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

Research Findings - Behavioral Research

Environmental Enrichment During Rearing Selectively Affects Dopamine Transport in the Prefrontal Cortex

In preclinical studies, early environmental enrichment (EC) affects subsequent behavioral responsivity to drugs of abuse such as amphetamine. For example, EC rats show an attenuated amphetamine-induced sensitization and a decrease in self-administration of this drug. EC also induces structural changes in neurons of the cortex and striatum. These structural changes may affect synaptic transmission in brain dopamine systems that give rise to behavioral effects of psychostimulants. Recently, NIDA-funded investigators at the University of Kentucky performed a kinetic analysis of dopamine transporter (DAT) function in the medial prefrontal cortex (mPFC), striatum and nucleus accumbens (NAS) of rats reared in EC conditions or in isolation (IC). Initially the investigators administered the selective DAT inhibitor, GBR 12935, to assess behavioral effects on the locomotor activity of EC and IC groups. Although EC animals had a lower basal level of behavioral activity, GBR increased activity to a greater extent in this group than in the IC group, when given acutely (dose range: 1.0-10.0 mg/kg). Surprisingly, when 3.0 or 5.6 mg/kg was given repeatedly, only the EC group developed a behavioral sensitization to the locomotor activating effects of GBR. The authors note that this contrasts with previous observations from repeated amphetamine administration, but behavioral differences may be accounted for by different neurochemical mechanisms of action in central dopamine neurons. Subsequent DAT analysis revealed no differences in Ki values of [3H]dopamine uptake between groups for any brain area. However, EC significantly decreased (36%) Vmax in the mPFC, in comparison to the IC condition. This difference was evident for the mPFC only, with no between group differences for subcortical areas. HPLC measures of the DA metabolite DOPAC also revealed a significant difference between groups for the mPFC only. The observation that EC selectively decreases DAT function and DA metabolism in the mPFC suggests that the environment can modulate the activity of central DA systems that participate in chronic neuroadaptations that give rise to psychostimulant craving and relapse. Zhu, J., Green, T., Bardo, M.T. and Dwoskin, L.P. Environmental Enrichment Enhances Sensitization to GBR 12935-induced Activity and Decreases Dopamine Transporter Function in the Medial Prefrontal Cortex. Behavioral Brain Research, 148, pp. 107-117, 2004.

Glutamate Group II mGluR2/3 Receptor Activation Attenuates Relapse Triggered by Drug-related Stimuli

Alterations of central glutamatergic neurotransmission are involved in the neuroadaptive changes that give rise to psychostimulant-induced behavioral sensitization. The metabatropic Glu2/3 agonist LY379268 attenuates amphetamine's acute behavioral activating effects and the locomotor sensitization produced with repeated cocaine treatment. A recent study conducted by Dr. Friedbert Weiss and colleagues at The Scripps Research Institute sought to determine if this glutamatergic receptor is also involved in relapse to drug-seeking behavior. These investigators employed a preclinical reinstatement paradigm that mimics the ability of drug-associated environmental cues that can trigger relapse in humans. Rats were taught to self-administer cocaine, and drug delivery was paired with a discrete stimulus cue. Other animals were taught to make a response for a non-drug reward — sweetened condensed milk. Milk delivery was also paired with a discrete cue. After animals were trained to respond to receive milk or self-administer cocaine, they underwent extinction procedures during which responses no longer had consequences (i.e., no drug and no milk delivery, and no cue presentation). After animals extinguished responding, reward-paired cues were reintroduced and the reinstatement of responding for milk or cocaine was measured. Results show that cocaine-paired cues prompted a return of drug-seeking behavior and that LY dose-dependently (0.0, 0.3, 1.0, 3.0 mg/kg) decreased reinstatement. Exposure to the milk-paired cue also triggered reinstatement, and LY also attenuated the relapse to operant responding for this non-drug reward, but only at the highest dose tested. When the investigators examined LY effects on primary reinforcement, they found the LY compound decreased the number of cocaine-reinforced responses, but only with the highest dose of this mGlu agonist, whereas responding for milk was not altered at any dose of LY. These findings show that a mGlu 2/3 agonist is more potent in reversing reinstatement induced by environmental stimuli paired with cocaine than in blocking cue-induced behavior per se. These data further suggest that group II metabotropic glutamate receptors may be a target for pharmacotherapeutic interventions in relapse prevention. Baptista, M.A.S., Martin-Fardon, R. and Weiss, F. Preferential Effects of the Metabotropic Glutamate 2/3 Receptor Agonist LY379268 on Conditioned Reinstatement Versus Primary Reinforcement: Comparison Between Cocaine and a Potent Conventional Reinforcer. Journal of Neuroscience, 24, pp. 4723-4727, 2004.

