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Director's Report to the National Advisory Council on Drug Abuse - May, 2008



Research Findings - Basic Behavioral Research

Sex Differences and Hormonal Factors in the Acquisition and Maintenance of Cocaine Self-administration in Adolescent Rat

Previous research has reported that females more rapidly acquire self-administration than males, that a greater percentage of females acquire self-administration, and that females exhibit greater motivation for cocaine as assessed via a progressive ratio (PR) schedule. Additionally, cocaine self-administration in females is modulated by estrogen, whereas testosterone has not been found to play a role in cocaine self-administration in males. Dr. Wendy Lynch compared these behavioral outcomes in male and female rats during adolescence. Replicating prior findings with adult rats, female adolescents acquired cocaine self-administration more rapidly than males, a greater percentage of females than males acquired self-administration, and females received more infusions than males under the PR schedule. In females, serum estradiol concentration, but not progesterone concentration, was positively correlated with number of infusions obtained under the PR schedule, and for four of the five rats it accounted for 50% of the variance in number of infusions. Additionally, number of infusions varied with the estrus cycle. In males however, serum testosterone was unrelated to the number of infusions. In a parallel control study, Dr. Lynch compared acquisition of lever-pressing for sucrose reinforcement and subsequent behavior under a PR schedule in adolescent males versus females, in order to assess potential sex differences in general learning and motivation. She found that males and females did not differ in the rate of acquisition, nor did they differ in the number of pellets received under the PR schedule. This research suggests that the observed sex differences in cocaine self-administration in adults, as well as the modulation by estrogen and the estrus cycle, are reflective of sex differences and underlying mechanisms that are present in adolescents. The contribution of the organization and activational effects of gonadal hormones in these sex differences remains to be understood. Lynch, W.J. Acquisition and Maintenance of Cocaine Self-Administration in Adolescent Rats: Effects of Sex and Gonadal Hormones. Psychopharmacology, 197, pp. 237-246, 2008.

Cued Reinstatement of MDMA (Ecstasy)-Seeking is Predicted by Magnitude of Prior Self-administration in Rats

MDMA produces subjective effects that resemble those characteristic of both hallucinogenic drugs and the psychostimulants. Animal studies using progressive ratio schedules of i.v. self-administration, to examine relative reinforcement, have demonstrated that MDMA is a weak reinforcer compared to stimulants (dopamine releasers) such as cocaine and methamphetamine. While there have been reports that some MDMA users meet diagnostic criteria for dependence, there is still controversy over the addictive properties of this drug, given the typical pattern of human abuse. That is, while most individuals abuse ecstasy on an intermittent basis, there are data to suggest that some develop a problematic pattern of abuse that is characteristic of addiction. One important feature of addiction is the relapse to drug taking behavior seen after a period of abstinence. The reinstatement model mimics features of human relapse in that animals develop self-administration, drug taking is extinguished, and then a return to drug seeking can be prompted by re-exposure to the drug, re-introduction of drug-associated cues, or stress. A recent study published by Dr. George Rebec and colleagues examined individual differences in i.v. self-administration of MDMA and assessed whether or not contingent drug cues, that readily reinstate psychostimulant seeking behavior, can also prompt a return to drug seeking for MDMA. In this study, seven animals acquired self-administration on a FR5 operant schedule, with a mean dose of 0.30 mg/kg/infusion. As has previously been reported for this drug, there were widespread differences in the magnitude of self injection, ranging from 4 to 135 responses/session. After 14 daily 2-hour sessions all animals underwent extinction, during which time saline was substituted for drug infusions. As expected, all rats extinguished lever press behavior (mean presses/session = 1.29). Reinstatement testing followed with drug-associated cue presentations delivered contingently upon responses made on the lever previously associated with MDMA infusions; however, saline was delivered through the i.v. catheters during this testing. Responses increased to an average of 33.57, but again with great variability across animals (SEM+15.33). The interesting finding from this study was that a strong positive correlation was found between individual mean response rates during the last five self-administration sessions and the rate of responding during cue presentation during reinstatement (r=0.97, p<0.001). Additional tests to examine drug-induced reinstatement were conducted with 5.0 mg/kg MDMA, (a dose known to elicit behavioral activation), and the researchers found no evidence for drug primed reinstatement (contrary to what is observed for cocaine or amphetamine). While preliminary, these findings are important not only because they demonstrate great individual variability in MDMA self-administration that parallels observations of human abuse patterns with this drug, but because they suggest that these different phenotypes may be predictive of the chronic relapsing condition of drug addiction with ecstasy. Animals that have higher rates of cocaine intake also are more vulnerable to reinstate drug-seeking behavior. However, unlike cocaine and amphetamine, MDMA relapse does not appear to be triggered by drug priming. These differences may reflect the drug's different patterns of neurotransmitter activation, as MDMA increases synaptic levels of both serotonin and dopamine. Ball, K.T., Walsh, K.M. and Rebec, G.V. Reinstatement of MDMA (Ecstasy) Seeking by Exposure to Discrete Drug-Conditioned Cues. Pharmacology, Biochemistry and Behavior, 87, pp. 420-425, 2007.

