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

Research Findings - Behavioral Research

Sex Differences in Running-Wheel Attenuation of Cocaine Self-administration in Rats

Previous animal studies have shown that the acquisition of drug self-administration can be reduced by the availability of alternative drug or nondrug reinforcers. Other studies have shown that exercise via wheel running can reduce established oral amphetamine and oral ethanol self-administration. Dr. Marilyn Carroll and her colleagues at the University of Minnesota have now reported that wheel running can also reduce established i.v. cocaine self-administration. The effect, however, occurred in females, but not males. After a baseline of wheel running was established, access to the wheel was terminated and rats were trained to self-administer cocaine (0.2mg/kg). Next, rats were given concurrent access to both cocaine self-administration and the running wheel, followed by a period of access only to cocaine and then a period of wheel only. The researchers found that providing concurrent access to both the wheel and cocaine produced: (A) a suppression of cocaine self-administration (relative to the cocaine-only period) that was significant in females (70.6%), but not in males (21.9%) and (B) a suppression in wheel running revolutions (relative to the wheel-alone period) in both males (63.7%) and females (61.5%). These data indicate that for females, but not males, wheel running can serve as an alternative reinforcer that significantly competes with established cocaine self-administration and that cocaine and wheel running are substitutable reinforcers. These data, along with research with humans indicating that exercise is an aid in human smoking cessation, suggest that exercise may be a useful adjunct in the treatment of cocaine dependence, especially for women. Cosgrove, K.P., Hunter, R.G. and Carroll, M.E. Wheel-Running Attenuates Cocaine Self-administration in Rats - Sex Differences. Pharmacology, Biochemistry and Behavior, 73, pp. 663-671, 2002.

Estrogen Plays a Role in the Acquisition of I.V. Heroin Self-Administration in Female Rats

Prior research from the laboratory of Dr. Marilyn Carroll of the University of Minnesota has shown that female rats acquire i.v. self-administration of both cocaine and heroin faster than male rats. Subsequent work from that laboratory found that blocking of estrogen, either surgically or chemically, reduced the percentage of females that met the acquisition criterion for cocaine self- administration. In the present experiment, Dr. Carroll and her colleagues assessed whether estrogen plays a similar role in heroin self-administration. Acquisition of low-dose (0.0075 mg/kg) heroin self-administration was examined in two estrogen groups, (a) ovariectomized (OVX) females treated with estradiol benzoate (OVX-EB) and (b) sham-operated (SH) females treated with the vehicle (SH-VEH). In a third group, estrogen was surgically blocked via ovariectomy and the females were treated with vehicle (OVX-VEH). The researchers report that the OVX-EB rats met criterion in significantly fewer days than the OVX-VEH (6.4 vs. 12.9) and self-administered more heroin infusions than the OVX-VEH rats. Unexpectedly, the SH-VEH group failed to exhibit faster acquistion than the OVX-VEH group, an outcome for which the researchers discuss several possible explanations. These data join a growing body of literature (from studies both in human subjects and preclinical research) demonstrating that estrogen influences the vulnerability to develop drug abuse behaviors and emphasizes the need for further research aimed at uncovering mechanisms for this effect. Roth, M.E., Casimir, A.G. and Carroll, M.E. Influence of Estrogen in the Acquisition of Intravenously Self-administered Heroin in Female Rats. Pharmacology, Biochemistry and Behavior, 72, pp. 313-318, 2002.

