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

Research Findings - Behavioral Research

Social Experience Alters Sensitivity to the Rewarding Properties of Drugs of Abuse

Interactions between environmental and genetic factors influence individual responses to drugs of abuse, but in humans and many animal models it is not easy to determine the relative contribution of these influences. The use of mice for such studies is a clear advantage, because they are the best-developed vertebrate genetic model organism. However, until recently there have been relatively few studies of environmental influences on drug-abuse behaviors in the mouse. In the present study, investigators studied how the social group experience of mice with opposite aggressive and non-aggressive behavioral strategies modulates reinforcing effects of morphine and cocaine. Level of aggression was identified within the stock group and during encounters with unknown intruders. Then, aggressive, moderately aggressive, and non-aggressive male mice were housed together in social triads for two weeks and subsequently tested for drug self-administration using tail vein infusions during restraint. Conditioned place preference (CPP) procedures were also performed with morphine and cocaine for all animals. Results showed that highly aggressive mice self-administered morphine and cocaine in higher unit concentrations (1.5 and 1.5 mg/ml) than non-aggressive animals (0.5 and 0.25, 0.5, 1.0 mg/ml). Both morphine (2.5, 5.0, 10.0, and 20.0 mg/kg) and cocaine (2.5, 5.0, and 10.0 mg/kg) induced a CPP in non-aggressive mice at all doses. In contrast, morphine had no effect in highly aggressive mice, while cocaine-induced a CPP at only the highest doses (10 mg/kg). These results illustrate that social experience in a stable group alters sensitivity to the rewarding properties of drugs of abuse. Vekovischeva, O.Y., Semenova, S.G., Verbitskaya, E.V. and Zvartau, E.E. Effects of Morphine and Cocaine in Mice with Stable High Aggressive and Nonaggressive Behavioral Strategy. Pharmacology Biochemistry and Behavior, 77, pp. 235-243, 2004.

Repeated Social Defeat Stress -- Long Lasting Effects on Behavioral and Neural Response to Amphetamine

Previous studies have shown that repeated exposure to stress induces cross-sensitization to psychostimulants. In the present study, Dr. Elena Nikulina and her colleagues looked for changes in neural activation that might be responsible for this environment x drug interaction. Social defeat stress was induced by subjecting rats to short confrontations with an aggressive resident rat once every third day over a period of 10 days. The rats then received d-amphetamine injections either 7 or 60 days after the last stress exposure. Amphetamine induced significantly greater locomotor activity in stressed animals than in controls, even two months after the last social stress exposure. The investigators used immunohistochemical techniques for Fos-like proteins to identify neural activation due to stress with or without an amphetamine challenge. At one-week post-stress, there was a significant increase in Fos-like immunoreactive (Fos-LI) labeling in prelimbic and infralimbic cortical regions, NAc shell and core, medial, central and basolateral amygdala, and VTA, due to the stress itself. Amphetamine challenge produced much higher Fos-LI in the dorsal striatum, NAc core, and medial amygdala in stressed animals compared to controls, but it is not clear whether this is an additive effect or reflects a cross sensitization to amphetamine. However, after two months, Fos-LI was no longer different between the stressed and control animals, but amphetamine challenge revealed sensitized Fos-LI labeling in the VTA and the central amygdala. These results suggest that episodes of repeated social stress induce long-lasting changes in neural activity of the VTA and amygdala, which might represent a neurobiological mechanism for enduring cross-sensitization to the effects of psychostimulant drugs. Nikulina, E.M., Covington, III, H.E., Ganschow, L., Hammer, Jr., R.P. and Miczek, K.A. Long-Term Behavioral and Neuronal Cross-Sensitization to Amphetamine Induced by Repeated Brief Social Defeat Stress: Fos in the Ventral Tegmental Area and Amygdala. Neuroscience, 123, pp. 857-865, 2004.