Relapse to Cocaine-seeking Behavior for Up To One Year After a Single Drug Exposure

Environmental stimuli associated with the reinforcing properties of drugs of abuse are able to trigger relapse during abstinence. However, it is not known whether these learned associations between the environment and early drug experiences contribute to the development of compulsive drug taking and addiction. Dr. Friedbert Weiss and colleagues trained rats to lever respond for food and then replaced food with cocaine for one training session. These drug deliveries were paired with a discrete cue. This cocaine self-administration session was followed by another conditioning session, where responding on a different lever produced saline infusions and a new cue. After this session, animals experienced daily extinction sessions wherein responses were without consequence (no i.v. infusions and no cue presentation), until animals reached a low level of responding during the session. Then animals were returned to their home cages and removed at three-month intervals to test for cue-induced relapse. In this model of relapse, animals were placed back in the test chamber where cues previously paired with drug or saline delivery were reintroduced. When the cues previously paired with a single cocaine self-administration were presented 3, 6 and 9 months later the cues induced drug seeking behavior, but not when the cues were introduced 12 months later. Presentation of the cue previously paired with saline did not reinstate responding. For comparison, a separate group of rats underwent a similar sequence of training and test procedures, but with a non-drug reward — sweetened condensed milk. While these animals did respond to receive milk, reinstatement was not seen following extinction when a milk-paired cue was reintroduced; nor was reinstatement seen 3 months later. The present findings indicate that environmental cues paired with a drug of abuse exert a potent and persistent effect on drug-motivated behavior. Environmental cues paired with a non-drug reward such as milk, do not exert as powerful a response. Moreover, these drug-paired cues can exert a long-lasting effect on behavior after only a single drug self-administration session, which suggest environmental cues may contribute to the transition from initial drug use to addiction. Ciccocioppo, R., Martin-Fardon, R. and Weiss, F. Stimuli Associated with a Single Cocaine Experience Elicit Long-lasting Cocaine-seeking. Nature Neuroscience, 7, pp. 495-496, 2004.

Chronic Cocaine Exposure Produces Learning Deficits on a Cognitive Task that Involves the Orbitofrontal Cortex

Studies in both humans and animals have shown that addictive drugs cause long-lasting neural changes in prefrontal cortex. The orbital frontal prefrontal cortex (OFC) is of particular interest because it appears to be involved in the integration of motivational information with environmental cues that signal reward, and in guiding goal-directed behavior. To test the hypothesis that OFC-mediated behaviors are altered by drug exposure, Dr. Geoffrey Schoenbaum and his colleagues examined the effects of cocaine exposure on performance in an odor discrimination task that involves the OFC. In this task, rats are trained to respond to odor cues to obtain reward and avoid punishment, and to modify these responses when the rules (i.e., cue-outcome associations) are reversed. Rats given injections of cocaine (30 mg/kg/d, i.p.) or for 14 days and then trained on this discrimination after a 2-week withdrawal from cocaine, failed to show normal changes in response latency during discrimination learning, and they were slower than control animals that did not receive cocaine to learn the reversal rules. These behavioral impairments seen in cocaine-exposed rats were identical to the effects seen in rats with OFC lesions. These data indicate that cocaine exposure can cause long-lasting effects on OFC-dependent functions. The experimenters also tested the rats for the development of behavioral sensitization to the locomotor activating effects of cocaine. They found no correlation between the degree of locomotor sensitization and the magnitude of the learning deficits, suggesting that the brain changes underlying the behavioral effects needed for the discrimination task are different from those mediating psychomotor sensitization. The results of this study, together with other studies of OFC function, indicate that cocaine exposure produces an impaired ability to use motivational value for guiding responding, which may help explain why addicts continue to take drugs, or to relapse, despite the adverse outcomes of drug taking. Dr. Schoenbaum is testing this idea in ongoing experiments in which rewards are systematically devalued. Schoenbaum, G., Saddoris, M.P., Ramus, S.J., Shaham, Y. and Setlow, B. Cocaine-experienced Rats Exhibit Learning Deficits in a Task Sensitive to Orbitofrontal Cortex Lesions. European Journal of Neuroscience, 19, pp. 1997-2002, 2004.