Early Life Stress in an Animal Model Accelerates Tolerance and Sensitization

A common procedure for inducing early life stress is maternal separation (MS), wherein rat pups are removed from the dam for several hours each day. Maternal separation produces profound changes in the brain's endogenous stress system and alters an animal's ability to respond to stress during adulthood. Concomitant with these changes in stress reactivity, animals are more responsive to behavioral effects of psychostimulants and more readily acquire drug self-administration. Dr. Stephen Holtzman and colleagues have reported that tolerance to the analgesic effects of morphine is also altered by early MS, and in a recent study, his research group found evidence that early life stress affects neuroadaptations that give rise to the behavioral effects of repeated morphine. These studies examined the effects of daily MS upon reactivity to a novel environment and to morphine-induced sensitization and tolerance when animals were tested as adults (more than 90 days old). MS litters were removed for 3 hrs daily on neonatal days 2-14. Handled (H) control pups were treated similarly but removed for only 15 min daily, and non-handled (NH) controls were left undisturbed with the dam until weaning. Results indicated that MS had a significant effect on the offspring's reactivity to a novel environment and to the development of opiate tolerance and sensitization as measured by changes in locomotor activity. Thus, MS rats exhibited robust increases (50-75%) in locomotor activity in a novel environment compared to NH controls; whereas H rats showed only modest increases (30%). When treated with 10mg/kg morphine repeatedly, only MS and H rats showed suppression of activity (horizontal counts) after the first and second injection. Tolerance to this initial behavioral suppression was observed over 10 drug administrations so that at the end of the 10 day treatment regimen, drug-induced activity seen in MS rats was double that of the NH controls, suggesting a sensitization of opiate-induced behavioral stimulation. Next, animals were withdrawn for 2 days and challenged with saline in an environment that had been paired with morphine. On this test for conditioned sensitization, only MS rats showed locomotor stimulation, suggesting that these animals had become conditioned to the drug paired environment. This observation is intriguing, in light of previous findings to suggest that repeated early MS is associated with enhanced long-term potentiation (LTP) -- a neural mechanism that may subserve associative processes of conditioning. The authors suggest that MS animals show an enhanced sensitivity to opiate-induced neuroadaptive phenomena, brought about by early life stress. Moreover, the acceleration of these neuroadpative processes may be linked to early developmental alterations in opioid receptor systems. Kalinichev, M., Easterling, K.W. and Holtzman, S.G. Early Neonatal Experience of Long-Evans Rats Results in Long-lasting Changes in Reactivity to a Novel Environment and Morphine-induced Sensitization and Tolerance. Neuropsychopharmacology, 27, pp. 518-533, 2002.

Adolescent Rats Respond Differently to Repeated Cocaine than Adults

Behavioral and neurochemical models of drug reactivity during the adolescent period are useful for studying influences on the vulnerability to acquire drug abuse behaviors or escalation to drug addiction during the teen years. Dr. Sari Izenwasser and colleagues have recently compared adult (170-200 g body weight) and periadolescent rats (75-100 g body weight) with behavioral and receptor-binding measures during repeated treatments with cocaine. Rats in these studies were given 50 mg/kg cocaine daily (in two injections) for 7 days. On day 8 and 16, a probe was conducted to determine if conditioned sensitization of locomotor activity was induced in the cocaine-paired environment. Then, on day 17, all animals were challenged with 15 mg/kg cocaine, and locomotor behavior and stereotypy were measured. In separate groups of animals, quantitative autoradiography was performed on post-mortem samples to measure D1 and D2 dopamine receptors, along with dopamine (DAT) and serotonin (SERT) transporter density. Cocaine increased behavioral activity over all seven days, in both adult and adolescent rats. However, whereas adult animals showed a sensitization i.e., increased locomotor activity over the 7 days, adolescent rats had an enhanced level of responding that remained constant, suggesting that they did not develop the behavioral sensitization seen in adults. Stereotypy was constant over all 7 days for both groups, indicating that this difference cannot be attributed to changes in stereotypical behaviors. None of the animals showed a conditioned behavioral response when injected with saline on days 8 or 16. However, upon challenge with 15 mg/kg cocaine after the chronic treatment regimen, only the adult rats with chronic cocaine experience showed a sensitized locomotor response (i.e., greater than the adult rats treated for 7 days with saline). By contrast, periadolescent rats treated with 7 days of 50mg/kg cocaine or the vehicle had a very similar level of behavioral stimulation to the test dose of cocaine. This observation further demonstrates that periadolescent rats did not develop behavioral sensitization, whereas the adults clearly did. Neurochemical findings parallel these behavioral data, in that adult animals had an increase in DAT density in caudate putamen areas, whereas periadolescent animals showed no change from controls. Furthermore, while D1 and D2 receptors were unchanged in both groups, SERT densities were increased in several areas measured from adults, but not periadolescents. Collectively these observations suggest that adolescent rats are less sensitive to neuroadaptations induced by repeated psychostimulant treatment than are adults. The authors suggest that perhaps a neurobiological developmental process may counteract the development or expression of these drug-induced neuroadaptive changes. Collins, S.L. and Izenwasser, S. Cocaine Differentially Alters Behavior and Neurochemistry in Periadolescent Versus Adult Rats. Developmental Brain Res., 138, pp. 27-34, 2002.