Human Gene Polymorphisms Predict Caffeine-Induced Anxiety

Caffeine is the most widely used psychoactive drug in the world and its popularity is likely due to its subjective effects, including enhanced alertness and stimulation. Yet, there are large individual differences in acute response to caffeine, with some people experiencing increased stimulation whereas others experience anxiety, an undesirable effect. Although the mechanism underlying individual differences to caffeine is not known, there is evidence that some of this variability might have a genetic basis. One source of inherited variability might lie in variation in the genes that code for the adenosine receptor, as activation of this CNS receptor gives rise to caffeine's psychological effects. Polymorphisms in the A1 and A2a adenosine receptor may account for variations in subjective responses to caffeine. Interestingly, the adenosine receptor system is also thought to be involved in the regulation of anxiety. In this study, NIDA grantee Harriet deWit examined the association between variations in anxiogenic responses to caffeine and polymorphisms in A1 and A2a adenosine receptor genes. Healthy, infrequent caffeine users (N = 94), recorded their subjective mood states following a 150 mg oral dose of caffeine freebase or placebo in a double-blind study. Dr. deWit and colleagues found a significant association between self-reported anxiety after caffeine administration and two linked polymorphisms on the A2a receptor gene, the 1976C>T and 2592C>Tins polymorphisms. Individuals with 1976T/T and 2592Tins/Tins genotypes reported greater increases in anxiety after caffeine administration than the other genotypic groups. The study shows that an adenosine receptor gene polymorphism that has been associated with panic disorder is also associated with anxiogenic effects of caffeine. Identifying the genetic basis for individual variation in quality or magnitude of response to addictive drugs may aid in understanding the vulnerability and resiliency for developing drug addiction. Alsene, K., Deckert, J., Sand, P., and de Wit, H. Association Between A(2a) Receptor Gene Polymorphisms and Caffeine-Induced Anxiety. Neuropsychopharmacology, 28(9), pp. 1694-1702, 2003.

Prescription Drug Abuse Liability: Subjective Effects of Oral Oxycodone

National surveys have noted significant increases in the abuse of prescription opioids. One particular opioid, oxycodone, is a semisynthetic derivative of thebaine that is indicated for the relief of moderate-to-severe pain. It has been available for clinical use since 1915, and while information about this drug is available from preclinical studies and investigations in drug abusing populations, there are no studies that address abuse liability of oral oxycodone in non-drug-abusing subjects. The purpose of the present study was to investigate the subjective, psychomotor, and physiological effects of oxycodone in non-drug-abusing volunteers and to compare the effects to morphine, an opiate with documented abuse liability. Eighteen subjects received oral placebo, 10 mg oxycodone, 20 mg oxycodone, 30 mg oxycodone, 40 mg morphine, or 2 mg lorazepam in a balanced, cross-over design. Measures were taken pre-drug and for 5-h after drug administration. End-of-session and 24-h post-session measures were taken to assess residual drug effects and overall subjects' assessments of the drug effects. In general, oxycodone produced effects similar to those of other mu opioid agonists. Its subjective effects were found to be dose-related, with the majority of statistically significant effects found at the two highest doses tested. Oxycodone produced both pleasant and unpleasant effects, and morphine in general produced effects similar in magnitude to those of 10 mg and 20 mg oxycodone. Peak "liking" and "drug-wanting" was increased by all doses of oxycodone and by morphine, and ratings of "dislike" were lower with 20-mg and 30-mg oxycodone relative to placebo. Post-session ratings of overall liking and wanting were not statistically significant. Cognitive and psychomotor impairment were obtained with high doses of oxycodone, but to a much lesser degree than that of lorazepam. Nevertheless, this observation suggests that patients taking higher doses of oxycodone (e.g., 20-30 mg) might have difficulty with demanding cognitive or psychomotor tasks. Although oxycodone produced abuse liability-related subjective effects, it also produced unpleasant effects, as is typically observed with opioid drug administration to non-drug-abusing volunteers. Zacny, J.P. and Gutierrez, S. Characterizing the Subjective, Psychomotor, and Physiological Effects of Oral Oxycodone In Non-Drug-Abusing Volunteers. Psychopharmacology, 170(3), pp. 242-254, 2003.

Prescription Drug Abuse Liability: Oral Propoxyphene Effects in Non-Drug-Abusing Subjects

Like morphine and methadone, other prescription opioids have a potential for human abuse. It is therefore important to assess liability-related subjective effects of some of the more commonly prescribed prescription opioids, such as propoxyphene. Propoxyphene napsylate (Darvon-NĘ) is a centrally acting mu opioid, which is indicated for the relief of mild-to-moderate pain. It is available as a single entity product or as a compound product containing acetominophen, or aspirin and caffeine. A good deal has been learned about the psychopharmacology of propoxyphene from both preclinical and clinical studies. Its profile of subjective, physiological, cognitive and behavioral effects is similar to that of other mu opioids. However, the present study was designed to provide a systematic and comprehensive characterization of subjective, psychomotor, and physiological effects of this drug in a population of "non-drug-abusing" volunteers. Eighteen subjects received oral placebo; 50 mg propoxyphene napsylate; 100 mg propoxyphene napsylate; 200 mg propoxyphene napsylate; 40 mg morphine sulfate; and 2 mg lorazepam in a balanced, cross-over design. Measurements were taken pre-drug and for 300 min. after drug administration. Results indicated that both morphine and lorazepam produced subjective effects, but no statistically significant subjective effects were obtained with any dose of propoxyphene in the group as a whole. This was true even with doses twice as high as the typical clinically prescribed dose of 100 mg. When examining individual subject data, the investigators noted that approximately 30-50% of the subjects did report subjective effects from this drug. "Drug liking" was not consistently observed in this subset. Propoxyphene, unlike lorazepam, did not impair psychomotor or cognitive performance. In general, the present results suggest that patients differ in their sensitivity to subjective effects of this prescription opioid and therefore may be differentially vulnerable on liability for abuse. Zacny, J.P. and Goldman, R.E. Characterizing the Subjective, Psychomotor, and Physiological Effects of Oral Propoxyphene in Non-Drug-Abusing Volunteers. Drug & Alcohol Dependence, 73(2), pp. 133-140, 2004.