Role of Dose and Delay in Drug Choice

Drug abuse is often considered a problem related to impulse-control disorders, but little is known about the factors that determine the choice to self-administer a drug in a self-control/impulsivity paradigm. Animal models provide excellent procedures for studying choice behavior and its control. The present study was designed to evaluate choice between a low dose of cocaine administered after a relatively short delay (impulsive option) and a high dose of cocaine following a relatively longer delay (self-control option). Rhesus monkeys self-administered intravenous cocaine in a discrete trials choice procedure. First, choice was between different 3:1 doses (0.3/0.1 and 0.1/0.03 mg/kg per injection) following equal 30-s delays to infusion. Second, choice was between equal doses (0.1 mg/kg per injection) following 3:1 delays (30 s/10 s, 90 s/30 s, 270 s/90 s, 810 s/270 s). Third, choice was between 0.1 or 0.03 mg/kg per injection after the same 3:1 delays with the larger dose following the longer delay and the smaller dose following the shorter delay. Fourth, the same 3:1 delays were used to study choice between 0.3 and 0.1 mg/kg per injection. The results showed that with equal delays, the larger dose of cocaine was chosen almost exclusively, and with equal doses, the shorter delay was chosen almost exclusively. When both dose and delay were manipulated, mean large-dose (0.1 mg/kg per injection) choices for three of four subjects was 98% when the delays were the shortest (30 s/10 s), but this preference reversed as the delays increased, so that 74% of choices were for the smaller dose (0.03 mg/kg per injection) at the longest delays (810 s/270 s). This systematic decrease in large-dose choices as the absolute, but not relative, values of the delays were increased, was also observed with the higher dose combination. Delay discounting was supported by the present findings in that the value of a large reinforcer (higher cocaine dose) was decreased as its delay to presentation was increased. The importance of not only relative, but also absolute, values of delays to drug reinforcement in determining drug choice was also demonstrated. Thus, a self-control/impulsivity paradigm can be extended to conditions with non-human subjects and drug reinforcers. Anderson, K.G. and Woolverton, W.L. Effects of Dose and Infusion Delay on Cocaine Self-administration Choice in Rhesus Monkeys. Psychopharmacology, 167(4), pp. 424-430, 2003.

Nicotine Sensitizes Responding For Conditioned Reinforcers

It has been known for many years that stimuli associated with an addictive drug can acquire conditioned reinforcing properties. That is, environmental stimuli present at the time of drug use can themselves reinforce responding (e.g., drug seeking and drug taking). Moreover, clinical observations indicate that smoking depends strongly upon conditioned reinforcement (i.e., cues support smoking behavior), but little is known about the effects of repeated nicotine exposure on these processes. The purpose of this study was to investigate the consequences of prior repeated nicotine exposure on responding with conditioned reinforcement and on the potentiation of conditioned reinforcement by intra-nucleus accumbens (NAc) amphetamine infusion. Rats received repeated saline or nicotine injections (0.35 mg/kg; 15 days) and were, following 3 days of withdrawal, trained to associate a tone + light stimulus with water reinforcement for 10 days. Animals were subsequently tested on acquisition of a new instrumental response with conditioned reinforcement (i.e., 14 days after the final nicotine injection). In additional experiments, animals received an infusion of amphetamine (20 microg in NAc) prior to the conditioned reinforcement test. The results indicated that prior repeated nicotine exposure produced a behaviorally specific enhancement of responding with conditioned reinforcement. Furthermore, repeated nicotine pretreatment also augmented the potentiation of conditioned reinforcement by intra-NAc amphetamine. These findings demonstrate that prior repeated nicotine exposure augments the control over behavior by a conditioned reinforcer. Such long-lasting alterations in incentive motivational processes produced by repeated nicotine exposure may depend on drug-induced neuroadaptations in dopamine-regulated signaling within limbic-striatal brain regions that could underlie persistent and compulsive aspects of addiction. Olausson, P., Jentsch, J.D. and Taylor, J.R. Repeated Nicotine Exposure Enhances Responding with Conditioned Reinforcement. Psychopharmacology, 173, pp. 98-104, 2004.