Devaluation of Natural Rewards: Cocaine-Induced Suppression of Saccharin Intake

It is commonplace to observe that drug addicted individuals choose drugs when given a choice between drugs and natural rewards (food, sex, recreation, etc.). Why this occurs is not fully understood, but according to Dr. Patricia Grigson's "Reward Comparison" hypothesis, natural rewards are devalued when they occur in association with more salient drug rewards. That is, in Dr. Grigson's research, rats learn to devalue a natural reward like saccharin, as a result of paired presentations of saccharin with more salient natural (e.g., sucrose) or drug rewards (e.g., morphine). In the present research, thirsty rats were given 5 min access to saccharin followed by the opportunity to self-administer cocaine (or saline). Results indicated that rats avoided intake of saccharin after saccharin-cocaine pairings and that greater avoidance of saccharin was associated with higher (subsequent) rates of cocaine self-administration. When evaluated in terms of individual differences in saccharin intake, the data revealed two separate patterns, or associations between saccharin avoidance and cocaine self-administration: A group of 'small suppressers' that consumed the natural saccharin reward but subsequently took few drug infusions; and a second group of 'large suppressers' that avoided intake of saccharin but initiated three times as many infusions of cocaine. Moreover, avoidance of the saccharin cue and the propensity to self-administer cocaine were both maintained after at least one month of abstinence, as were the individual patterns described above. The neurobiological substrates for these effects are not yet known, but the gustatory thalamus and the mesolimbic dopamine pathway have been implicated. Finally, although the tendency to compare rewards can lead to the devaluation of a natural reward, evidence suggests that under the right circumstances, a highly reinforcing natural reward can lead to the devaluation of a drug of abuse. The treatment implications of this particular circumstance demand further attention. Grigson, P.S., and Twining, R.C. Cocaine Induced Suppression of Saccharin Intake: A Model of Drug-induced Devaluation of Natural Rewards. Behavioral Neuroscience, 116(2), pp. 321-333, 2002.

Discounting Future Events and Drug Addiction

Investigators at the University of Vermont have shown that substance use disorder is associated with excessive temporal discounting of delayed rewards. Their research has clearly shown that individuals addicted to drugs of abuse such as heroin and nicotine (tobacco) value future events less than non-addicted individuals. Little is known, however, about whether or not an individual's temporal discounting changes with the "drug state" (i.e., having just used the drug vs. not having used for a period of time). To examine how drug state affects an individual's discount rate, opioid-dependent subjects maintained on buprenorphine completed a hypothetical choice task in which they chose between an immediate smaller outcome or a larger more delayed outcome. Results showed that an individual's preference for the immediate smaller reward was greater just before they received buprenorphine, when they were in a relatively less medicated state, than following buprenorphine administration. These results have important clinical implications. First, the "myopic" temporal horizon observed in these individuals, regardless of medicated state, suggests that immediate and rewarding outcomes are needed in drug treatment settings, such as are used in contingency management therapies or 12-step approaches. Furthermore, clinical research will be able to capitalize on this discovery to develop more effective treatment interventions. Finally, these findings suggest that drug withdrawal or being in a less medicated state is associated with more impulsivity which may subsequently lead to high risk patterns of behavior. Giordano, L.A., Bickel, W.K., Loewenstein, G., Jacobs, E.A., Marsch, L., and Badger, G.J. Mild Opioid Deprivation Increases the Degree that Opioid-dependent Outpatients Discount Delayed Heroin and Money. Psychopharmacology, 163, pp. 174-182, 2002.