Early Life Events Increase Susceptibility for Cocaine Self-Administration: The Identification of "Sensitive Periods" in Development

Individual differences in susceptibility to drug abuse and addiction are influenced by both genetic and environmental factors, such as early life stressors and maternal care. In this study, the investigators compared the effects of manipulations during week 1 vs. week 2 of life on subsequent propensity to self-administer cocaine. Pups received daily subcutaneous saline injections, were handled briefly, or remained undisturbed during their respective treatment periods. The rats were then given the opportunity to self-administer cocaine when they were 70 days old. Only animals manipulated during the second week of life acquired drug-taking behavior. These effects were both stimulus- and gender-specific: Females handled during the second week of life acquired cocaine self-administration at the lowest dose, and females injected during the second week of life acquired at the intermediate dose. Males injected during the second week of life showed a similar, but more variable, drug-taking pattern. In addition, females that were either handled or saline injected during the first week of life were the most resistant to acquiring self-administration. The authors conclude that the second week of life represents a sensitive period in this preclinical model of environmental manipulations, for influencing the vulnerability to acquire cocaine self-administration, especially in females. The observed gender difference is consistent with findings from many other studies comparing vulnerability for self-administration in male versus female subjects. The results also support previous observations that increased maternal attention following stressful events during early development can confers protective effects for subsequent drug taking behaviors. This study makes a valuable contribution to understanding how early life events alter neurobiological substrates that may confer differential susceptibility to drugs of abuse in adolescents and adults. Flagel, S.B., Vazquez, D.M. and Robinson T.E. Manipulations During the Second, but not the First, Week of Life Increase Susceptibility to Cocaine Self-Administration in Female Rats. Neuropsychopharmacology, 28, pp. 1741-1751, 2003.

Stress Affects Response to Methamphetamine in Human Subjects

The present study by Dr. Harriet de wit and colleagues was designed to study the effects of acute stress on subjective and physiological responses to methamphetamine (METH) in human volunteers. Prior studies in laboratory animals indicate that both acute and chronic stress increase self-administration of psychostimulants such as amphetamine and cocaine. In this study healthy volunteers were exposed to an acute social stressor (using the Trier Social Stress Test (TSST), or no stress, immediately before10mg of METH or placebo. In this test, subjects are asked to perform a challenging arithmetic test in the presence of other people. The TSST has been shown to reliably induce increases in cardiovascular and endocrine parameters as well as subjective ratings of stress. Based on the preponderance of preclinical data, it was hypothesized that stress would enhance the subjective responses to METH as a consequence activating the HPA axis. Twenty-eight male subjects participated in two sessions, one with stress and the other without. They were randomly assigned to two groups that received either METH (n=16) or placebo (n=12) on both sessions. During each session, subjects underwent the TSST or no TSST, and then ingested METH) or placebo (PLAC). Over the next 1.5 hr self-reported mood measures and physiological measures, including salivary cortisol, were collected at regular intervals. Results indicated that both acute stress and METH produced mood-altering and physiological effects. Stress increased ratings of anxiety immediately after the TSST and increased salivary cortisol levels 20 min later. METH increased feelings of stimulation, and decreased fatigue and sedation, beginning about 20 min after drug administration and peaking at 60 and 90 min. Most interesting and surprising was the finding that stress dampened some early responses to METH (i.e., at 20 min), in particular reports of "energetic" and "calming" effects. By contrast, the stress manipulation increased responses to METH early in the sessions was on ratings of "want more drug." These results suggest that acute stress can alter the subjective responses to a low dose of METH, but these effects are short-lived. In addition, it is not always possible to predict "wanting" more drug, from changes in other drug-induced subjective states. Furthermore, paradigms such as the one employed in this study may be useful for studying self-medication models of drug abuse and addiction. Soderpalm, A., Nikolayev, L., and de Wit, H. Effects of Stress on Responses to Methamphetamine in Humans. Psychopharmacology, 170 (2), pp. 188-199, 2003.