Morphine-elicited Morphine Withdrawal

Recent evidence indicates that associative learning processes are important for regulating basic aspects of drug addiction. In particular, Pavlovian conditioning mechanisms have been hypothesized by NIDA grantee Shepard Siegel to mediate drug tolerance and withdrawal. According to this analysis, cues present at the time of drug administration function as conditioned stimuli (CSs). The direct effect of the drug constitutes the unconditioned stimulus (UCS), which prior to any learning elicits unconditioned responses (UCRs) that compensate for drug-induced disturbances. After paired presentations of the CS and UCS, drug compensatory responses are elicited by predrug cues (i.e., CSs). These conditioned compensatory responses (CCRs) are hypothesized to mediate the development of tolerance and the elicitation of withdrawal in drug-associated contexts. Although many drug associated CSs are exteroceptive (i.e., in the environment) , another source of drug associated CSs can be found in the early, drug-onset cues (DOCs) or sensations that precede and signal the later, larger drug effect. The present experiment evaluated the contribution of DOCs to morphine withdrawal in rats. It was hypothesized that DOCs would elicit CCRs in the form of hypoalgesia and other withdrawal signs. In these experiments, rats were given a 50mg/kg injection of morphine on 10 consecutive days and tested on a separate day with a 5mg/kg dose. The rationale was that the small test dose would simulate the DOCs associated with the 50mg/kg dose. The results indicated that the 5mg/kg dose elicited behavioral and thermic withdrawal symptoms and that these symptoms were not a sensitized response to the opiate. That is, a small dose of a drug can serve as a cue for a larger dose of that drug and can function as a CS to elicit withdrawal CCRs in the absence of the high dose. What makes this report especially intriguing is that Siegel supports the associative hypothesis by demonstrating that morphine withdrawal can be elicited by morphine itself. Previously, it was believed that withdrawal symptoms are uniquely associated with drug absence. The inclusion of such DOCSs during extinction- based treatment might better reproduce the CSs responsible for craving and relapse. McDonald, R.V. and Siegel, S. Intra-Administration Associations and Withdrawal Symptoms: Morphine-Elicited Morphine Withdrawal. Experimental and Clinical Psychopharmacology, 12(1), pp. 3-11, 2004.

The Ventral Pallidum Dynamically Encodes Information About Reward and Reward-Related Cues During Learning

The ventral pallidum (VP) is a critical integration, output and feedback pathway of the mesocorticolimbic reward circuit in the brain. Behavioral studies have shown that VP mediates both the hedonic value of, and an animal's response to, drug and natural rewards, and electrical or pharmacological stimulation of this nucleus elicits appetitive and reward-related behaviors. However, little is known about how information is processed in VP. Dr. Wayne Aldridge and his colleagues have now recorded the activity of individual VP neurons while rats learned a Pavlovian reward association. Rats learned to distinguish a tone that predicted sucrose pellets (CS+) from a different tone with no predictive value (CS-). As training proceeded, many VP neurons became responsive to CS+, but few of them responded to CS-. Neurons also responded to a second CS+ (the click of the feeder), but after extensive training, responses to the tone were much more prevalent than to the second predictor. Many VP units were also activated when the sucrose reward was received, and unlike neurons in other parts of the reward system, they did not stop responding to reward as they became responsive to the CS+. Thus, after training, cells that responded to both CS+ and sucrose reward were common. The authors characterized the neural representation of information about reward and reward learning as a population code. That is, the population of neurons that responded to CS+ increased with learning, whereas the population that responded to the primary reward did not change. Neurons also encoded information in their relative firing rates, in that neurons that responded to multiple stimuli did so with different levels of firing. These differences in firing rate to the various stimuli were acquired early in training and remained stable as training went on, whereas population codes and behavioral conditioned responses continued to develop during subsequent training. Thus, the VP makes use of dynamic population and rate codes to conditioned stimuli to encode Pavlovian reward cues in reward learning and uses stable population and firing codes to encode sucrose reward itself. Dr. Aldridge is currently carrying out experiments to determine how motivational information (reward value) is encoded in VP. These studies will help us understand how compulsive drug seeking arises in the brain. Tindell, A.J., Berridge, K.C. and Aldridge J.W. Ventral Pallidal Representation of Pavlovian Cues and Reward: Population and Rate Codes. Journal of Neuroscience, 24, pp. 1058-1069, 2004.