Differential Drug Access Determines the Pattern of Cocaine Self-administration and Influences Reinforcing Efficacy

Humans usually begin to use cocaine on an occasional or limited daily basis, and then, although patterns vary between individuals, most addicts progress to binging and compulsive use. Dr. David Roberts and his colleagues have been developing procedures for cocaine self-administration in rats that closely model the development of human usage patterns. In a recent investigation (Roberts et al., 2002) using their discrete trials (DT) procedure, rats were allowed to press a lever to receive cocaine 24 hrs a day, but different groups of animals were limited to either 2, 3, 4, or 5 discrete trials per hour (dosage of 1.5 mg/kg/injection) for 21 days. Both the circadian pattern and the total amount of cocaine intake were correlated with the number of discrete trials allowed. For example, animals on the DT2 schedule (two trials per hour) took 80% of their injections in the dark phase of the light:dark cycle, whereas animals on the DT5 schedule self-administered almost round the clock, with only 60% of their injections in the dark phase. Average total intake for the DT2 group was about 20 mg/kg/day, whereas the DT5 group self-administered an average of almost 100 mg/kg/day. Remarkably, this procedure allows for very high cocaine intake without toxicity. Animals in the DT3, 4 and 5 groups also showed binge-like behavior over the first 2-3 days, but responding stabilized thereafter. At the end of the 21 days, the DT5 animals were tested using a progressive ratio (PR) schedule to determine whether they found cocaine more or less reinforcing compared to a PR pretest, given before the discrete trials schedule began. At all doses tested (0.38, 1.5 and 3.0 mg/kg/inj), breakpoints in the post-test were lower than in the pretest, indicating that animals had developed tolerance to the reinforcing effects of cocaine from their very high intake during the DT schedule. In a separate set of experiments (Morgan et al., 2002), the DT procedure was used to investigate whether a history of different patterns of drug intake would increase the reinforcing efficacy of cocaine after various periods of abstinence. With the PR test, animals exposed to DT4 conditions for either 7 or 10 days showed a slight (but not significant) decrease in breakpoint when retested immediately, or with one day of abstinence, after the DT schedule ended. However, breakpoints significantly increased after 7 days of abstinence. This finding is in agreement with animal studies and clinical impressions indicating that there is an "incubation" of drug-seeking behavior that develops over the withdrawal period. The current study is the first to demonstrate that the reinforcing efficacy of cocaine increases over time "off drug". Roberts, D.C.S., Brebner, K., Vincler, M., and Lynch, W.J. Patterns of Cocaine Self-administration in Rats Produced by Various Access Conditions Under a Discrete Trials Procedure. Drug and Alcohol Dependence 67, pp. 291-299, 2002; Morgan, D., Brebner, K., Lynch, W.J., and Roberts, D.C.S. Increases in the Reinforcing Efficacy of Cocaine after Particular Histories of Reinforcement. Behavioural Pharmacology, 13, pp. 389-396, 2002.

Tolerance to the Disruptive Effects of Marijuana on Learning in Rats

Considering the widespread use of marijuana by school age adolescents and young adults, determination of marijuana's acute and chronic effects on learning is critically important. Chronic administration of marijuana is known to produce both tolerance and dependence (i.e., a withdrawal syndrome). The present study investigated the effects of tolerance and dependence following chronic administration of delta-9-THC (THC), the psychoactive ingredient in marijuana, on learning and performance in rats. Animals were trained on a complex discrimination to make sequences of three responses for food reinforcement. The discrimination was arranged such that drug effects could be evaluated separately on the learning (i.e., acquiring a new response sequence) and on the performance (i.e., executing a learned sequence) components of the task. The acute and chronic effects of THC were examined. To study the effects of dependence induced by repeated THC administration, learning and performance were also assessed after administration of a cannabinoid (CB1) receptor antagonist in chronically treated animals. Results indicated that a 5.6 mg/kg dose of THC disrupted learning and performance of the discrimination, but that tolerance developed to both the rate-decreasing and error-increasing effects of this dose during the learning and the performance components of the task. During chronic administration of THC, the CB1 antagonist, SR141716A, was occasionally given in place of THC. Whereas 1 mg/kg SR141716A alone is without effect on learning and performance measures in this paradigm, when substituted for THC in monkeys receiving a repeated regiment of THC injections, it selectively increased errors in learning but had little or no effect on performance. These data demonstrate that learning is more sensitive than performance to the disruptive effects of chronic dosing with THC, and suggest that this paradigm is useful for detecting subtle disruptions in cognitive function under conditions of withdrawal from THC. Delatte, M.S., Winsauer, P.J., and Moerschbaecher, J.M. Tolerance to the Disruptive Effects of delta-9-THC on Learning in Rats. Pharmacology, Biochemistry & Behavior, 74(1), pp. 129-140, 2002.