A Novel Self-Administration Paradigm for Assessing "Affective" Properties

Drugs of abuse produce a wide range of affective experiences, from the more familiar euphorigenic or reinforcing effects, to aversive subjective states. Little is known about how this range of effects influences vulnerability to initiate drug abuse or progress to compulsive, uncontrollable addiction. We do know that individuals vary greatly on their initial response to drugs such as psychostimulants, and these individual differences may be an important influence on vulnerability. Few preclinical behavioral paradigms are available for the assessment of affective drug effects that fall along an appetitive - aversive continuum. Dr. William Woolverton at the University of Mississippi has developed a novel choice procedure to measure these effects in non-human primates. Animals are given a choice to perform operant responses to receive food reward only, or food reward plus drug on a concurrent (VR10 VR10 schedule). With this procedure, the degree to which a drug produces "positive" subjective states has been shown to determine preference for the drug plus food option. For example, when histamine is offered, preferences for the drug+food option decreases in a dose-related manner. However, when the drug choice is cocaine, preference for the drug+food option increases in a dose-related manner. This approach provides a new behavioral assay to investigate the affective effects of drugs of abuse, and will be useful for studying changes in subjective state over repeated drug exposures, under varying contextual influences, and individual differences. Woolverton, W.L. A Novel Choice Method for Studying Drugs as Punishers. Pharmacol Biochem Behav, 76, pp. 125-131, 2003.

Malleability of Early Social and Environmental Enrichment Effects in the Rat

Early social and environmental enrichment experiences have been shown to have profound effects on subsequent responsivity and vulnerability to drugs of abuse in animals. For example, studies on opiates have shown that group-housed rats are more sensitive than isolates to both antinociceptive and reinforcing effects of opioid mu agonists such as morphine and heroin. Previous studies suggest that these effects may be due to differences in opiate receptor density, which is increased under conditions of group housing. The present study examined the effects of these environmental manipulations on sensitivity to kappa opioid agonists. Animals were obtained at weaning (21 days) and assigned to isolate (IC) or group housed (enriched or EC) conditions for seven weeks. EC rats were reared in an enriched environment with various objects for exploration and interaction. The EC group was subsequently found to be significantly more sensitive to analgesia produced by highly selective kappa agonists. When tested for conditioned place preference, all animals spent less time in the compartment previously paired with a kappa agonist (as has previously been reported), but enriched rats were more sensitive to this effect. At week fourteen, the investigators reversed housing conditions in these two groups - isolates were switched to group housing with enrichment and group housed rats were switched to isolated housing. Seven weeks later tail-flick analgesia was re-determined and a reversal of the housing condition influence was observed. Hence, the kappa agonist produced less analgesia in previously EC animals switched to IC, and more analgesia in IC rats now living under EC conditions. While additional behavioral investigations need to be conducted to determine if this observation generalizes to direct measures of drug reinforcement and reward, it suggests that the effects of early, deleterious environmental conditions may be overcome by subsequent environmental stimulation. Smith, M.A., Bryant, P.S. and McClean, J.M. Social and Environmental Enrichment Enhances Sensitivity to the Effects of Kappa Opioids: Studies on Antinociception, Diuresis and Conditioned Place Preference. Pharmacol Biochem Behav, 76, pp. 93-101, 2003.