Amphetamine Self-administration Produces Specific Effects on Dendritic Morphology in Medial and Orbital Prefrontal Cortex that May Underlie Long-lasting Behavioral Consequences of Drug Exposure

Changes in dendritic branching and spine density of neurons are thought to reflect changes in the synaptic connectivity and operation of a brain area, and consequently its role in behavior. The laboratories of Dr. Terry Robinson and Dr. Brian Kolb are investigating long-term changes in the anatomical structure of neurons produced by drugs of abuse. In many of their previous studies, drugs were administered by the experimenters. In the current study, headed by Dr. Hans Crombag, they have used a drug self-administration paradigm and focused on additional brain areas involved in learning. Specifically, they measured the effects of amphetamine self-administration on dendritic spine density in nucleus accumbens (NAc), medial (MPC) and orbital prefrontal cortex (OFC), and the hippocampus (areas CA1 and the dentate gyrus). In a separate group of animals, they examined these same brain regions after training animals to respond for a sucrose reward. By comparing sucrose reward training versus drug self-administration, they were able to determine whether changes were produced by drug exposure, operant learning, or both. Rats were trained under a continuous schedule of reinforcement to nose-poke for infusions of amphetamine (0.125 mg/kg/inf) or to receive sucrose pellets during 2 h daily test sessions for 14-20 days. One month after the last training session, the brains were collected and processed for Golgi-Cox staining, which reveals the fine details of neuronal anatomy. Amphetamine self-administration experience selectively increased spine density on medium spiny neurons in the NAc and pyramidal neurons in the MPC, whereas sucrose reward training had no effect in these areas. In contrast, in OFC, spine density was decreased by amphetamine self-administration, but increased by sucrose-reward training. Both amphetamine self-administration and sucrose reward experience increased the number of spines in hippocampal CA1, and produced no effect in the dentate gyrus. These results demonstrate that amphetamine self-administration experience produces long-lasting and regionally-selective morphological alterations in the rat forebrain. To the extent that the current study is comparable to previous ones from this group, both self-administered and experimenter administered amphetamine produce similar effects in the NAc and MPC, which may underlie long lasting increases in sensitivity to the motor effects of psychostimulants and to drug-associated stimuli after chronic drug exposure. The increase in spine density in NAc and MPC, and the decrease in OFC, were specific for the animals' experience with amphetamine, as these effects were different from those observed after training for sucrose reward. This observation contrasts with morphological changes typically observed for the hippocampus, where learning about drug and natural rewards both increase spine density in CA1. Moreover, these specific results for the OFC are consistent with findings of OFC abnormalities and cognitive deficits in human stimulant users. Both human and animal studies suggest that the OFC is part of a circuit for attaching motivational information with cues that signal rewards. Overall, the alterations in NAc, MPC, and OFC may underlie some of the persistent psychomotor, cognitive and motivational consequences of chronic drug exposure. Crombag, H.S., Gorny, G., Li, Y., Kolb, B. and Robinson, T.E. Opposite Effects of Amphetamine Self-administration Experience on Dendritic Spines in the Medial and Orbital Prefrontal Cortex. Cerebral Cortex Advance Access, DOI:10.1093/cercor/bhh136, published July 21, 2004.

The Effects of Prenatal Cocaine Exposure on Reversal Learning Using a Simple Visual Discrimination Task in Rhesus Monkeys

Dr. John Chelonis and colleagues at the University of Arkansas and the National Center for Toxicological Research report behavioral effects of prenatal exposure to cocaine in adult rhesus monkeys. At ages 1.5 and 3.0 the monkeys had undergone extensive behavioral testing involving a large battery of tasks that correlate with IQ in humans and had failed to exhibit any behavioral deficits. When tested as adults, however, data suggest possible deficits in behavioral adaptation to changing contingencies. At age 7, after the monkeys had been performing an operant conditional discrimination task based on color and response position for six years, the discrimination rules for reinforcement were reversed. This reversal in the reinforcement rules led to impairment in performance compared to monkeys that had not been prenatally exposed to cocaine. In some cases, the impairment was still evident two and a half years after the reversal when the observations were terminated, thus suggesting that the deficit may be permanent. When these animals learned the initial discrimination six years prior, they did not exhibit any impairment in acquiring the discrimination. The reversal task, of course, is more demanding because it involves extinction of the old behavior and acquisition of new behavior incompatible with the old. This work could have implications for research on prenatal cocaine exposure in humans. Based on the authors prior age-related work with these same monkeys showing that adults are 10-30 times more sensitive to dopaminergic challenges than are young monkeys, the authors suggest that some effects of prenatal cocaine may not be manifest until certain neurotransmitter systems are fully functional. Alternatively, the authors raise the possibility that had the reversal procedure been implemented at an earlier age, the same deficit may have occurred. Chelonis, J.J., Gillam, M.P. and Paule, M.G. The Effects of Prenatal Cocaine Exposure on Reversal Learning Using a Simple Visual Discrimination Task in Rhesus Monkeys. Neurotoxicology and Teratology, 25, pp. 437-447, 2003.