The Cocaine Metabolite, Cocaethylene, May Prolong Euphoria and Attenuate Cocaine's Anxiogenic Effects

Dr. Aaron Ettenberg and his colleagues at the University of California have previously demonstrated that cocaine has both rewarding and anxiogenic effects. In their behavioral procedure, rats are trained to run a straight alley to receive a single cocaine injection. Animals show a pattern of "approach-avoidance" responding in this alley, suggesting that they retain a mixed association of both reward and anxiety with the drug-associated environment, prompting occasional 'retreats' during their traverse down the alley to the goal box. In a new study, the investigator was interested in the effects of concurrent alcohol on this biphasic effect of cocaine. Clinical studies report that alcohol prolongs the cocaine "high" while reducing any associated anxiety. Dr. Ettenberg proposed that the ethyl ester of the cocaine metabolite benzoylecgonine -- cocaethylene (CE) -- might be responsible for this effect. CE is formed only when alcohol is present with cocaine in the liver and has been observed to have many of the same behavioral effects of cocaine, suggesting that CE induces psychostimulant-like euphoria. However, CE has a more delayed onset of action than cocaine, so although it also produces a later anxiogenic effect, a prolongation of the positive/pleasant effects from CE may mask the aversive effect of cocaine. To test his hypothesis, the investigator administered i.v. cocaine or CE and tested animals in a conditioned place preference (CPP) procedure at various times after drug or metabolite infusion. Cocaine produced the usual place preference when conditioning (placement into the box) took place immediately after cocaine infusion, but animals that were not placed into the apparatus until 15 min after cocaine showed an aversion to the drug-paired environment during testing. Rats given i.v. CE were conditioned to the CPP apparatus at 0 min, 5 min, 15 min, and 30 min following CE infusion. As expected, a place preference developed in CE rats placed immediately into the box, but an aversion was seen in rats that had been exposed to the box 30-min post-administration. The aversion seen 30 min post-CE, however, was not as strong as that seen after 15 min post-cocaine. Thus, the time course of CE-induced reward and aversion appear consistent with the metabolite's relatively long half-life. Accordingly, the delayed euphoria induced by CE may indeed mask a dysphoric effect of cocaine when co-administered with alcohol, because plasma CE levels remain high even as an aversive opponent process is induced by falling cocaine plasma concentrations. Knackstedt, L.A., Samimi, M.M. and Ettenberg, A. Evidence for Opponent-process Actions of Intravenous Cocaine and Cocaethylene. Pharmacology, Biochemistry and Behavior, 72, pp. 931-936, 2002.

Only Five Days of Cocaine Self-administration Activates Brain Circuits Involved in Working Memory