Exercise Effects Central Opioid Systems - Behavioral Evidence of Cross-Tolerance

Exercise stimulates the release of endogenous opioid peptides and increases nociceptive thresholds in humans and animals. This observation suggests that repeated exercise might induce a tolerance in endogenous opioid systems. To test this hypothesis, Dr. Mark A. Smith and colleagues recently conducted a study with rats assigned to either sedentary (S) or exercise (E) conditions, from the time of weaning at age 21 days. Rats in the E group were housed in cages with a 35cm diameter exercise wheel. These housing conditions remained in effect for six weeks, at which time weekly testing was conducted with tail flick measures to assess analgesia. E rats were found to have higher baseline tail-withdrawal latencies in warm water when tested in the dark phase of the light cycle. Morphine produced 1.6 to 2.7 times greater analgesia in the S group at 50 and 55 degrees, respectively. Similar results were obtained with levorphanol, buprenorphine, butorphanol and nalbuphine. A naloxone challenge revealed withdrawal symptoms in both E and S group, but the mean symptom withdrawal score for E rats was two times greater than seen under S conditions, with a significant group X treatment (naloxone versus saline) interaction. At 15 weeks, housing conditions were reversed and after 6 weeks under these new conditions, analgesia testing was repeated with buprenorphine. E rats now living in S conditions showed an enhanced sensitivity to the analgesic effects of this opiate, whereas S rats changed to E conditions now were less sensitive to buprenorphine in the tail flick test. These findings support the hypothesis that exercise produced functional changes in the mu-opioid receptor system. In addition, these receptor substrate alterations appear malleable to subsequent change in physical activity level. Smith, M.A. and Yancey, D.L. Sensitivity to the Effects of Opioids in Rats with Free Access to Exercise Wheels: _-Opioid Tolerance and Physical Dependence. Psychopharmacol, 168, pp. 426-434, 2003.

Early Environmental Enrichment Alters Nicotine's Behavioral Activating Effects

There are suggestions from the literature that adolescent animals may be more sensitive to both the behavioral stimulatory effects of nicotine, and to its reinforcing properties. Thus, it is important to investigate how environmental factors affect these differential sensitivities. Many previous investigations with animals have revealed that environmental enrichment (EC) conditions affect subsequent response to drugs of abuse. For example, EC rats are more sensitive to the acute behavioral and neurochemical effects of amphetamine than those raised in an impoverished (IC) environment. EC rats also exhibit less locomotor sensitization to repeated amphetamine treatment, probably due to this greater initial sensitivity. In the laboratory of Dr. Michael Bardo, investigators have been studying how early environmental conditions influence the behavioral effects of psychostimulants. In the present study, 21-day-old rats were assigned to EC, IC or a social (SC) enrichment condition. SC rats were group housed, and EC animals also had the additional stimulation of objects to explore in their environment. In two separate assessments, conducted at 51 days of age, animals were tested for locomotor effects of s.c. 0.2 or 0.8 mg/kg of nicotine, compared to a saline control injection. Eight drug challenges were performed -- one every 48 hours. On the ninth session, rats were tested for sensitization with 0.8 mg/kg nicotine. In Experiment 1, data from IC and EC rats were examined from the first and the last drug treatment (session 1 and 8). EC rats exhibited significantly less nicotine-induced locomotor change over the 60 min post injection than did IC animals. This was true of both early session hypoactivity, and later session hyperactivity produced by 0.2 mg/kg. On the high dose test for sensitization, EC rats again showed less locomotor effects from the nicotine injection. In Experiment 2, EC and SC groups were examined with only 0.2 mg/kg nicotine over a similar eight sessions. Neither group showed locomotor effects after nicotine on session one and there were few changes from saline controls on session 8. On a day nine challenge with 0.8 mg/kg, only SC rats exhibited nicotine hyperactivity, suggesting that EC blocked the development of behavioral sensitization. Overall, these observations suggest that early environmental enrichment induces a neurobiological substrate change that subsequently renders an animal less sensitive to nicotine's behavioral stimulation. Additional studies are needed to determine the effect of EC on the reinforcing properties of nicotine. Green, T.A., Cain, M.E., Thompson, M. and Bardo, M.T. Environmental Enrichment Decreases Nicotine-induced Hyperactivity in Rats. Psychopharmacol, 170, pp. 235-241, 2003.

Compulsive Drug use and Behavioral Sensitization: Are They Related?