Alcohol Outcome Expectancies, Risk For Alcohol Use Problems, and Menstrual Cycle Effects in Women with and Without a Family History of Alcoholism

Drs. Allison Dorlen and Suzette Evans at the New York State Psychiatric Institute studied the role of alcohol outcome expectancies in the risk for alcoholism in women with either a family-history-positive (FHP) or family-history-negative (FHN) background for alcoholism. They prospectively tracked 85 women, ranging in age from 18-35, with regard to mood, alcohol use, and daily positive and negative consequences of alcohol used across one menstrual cycle. Results indicate that (a) at screening, expectancy scores on the Alcohol Expectancy Questionnaire (AEQ) were significantly higher in FHP than FHN women, regardless of drinking level, on four of the six AEQ subscales and on the composite score, (b) AEQ scores correlated with drinking behavior among FHN women, but among FHP women, AEQ scores were elevated independently of their level of drinking, (c) following prospective tracking of their drinking behavior and its consequences, AEQ scores decreased among FHP, but not FHN, women, and (d) independently of family history status, in moderate drinkers alcohol use was significantly greater during menses than during the follicular and luteal phases of the menstrual cycle, but this increased use during menses was not associated with significant increases in negative mood or physical discomfort. These data suggest that alcohol expectancies prospectively predict drinking behavior and may be associated with further risk for the development of alcohol use problems among high-risk women. Pastor, A.D. and Evans, S.M. Alcohol Outcome Expectancies and Risk for Alcohol Use Problems in Women With and Without a Family History of Alcoholism. Drug and Alcohol Dependence, 70, pp. 201-214, 2003.

Pharmacogenetic Analysis of Sex Differences in Opioid Antinociception in Rats

Animal research has shown that males are, in general, more sensitive to painkillers than females. This sex difference in the antinociceptive properties of opiates has been described in mice, rats and monkeys. There are some inconsistencies, however, in the outcomes of these experiments, inconsistencies that Dr. Jolan Terner from University of North Carolina at Chapel Hill hypothesized may be due in part to different genetic backgrounds of experimental animals and to the relative efficacy of the tested opioids. To assess this hypothesis, Dr. Terner and her colleagues used 12 rat strains and a warm-water tail-withdrawal procedure to test the antinociceptive properties of four different opioids (butorphanol, nalbuphine, morphine and buprenorphine). Males were more sensitive to the opiates than females in all 12 strains and for all four opiates. Among the opiates, the largest sex differences in the potency of the opioids were found with the low-efficacy opioids, butorphanol and nalbuphine, which were on average 14 times more potent in males than females, while the smallest differences were found with the high efficacy opiates, morphine and buprenorphine, which were on average 2.4 times more potent in males than females. Among the 12 strains, the largest sex differences were found in the F344 and F344-Sasco strains and the smallest differences were found in the Long Evans - Blue Spruce, Long Evans, Brown Norway, and Holtzman strains. This work suggests that studying strain variation response to low-efficacy opioids might be useful for understanding the mechanisms underlying sex differences in opioid antinociception. Terner, J.M., Lomas, L.M., Smith, E.S., Barrett, A.C., and Picker, M.J. Pharmacogenetic Analysis of Sex Differences in Opioid Antinociception in Rats. Pain, 106, pp. 381-391, 2003.