Dr. Linda Porrino and her colleagues have been using a metabolic mapping technique (the 2-[14C]deoxyglucose method) to define brain circuits that are activated during various stages of cocaine dependency. The purpose of the current study was to define substrates that mediate the initial effects of cocaine in a nonhuman primate model of cocaine self-administration. While most brain imaging studies with human subjects are typically carried out on subjects who are already dependent, this primate model is ideally suited for identifying neurobiological correlates of drug-seeking and drug-taking behavior in the early stages of substance dependence. Rhesus monkeys were trained to self-administer cocaine and compared with monkeys trained to respond under an identical schedule of food reinforcement, over a five-day period, to model initial stages of drug taking in humans. Cocaine self-administration reduced glucose utilization in the mesolimbic system, including the ventral tegmental area, ventral striatum, and medial prefrontal cortex paralleling areas previously identified as being activated by experimenter-administered cocaine. However, in the current study, following self-administration, metabolic activity was also found to be increased in the dorsolateral and dorsomedial prefrontal cortex, and in the mediodorsal nucleus of the thalamus areas not activated by non-contingent drug delivery in the previous study. These findings reveal that self-administered cocaine engages additional brain circuits not activated merely by the pharmacological actions of this drug. Because these additional brain areas are involved in working memory, the present findings suggest that strong associations between cocaine and the internal and external environment are formed from the very outset of cocaine self-administration. Porrino, L.J., Lyons, D., Miller, M.D., Smith, H.R., Friedman, D.P., Daunais, J.B. and Nader, M.A. Metabolic Mapping of the Effects of Cocaine during the Initial Phases of Self-administration in the Nonhuman Primate. Journal of Neuroscience 22, pp. 7687-7694, 2002.

Tracking the Conditioned Effects of Cocaine During Abstinence

Human addicts are known to have persistent changes in indices of brain chemistry for a prolonged period of time after drug use has subsided. Likewise, cravings for cocaine are reported to be long-lived and persistent, providing the greatest challenge to effective treatment. Animal models have recently been extending the imposed withdrawal period and examining changes in underlying neurobiological substrates that may be associated with continued drug-seeking and craving or relapse. For example, exposure to drug-associated cues can prompt drug-seeking in rats previously self-administering cocaine for up to 4 months after extinction. Recent studies in the laboratory of Dr. Conan Kornetsky have mapped changes in brain glucose utilization (using 2-deoxy-D-[l-14C]glucose, or 2-DG) at 6 and 13 days after only a few high doses of morphine. They have found that changes are more widespread when animals have been conditioned to a morphine-paired environment and glucose utilization is assessed after placement back into this environment. Thus, with this technique, the investigators are able to ascertain which areas and circuits are activated by conditioned associations, long after an animal has received the drug. In the study reported here, rats were treated with 30mg/kg of cocaine or the saline vehicle, once daily for 7 consecutive days. Half of the rats were treated in the 2-DG chamber, where they remained for 1 hour following drug or saline administration, and others received injections in the home cage. On the eighth day after daily injections were stopped, all rats were sacrificed after 45 minutes in the 2-DG environment. The investigators noted a more extensive pattern of changes in glucose utilization in cocaine-conditioned animals (cocaine paired with 2-DG environment), than in those from the unconditioned group (cocaine paired with home cage). Local cerebral metabolic rates of glucose (LCMRglu) were significantly different from control rats in 12 areas from the conditioned group, and in only four from the unconditioned group. Common areas of decreased LCMRglu included the ventrolateral orbital cortex, the anterior nucleus accumbens, and area CA3 of the hippocampus -- indicating persistent changes in activity of these regions eight days after cessation of drug. But in addition, conditioned animals had decreased LCMRglu in the agranular insular cortex, the dorsomedial and lateral caudate, the basolateral amygdaloid nucleus, the subiculum, the medial and lateral thalamus and the lateral habenular nucleus. This differential pattern of activation implicates these additional structures in the long-lasting associations that form between cocaine and its associated environment. Involvement of structures such as the basolateral amygdala and the ventral subiculum have in fact been implicated in relapse, from studies of reinstated cocaine-seeking behavior in animals previously extinguished from self-administration. Future studies employing this 2-DG methodology hold potential to examine patterns of activation in animals withdrawn from drug, (including self-administered drug), over a more protracted period of time and thus, continue to map out the potential circuits of prolonged drug craving. Knapp, C.M., Printseva, B., Cottam, N. and Kornetsky, C. Effects of Cue Exposure on Brain Utilization 8 Days after Repeated Cocaine Administration. Brain Research, 950, pp. 119-126, 2002.


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