Enhanced dopaminergic activation and behavioral stimulation have been well documented in preclinical studies of repeated psychostimulant administration. This psychostimulant sensitization has been implicated in neurobiological substrate changes that may contribute to the process of addiction. As addiction involves an escalation of drug use over time, Dr. George Koob and colleagues at The Scripps Research Institute have suggested that a 6 hr drug access model may mimic the transition to compulsive abuse. In this procedure, groups of animals are initially trained to respond for food reward and then allowed to self-administer cocaine for either 1 (short access, SA) hr or 6 (long access, LA) hr periods per day. SA animals typically develop stable daily intake, whereas LA rats show dramatic increases in number of cocaine infusions taken. Recently Dr. Koob compared animals trained in these two procedures, versus saline control groups, on measures of brain c-fos activation and locomotor response to a challenge injection of cocaine. In this study, all groups self-injected for 8 days and then underwent a 14-day withdrawal. On day 14 animals were returned to the operant chambers and allowed to bar press for one cocaine infusion. For some rats, the lever was withdrawn and they remained in the operant chamber without further drug availability, for one hour, after which they were sacrificed for c-fos measurements. C-fos counts showed that SA rats (versus 1 hr saline animals) had a significant elevation of this intermediate early gene in the lateral habenula, the prefrontal cortex and the nucleus accumbens core. There were no significant differences in the ventral tegmental area, central nucleus of the amygdala, bed nucleus of the stria terminalis, striatum or nucleus accumbens shell. LA rats showed no changes in c-fos in any area of the brain. Other animals were transferred immediately after a single cocaine infusion to locomotor activity chambers. Locomotor activity measures were compared with baseline activity counts from the previous (non-drug) day (i.e., from day 13 of withdrawal). While all saline and drug groups had similar activity counts on the baseline test, SA rats showed elevated activity scores (significantly greater than 1 hr saline rats) after a single cocaine self-injection, indicating the development of sensitization. LA rats, however, failed to show locomotor activation to cocaine on withdrawal day 14 -- their locomotor activity was not significantly different from their own baseline or from a saline group that also received 1 cocaine infusion immediately before testing. The investigators suggest that LA animals underwent neuroadaptations that homeostatically countered the development of sensitization seen in the SA group. The mechanisms involved in this process remain to be identified. Ben-Shahar, L., Ahmed, S.H., Koob, G.F. and Ettenberg, A. The Transition from Controlled to Compulsive Drug Use is Associated with a Loss of Sensitization. Brain Res, 995, pp. 46-54, 2004.

Early Lead Exposure Enhances Vulnerability for Cocaine Self-Administration

Dr. Jack Nation at Texas A&M University has been studying the effects of prenatal exposure to metals and the subsequent effects of this exposure on indices of drug abuse vulnerability in an animal model. Previously he has demonstrated that developmental lead exposure enhances behavioral sensitization with repeated cocaine administration but reduces the behavioral effects of acute cocaine. In the present study, female rats received 30 days of 16mg oral lead exposure and were bred with non-exposed males. Lead dosing was continued during gestation and into the lactation period. Pups were weaned on post-natal day 21 and tested for i.v. cocaine self-administration beginning on day 70. After training on stable responding for doses between 0.030 and 0.500 mg/kg/infusion, a dose response curve was determined. Blood and tissue samples were then collected and analyzed for lead concentration. Comparisons between lead exposed rats and those from dams receiving only sodium acetate vehicle revealed that the lead group was more sensitive to low doses of i.v. cocaine. Thus, whereas little self-administration was seen with 0.030 mg/kg for either group, at 0.060 mg/kg lead exposed rats made responses to receive cocaine at a rate greater than two times that seen in vehicle exposed animals. Lead analysis indicated that high concentrations detected in littermates at post-natal days 1 and 21 had returned to control levels by the time of self-administration testing. These results suggest that lead exposure during development may enhance the vulnerability to acquire drug abuse behaviors, because there is an enhanced sensitivity to the drug. The mechanism for this change in sensitivity remains to be determined but the authors suggest that either pharmacokinetic changes or alterations in central mesocorticolimbic dopaminergic systems produced by lead may be responsible. Nation, J.R., Smith, K.R. and Bratton, G.R. Early Developmental Lead Exposure Increases Sensitivity to Cocaine in a Self-Administration Paradigm. Pharmacol Biochem Behav, 77, pp. 127-135, 2004.

Are There Critical Periods for the Effect of Methamphetamine-Induced Cognitive Deficits?