Sex Differences in the Conditioned Rewarding Effects of Cocaine

Studies have shown the importance of the hypothalamic-pituitary-adrenal axis in the acquisition of cocaine self-administration in rats. When corticosterone levels, for example, are decreased by either surgical or pharmacological adrenalectomy, cocaine self-administration is abolished. In the present study, Drs. Scott Russo and Vanya Quinones-Jenab and colleagues at Hunter College investigated the effects of surgical adrenalectomy on conditioned place preference (CPP) induced by cocaine in male and female rats. In the CPP design, rats receive cocaine or saline in separate, distinctive experimental chambers for 4 or 8 days followed by a test day in which preference for the cocaine-paired chamber is assessed. In the present experiment, intact female rats developed CPP for cocaine at lower doses and with fewer trials than intact males. Adrenal-ectomy, however, did not affect the acquisition of cocaine CPP in either males or females. The authors interpret these results as indicating that females are more sensitive to the rewarding effects of cocaine and that this higher sensitivity is not dependent on the HPA axis. Russo, S.J., Jenab, S., Fabian, S.J., Festa, E.D., Kemen, L.M. and Quinones-Jenab, V. Sex Differences in the Conditioned Rewarding Effects of Cocaine. Brain Research, 970, pp. 214-220, 2003.

Sex and Estrogen Influence Drug Abuse

In this review article, Dr. Marilyn Carroll and colleagues from the University of Minnesota describe animal and clinical research showing sex differences in all the phases of drug abuse: acquisition, maintenance, escalation, dependence, withdrawal, relapse and treatment. Animal models, for example, have shown that females are more sensitive than males to the rewarding effects of a variety of drugs, they often acquire self-administration faster and at lower doses than males, and they self-administer more drugs than males during the maintenance and escalation phases. Similar to the results obtained with animals, clinical studies, for example, show that women progress from drug use to abuse/dependence faster than men. Some of these sex differences are related to estrogen levels and to the role estrogen plays in reward. The research findings reviewed in this article serve to highlight the importance of sex and sex hormones in both animal models of drug abuse and in clinical research on drug abuse. Carroll, M.E., Lynch, W.J., Roth, M.E., Morgan, A.D. and Cosgrove, K.P. Sex and Estrogen Influence Drug Abuse. Trends in Pharmacological Sciences, 25, pp. 273-279, 2004.

Sex Differences in the Behavioral Effects of 24-h/day Access to Cocaine under a Discrete Trial Procedure

Clinical studies have shown a variety of sex differences in drug abuse. Women, for example, have an accelerated transition from casual use of cocaine to compulsive use when compared to men. Women also report higher levels of cocaine cravings than men suggesting greater motivation to use cocaine. These differences, which could be due to either sociocultural factors and/or to biological factors, were recently examined by Dr. Wendy Lynch and colleagues at Yale University using animal models of cocaine self-administration that permit study of the transition from use/abuse to addiction and that permit assessment of motivation for cocaine following that transition. The transition from use/abuse to addiction was studied by providing rats with a high-access to a cocaine regimen in which they could self-administer during four 10-min trials per hour, 24-hr per day, for seven days. This procedure has previously been shown to result in an escalation of cocaine self-administration and a binge-abstinence pattern of intake. Dr. Lynch and her colleagues found that under this procedure, compared to males, females self-administered more cocaine, self-administered for longer periods of time, showed greater disruption in the diurnal control over cocaine intake, and exhibited more cocaine toxicity as evidenced by rapid weight loss and death. In order to study the effect of the 7-day binge period on subsequent motivation to use cocaine, following a 10-day forced abstinence period, rats responded for cocaine under a progressive ratio (PR) schedule in which the number of responses required to receive a cocaine infusion was increased over successive infusions. Females exhibited an increase in PR responding compared to their own baseline of PR responding prior to the binge period. Males, however, did not exhibit an increase in PR responding following the binge period. The authors interpret their data as an indication that females have greater biological vulnerability to cocaine addiction than males and that following addiction females have greater motivation or compulsion for cocaine than males. Lynch, W.J. and Taylor, J.R. Sex Differences in the Behavioral Effects of 24-h/day Access to Cocaine Under a Discrete Trial Procedure. Neuropsychopharmacology, 29, pp. 943-951, 2004.

