

A Non-drug Reinforcer, Saccharin, Reduces Oral Self-administration of Phencyclidine (PCP) in Male and Female Rhesus Monkeys

Prior research with non-human primates and rats has clearly established that under a wide variety of conditions the availability of non-drug reinforcers can reduce the acquisition and/or maintenance of drug self-administration. Dr. Carroll has previously demonstrated the suppressive effects of concurrent saccharin on PCP oral self-administration in male monkeys and in a recent study sought to directly compare such effects in males and females. Seven male and seven female subjects responded for oral PCP under fixed-ratio (FR) schedules of 4, 8, 16, 32, 64 and 128 during concurrent availability of either saccharin or water. In both males and females, saccharin availability suppressed the number of operant responses for PCP and the number of PCP deliveries at low to intermediate FR values. Suppression in the number of deliveries was greater for females than males at FR values of 4, 8, 16, and 32. Saccharin produced suppression in the mg/kg consumption of PCP in both males and females with a sex difference in the degree of suppression occurring at FR 32, wherein the suppression seen was greater in females. These data extend to females the prior finding that saccharin can suppress PCP consumption, and further suggest that at certain parameters, suppression may be greater in females. These sex differences are of interest in view of prior work from Dr. Carroll's lab reporting that availability of wheel-running suppressed i.v. cocaine self-administration only in female rats (Cosgrove et al. 2002), and that females exhibited more suppression of i.v. cocaine self-administration than males in response to baclofen (Campbell et al., 2002) and to ketaconazole (Carroll et al, 2001). Such differences point to the need for both animal and human research to continue to examine to sex differences in studies aimed at strategies to reduce drug intake. Cosgrove, K.P. and Carroll, M.E. Effects of a Non-drug Reinforcer, Saccharin, on Oral Self-administration of Phencyclidine in Male and Female Rhesus Monkeys. Psychopharmacology, 170, pp. 9-16, 2003.

A Simulated Neural Model of the Midbrain Dopamine System, Embodied in a Robot, Provides Novel Insights into Reward Processing

Dr. Olaf Sporns was recently funded through NIDA's CEBRA program to extend his neural modeling studies of reward learning to drug abuse applications. A number of laboratories have developed computational models to understand the role of neuromodulatory systems in creating and maintaining stable and adaptive neuronal representations. A unique feature of Sporns' work, however, is that his model is imbedded in a physical robot that can interact with a real environment to investigate what happens under conditions of changing stimulus content and demands of the environment. In this paper, Sporns and his graduate student William Alexander describe a neural network model of the dopaminergic system based on observed anatomical and physiological properties of the primate midbrain. The model relies on value-dependent synaptic modifications to acquire temporal information about the association between reward-related events and environmental stimuli. The model generates phasic "neuromodulatory" responses corresponding to prediction errors, which act as a value signal with positive and negative components, representing the unpredicted occurrence of rewarding stimuli or the omission of an expected reward, respectively. The value signal modulates widespread synaptic changes, including afferent connections of the value system itself. The model was embedded in an autonomous robot, and its behavior was tested as changes were made in the robot's motor characteristics and in the stimulus content of the environment. The robot (named "Monad") could move around in its environment and contact objects with a gripper arm. Neural units in the simulation triggered all actions of the robot, which could sense its environment with a camera and sensors on the inner surface of the gripper, defined as "appetitive taste" sensors. Initially, Monad was programmed to emit an "innate," unconditioned response of prolonged gripping of each object it encountered. After learning (essentially an instrumental conditioning paradigm), objects visually triggered a conditioned response consisting of immediate approach and gripping of the object. The researchers then observed the development of neural activity in the simulated nervous system as conditioning of reward-related behaviors occurred through the interaction between the robot and its surroundings. By using an embodied system, they were able to make unique observations about the pace of learning in various unpredictable environments, which cannot be done in pure simulations. For example, when many objects were in the environment, the objects became bunched as the robot handled them. Subsequently Monad was rewarded at a faster pace and the neural representation of reward prediction shifted to an earlier time. Results of this work show how the coupling of brain, body, and environment can affect ongoing plasticity in ways that are unexpected. The system provides a platform for understanding how real neuromodulatory systems control plasticity in natural environments, without external control over stimulus-response schedules. A deeper understanding of how neuromodulation operates in complex behavioral contexts may highlight how reward processing is altered in diseases such as addiction. Alexander, W.H. and Sporns, O. An Embodied Model of Learning, Plasticity, and Reward. Adaptive Behavior, 10, pp. 143-159, 2002.


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