In an animal model of postnatal methamphetamine (MA) administration, exposure during post-natal (PN) days 11 to 20 produces lasting deficits in spatial learning and memory, while early exposure (PN days 1-10) is without effect. PN days 1-20 represent a pre-weaning period in the rat that corresponds to the third trimester of human gestation, and it is likely that drug effects on brain hippocampal development in particular underlie these cognitive effects. In particular, rapid neuronal growth and differentiation is seen in the hippocampus during PN days 11-15. The investigators suggest that since MA produces prolonged elevations of corticosterone on PN day 11, neurotoxic effects of this stress hormone on hippocampal development may be responsible for subsequent cognitive deficits. In the present study, Dr. Vorhees used the Morris water maze as a behavioral test of hippocampally-mediated learning and memory. MA in a dose of 10 mg/kg was administered to pregnant dams four times daily on either PN days11-15 or PN days 16-20. Behavioral testing in offspring began on PN day 50 using a modified Morris maze procedure with a small platform to test learning. Animals were first trained with the platform in a familiar underwater location, and then assessed in a "shifted platform" version of the task where they have to learn a new platform location. During acquisition several dependent measures of learning are collected, including time to locate the platform, path length and distance from the platform. "Probe" tests were conducted following acquisition to assess memory. Average distance from the platform and percent time in the target quadrant of the pool were measured during the probe tests. MA administration impaired the ability of animals to learn the maze task following PN exposure on days 11-15, and during probe tests MA rats tended to be further from the former platform site. Animals exposed later during the PN period showed no deficits in learning the task. When tested with the shifted platform, again rats exposed on PN days 11-15 showed deficits in learning, but there were no treatment-related group differences on the probe test for memory. No effects were seen on learning or memory in this shifted-platform test by animals exposed later during the PN period. These differences reveal a critical window for MA exposure to produce cognitive deficits seen in adulthood. Thus, spatial navigation deficits in both 'learning' and 'shifting' response sets were apparent in animals exposed to MA on PN days 11-15, whereas drug exposure beginning five days later was without effect. As this critical period corresponds to development in the central HPA axis that influences hippocampal integrity, it is possible that MA compromises this integrity via glucocorticoid release and its ensuing neurotoxic effects on hippocampal neurons. Williams, M.T., Moran, M.S. and Vorhees, C.V. Refining the Critical Period for Methamphetamine-Induced Spatial Deficits in the Morris Water Maze. Psychopharmacology, 168, pp. 329-338, 2003.

Serotonin Challenge Reveals Long-Term Cognitive Deficits in a Primate Model of MDMA Abuse

Numerous recent reports have suggested that MDMA (ecstasy) abuse in human abusers may produce long-term cognitive deficits, most notably in short-term memory. However, studies on human abusers are fraught with problems of "street drug" contamination, the unreliability of self-report, and high rates of poly-drug abuse. Studies with non-human primates can assess drug effects on complex cognitive function under strictly controlled conditions where typical street doses of MDMA can be administered. In the research program of Dr. Michael Taffe at The Scripps Research Institute, investigators have been studying the effects of repeated, high dose MDMA (4 days, 10 mg/kg i.m., b.i.d., as the salt). The present study was conducted 11 months after drug administration to three male rhesus monkeys, with three others serving as controls for yoked vehicle administration. This regimen reduced CSF 5-HIAA (the major metabolite of serotonin) approximately 50% for up to 17 weeks. Upon sacrifice at 5-8 months after completion of this study, postmortem analyses revealed 76-93% reductions in neocortical and hippocampal 5-HT content in the MDMA exposed animals versus controls. The six monkeys were treated with a rapid tryptophan depletion (RTD) procedure that dramatically lowers tryptophan in plasma and CSF in both humans and nonhuman primates. The control procedure involved oral administration of a balanced amino acid mixture. Electrophysiological measures of brainstem auditory evoked potentials (BSAEP) were taken following gavage with either the RTD mixture or the amino acid control, and behavioral testing was conducted on memory (SOSS, DNMS), reinforcer efficacy (with Progressive Ratio responding), reaction time and BMS. In addition, cognitive assessments were made with a modified CANTAB battery, previously used by this investigator. The RTD treatment produced significant reductions in P4 latencies on BSAEP in animals with a MDMA drug history, while not affecting latencies in vehicle treated monkeys. On self-ordered spatial search (SOSS), performance of control animals was significantly improved by the RTD, but there were no changes in performance of MDMA monkeys. No other differences were noted. These findings suggest that heavy MDMA use may produce long-lasting neurobiological changes, with cognitive consequences that do not become evident until unmasked by a challenge to the central 5-HT system. The observation that differences were seen on SOSS measures only might indicate that working memory is more sensitive to alterations of the serotonergic system. Furthermore, the RTD-induced impairment of early auditory processing in MDMA treated monkeys resembles P4 latency decreases seen during original drug exposure - an effect that persisted for 13 weeks post-drug. Overall, these observations are significant because challenges to the central 5-HT system later in the life of young ecstasy abusers, (e.g., stroke, degenerative disease or central transmitter changes with normal aging), may unmask the appearance of long-lasting MDMA-induced cognitive and central processing deficits. Taffe, M.A., Huitron-Resendiz, S., Schroeder, R., Parsons, L.H., Henriksen, S.J. and Gold, L.H. MDMA Exposure Alters Cognitive and Electrophysiological Sensitivity to Rapid Tryptophan Depletion in Rhesus Monkeys. Pharmacol Biochem Behav, 76, pp. 141-152, 2003.