Sex Differences in the Acquisition of IV Methamphetamine Self-administration and Subsequent Maintenance under a Progressive Ratio Schedule in Rats

Studies have shown that female rats are more vulnerable than male rats to the acquisition of i.v. cocaine self-administration as evidenced by a faster rate of acquisition and by a greater percentage of females than males meeting the acquisition criterion. Additionally, female rats exhibit greater motivation for cocaine as evidenced by performance on a progressive ratio schedule wherein the number of responses required to obtain a cocaine infusion increases over successive infusion deliveries. Responding for cocaine under this schedule is greater by females than males. The present study by Drs. Megan Roth, Marilyn Carroll, and colleagues at the University of Minnesota extends those findings to another psychostimulant drug, methamphetamine (METH). In order to meet criterion for METH acquisition, rats had to self-administer a mean total of 500 infusions over a 5-day period. This criterion was met by over 50% (five out of nine) of the females, but only by 11 % of the males (one out of nine). Not only did more females than males meet the acquisition criterion, they did so faster. The female rats met criterion in an average of 9.4 days, whereas the single male that met criterion did so in 20 days. Sex differences were also observed during the maintenance phase of study in which under a progressive ratio schedule, females self-administered significantly more METH than males at each of four doses of cocaine (0.01, 0.02, 0.04 and 0.08 mg/kg) tested. The authors conclude that these data suggest that female rats are more vulnerable than males to the acquisition of METH self-administration and that they exhibit more motivation for METH. Roth, M.E. and Carroll, M.E. Sex Differences in the Acquisition of IV Methamphetamine Self-administration and Subsequent Maintenance Under a Progressive Ratio Schedule in Rats. Psychopharmacology, 172, pp. 443-449, 2004.

Emotion Regulation and Behavior During a Separation Procedure in 18-month-old cocaine-and-other-drug-exposed Children

Dr. Linda Mayes and colleagues at Yale University report that among toddlers prenatally exposed to cocaine, both maternal and child impairment was observed during a maternal-child separation procedure. The researchers observed 78 18-month old toddlers and their mothers before, during and after a play period during which a stranger entered the playroom and subsequently the mother left for approximately 3-minutes. Three groups of mother-child dyads from an ongoing longitudinal study were studied: those prenatally exposed to cocaine and other drugs (n= 26), those exposed to other drugs including alcohol, tobacco, and/or marijuana but not cocaine (n= 26), and those not exposed to any drugs prenatally (n= 26). All three groups are a very high-risk sample characterized by extreme poverty, adversity, and environmental instability. Upon separation from the mothers, the toddlers from the cocaine group did not show heightened reactivity, but rather showed the least level of reactivity. This effect was unrelated to various measures of maternal psychological functioning, other drug use, or by demographic or perinatal differences. During the mother-child reunion following the separation, the mothers in the cocaine group exhibited significantly less emotional engagement than the non-drug using mothers, an effect related to alcohol use among mothers in the cocaine group. The cocaine-exposed toddlers upon reunion exhibited less positive emotional engagement with their mothers compared to toddlers from the non-drug-using group. This effect was mediated by the mother's low level of emotional engagement and by a lower birth weight status in the cocaine group. Molitor, A., Mayes, L.C. and Ward, A. Emotion Regulation and Behavior During a Separation Procedure in 18-month-old cocaine-and-other-drug-exposed Children. Development and Psychopathology, 15, pp. 39-54, 2003.

Developmental Trajectories of Cocaine-and-other-drug Exposed and Non-cocaine-exposed Children

Dr. Linda Mayes and colleagues at Yale University report data on the effects of prenatal cocaine exposure on the developmental trajectory of mental and motor performance, as measured by the Bayley Scales of Infant Development-II, in children assessed bi-yearly from age 3 months to age 36 months. Three groups of children in an ongoing longitudinal study were studied: those prenatally exposed to cocaine and other drugs (n= 265), those exposed to other drugs including alcohol, tobacco, and/or marijuana but not cocaine (n= 66), and those not exposed to any drugs prenatally (n= 129). All three groups are a very high-risk sample characterized by extreme poverty, adversity, and environmental instability. Dr. Mayes and her colleagues found that the Bayley motor index indicated a decline in motor performance across time in all three groups. The decline was greater in the cocaine-exposed group, though not statistically significant. The Bayley mental index also indicated a decline across age, but only to 24 months. Although the rate of mental performance decline, i.e., the trajectory, did not differ among the groups, the cocaine-exposed children had lower mental performance scores than those in the other two groups at each age level. These data indicate that impoverished cocaine- and non-cocaine-exposed children develop along the same trajectories in the mental and motor domains, but that cocaine-exposed children exhibit delays in mental development relative to the non-cocaine-exposed children. Mayes, L.C., Cicchetti, D., Acharyya, S. and Zhang, H. Developmental Trajectories of Cocaine-and-other-drug exposed and Non-cocaine-exposed Children. Journal of Developmental and Behavioral Pediatrics, 24, pp. 1-13, 2003.


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