Estrogen Enhances Stimulant-Induced Behavioral Activity in Female Rats

It is well established that locomotor activating effects of cocaine are greater in female than male rats. Several observations suggest that this sex difference is mediated by estrogen: For example, these sex differences emerge after puberty; cocaine-induced locomotion is greater during proestrus (when estrogen is highest) and estrous, than during diestrus; and cocaine-induced locomotion in ovariectomized rats is enhanced by the chronic administration of estrogen. Drs. Kathryn Cunningham, Mary Thomas and colleagues at the University of Texas Medical Branch have found evidence that the locomotor hyperactivity induced by 3,4methylenedioxymeth-amphetamine (MDMA, ecstasy) is also greater in female than male rats. They previously reported greater locomotor hyperactivity in female than male rats in response to 4 mg/kg doses of (+)-MDMA (Bubar, Thomas, & Cunningham, 2001). In a follow-up study, these researchers compared locomotor activity induced by either (+)-MDMA or cocaine, in rats that were ovariectomized (OVX) and in rats that were ovariectomized plus given a 17_-estradiol (E2) implant (OVX+E2). Locomotor activity was examined for two hours following (+)-MDMA (1, 2, 4 mg/kg ip) or cocaine (5, 10, 20 mg/kg ip). During initial habituation to the open field activity chambers, activity declined from Day 1 to Day 3. The investigators observed that the OVX+E2 group displayed retarded habituation of vertical and horizontal activity relative to the OVX group, although this difference did not achieve statistical significance. Both MDMA and cocaine administration dose-dependently increased locomotor activity. Both horizontal and vertical activity were elevated in the OVX+E2 group relative to the OVX group at the highest MDMA dose (4 mg/kg) and at the highest two cocaine doses (10 and 20 mg/kg), indicating E2 enhancement of MDMA-induced and cocaine-induced locomotor activation at those doses. Examination of the time course of locomotor activation indicated differential effects of MDMA and cocaine. Within 5-min of cocaine administration, both OVX and OVX+E rats exhibited hyperactivity followed by a decline over the 2-hr session. In contrast, MDMA activity increased only slightly in the first 20 min followed by hyperactivity between 20 and 40 min following injection. These differences appear in part to be related to the pharmacokinetic profiles of MDMA and cocaine. Although both drugs potentiate efflux of dopamine (DA) and 5-hydroxytryptamine (5-HT, serotonin), the drugs have different time courses for this potentiation -- MDMA produces an immediate increase in 5-HT, but a delayed increase in DA, whereas cocaine produces an immediate increase in both 5-HT and DA. Thus, the present data suggest that E2 may play a greater role in altering DA activity than 5-HT activity. Zhou, W., Cunningham, K.A., and Thomas, M.L. Estrogen Effects on the Hyperactivity Induced by (+)-MDMA and Cocaine in Female Rats. Behavioral Neuroscience, 117, pp. 84-94, 2003.

Sex-Dependent Effects of Δ9-tetrahydrocannabinol on Locomotor Activity in Mice

Prior research on the locomotor-altering effects of Δ9-tetrahydrocannabinol in rodents has shown suppressive effects at higher doses, facilitation at lower doses, and tolerance to the suppressive effects with repeated dosing. In the present study, Dr. Jenny Wiley of the Virginia Commonwealth University examined sex differences in Δ9-tetrahydrocannabinol's locomotor effects in mice. A range of single-injection doses, 1 - 30 mg/kg ip, was delivered to separate groups of mice on two separate test days. On Day 1, males did not exhibit increased locomotor activity compared to vehicle at any dose. Females, on the other hand, exhibited elevated locomotion at 1, 3, and 10 mg/kg. The enhancement at 1 and 10 mg/kg were each statistically higher than vehicle effects, and statistically higher than effects seen in males. Following 3 days of daily injections of 10 mg/kg (two injection on Days 2 and 3 and one injection on Day 4), on Day 5, the dose-response curve was re-determined. Again, males did not exhibit increased locomotor activity compared to vehicle at any dose. Females, however, exhibited statistically significantly increased locomotor activity with the 3, 10, and 30 mg/kg dose. However, at the 1mg/kg dose, no enhancement of locomotor activity was observed, suggesting the development of tolerance. At none of the doses was activity-suppression observed in either males or females. Δ9-tetrahydrocannabinol's activity-inducing effects in females, but not in males, observed in the present study is consistent with prior observations from rats showing greater female sensitivity to Δ9-tetrahydrocannabinol's locomotor-suppressive effects, antinociceptive effects, and cataleptic effects. Wiley, J.L. Sex-Dependent Effects of Δ9-tetrahydrocannabinol on Locomotor Activity in Mice. Neuroscience Letters, 352, pp. 77-80, 2003.


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