Reducing Dopamine Transmission Increases Demand for Cigarettes and Reduces Attentional Bias

NIDA K08 awardee, Brian Hitsman, investigated the effect of depleting the amino acid tyrosine/phenylalanine, which results in reduced dopamine transmission, on attentional bias to smoking related cues, the relative value of cigarettes, craving, and mood. To do this, smokers were restricted to a low protein diet for 24 hours, and fasted overnight, prior to a test session. Using a within-subject, double-blind methodology, each participant was given a tyrosine/phenylanine-free beverage (depleted session), or a beverage with balanced amino acids (non-depleted session). Reaction times during a modified Stroop task containing smoking-related words and neutral words were used to assess attentional bias. Relative value of cigarettes versus money was assessed using a cigarette purchase task (CPT). The brief questionnaire of smoking urges (QSU-brief) was used to assess craving and mood, and the Hamilton depression rating scale (HDRS) was used to assess depressive symptoms. There were no differences between the depleted and non-depleted sessions in the QSU-brief or the HDRS. The "depleted session" was associated with a significant increase in intensity of demand for cigarettes relative to money. There was also a trend towards a more persistent willingness to purchase cigarettes during the "depleted session." There was a decreased attentional bias to smoking-related cues during the "depleted session;" however this was only present when it was preceded by the "non-depleted session." The finding that tyrosine/phenylanine depletion caused an increased demand for cigarettes is consistent with the literature. However the lack of an effect on craving was surprising. It is suggested that this discrepancy may be due to different mechanisms of reducing dopamine transmission (e.g., dopamine antagonist administration versus dopamine depletion). Acute tyrosine/phenylanaline depletion may influence smoking behavior. However additional studies (perhaps with alternative measures of craving and attention) are needed. Hitsman, B., MacKillop, J., Lingford-Hughes, A., Williams, T.M., Ahmad, F., Adams, S., Nutt, D.J. and Munafo, M.R. Effects of Acute Tyrosine/Phenylalanine Depletion on the Selective Processing of Smoking-Related Cues and the Relative Value of Cigarettes in Smokers. Psychopharmacology, 196, pp. 611-621, 2008.

CRF Receptors Mediate Nicotine-Seeking Behavior in an Animal Model of Relapse

Smokers trying to quit often relapse when under stress. NIDA grantee Dr. Bruijnzeel and colleagues have modeled human relapse with an animal model called "response reinstatement". In this model, rats previously allowed to self-administer nicotine by pressing a lever are put through a period of extinction, when no nicotine is available. Over time, the nicotine seeking behavior (e.g., leverpress behavior) stops, or extinguishes. Once the behavior has been extinguished, a mild footshock reinstates the nicotine-seeking behavior and the animal once again engages in lever pressing behavior in an attempt to obtain nicotine (nicotine seeking behavior). Since both norepinephrine and corticotropin-releasing factor (CRF; a hormone involved in biological responses to stress) have been implicated as modifiers of stress-induced relapse, the effects of pretreatment with clonidine (an _2 adrenergic agonist) and the CRF antagonist D-Phe CRF(21-41) were evaluated. Blockade of CRF receptors significantly attenuated footshock-induced reinstatement of leverpress behavior (e.g., nicotine-seeking), as did clonidine treatment. Blockade of CRF receptors appeared to be selective for nicotine-seeking, as control rats that lever-pressed for food returned to their lever-pressing behavior. Thus, pretreatment with D-Phe CRF(21-41) attenuated footshock-induced reinstatement of nicotine-seeking, but not food-seeking. This was not the case with clonidine because it significantly reduced both nicotine- and food-seeking. These results suggest that CRF receptors may be a potential target for pharmacotherapies aimed at reducing stress-induced relapse to smoking. Zislis, G., Desai, T.V., Prado, M., Shah, H.P. and Bruijneel, A.W. Effects of the CRF Antagonist D-Phe CRF(21-41) and the _2-adrenergic Receptor Agonist Clonidine on Stress-Induced Reinstatement of Nicotine-Seeking Behavior in Rats. Neuropharm., 53, pp. 958-966, 2007.

Cocaine's Behavioral Differences in Adolescence Suggests a Developmental Dissociation Between Locomotor and Reward Effects

Adolescence is a period of development associated with the highest incidence of drug use initiation. Early use is predictive of later problem abuse behaviors, dependence and addiction. Therefore recent research efforts using animal models have examined age-related differences in the sensitivity to drugs of abuse, and the vulnerability to initiate drug taking behavior. These studies report that periadolescent rats (post-natal days 21-37) are less responsive to psychomotor stimulant effects, show a similar or lower degree of psychostimulant-induced sensitization, lower neuroendocrine effects from cocaine, and less taste aversion with amphetamine. However, there are conflicting reports that indicate no age-related difference in operant responding or conditioned place preference for cocaine. Thus, Dr. Loren Parsons and his colleagues undertook an investigation to examine both locomotor and reinforcing effects of cocaine in periadolescent (PA) versus adult (A) rats, and also assessed basal extracellular levels of dopamine (DA) in the nucleus accumbens after i.v. or i.p. drug administration. To test for differences in cocaine induced motor activity, testing was begun on PND 37-39 (periadolescent) or 73-75 (adult) and animals were injected with 10 or 20mg/kg i.p. cocaine versus vehicle on days 1, 5, 10 and 15 of the study. Separate groups of animals were implanted with i.v. catheters on PND 29-31 (PA) or 67-69 (A) and tested for spontaneous acquisition of cocaine self-administration (0.25mg/infusion) 7-9 days later. Other groups received either i.v. or i.p. cocaine on PND 30-33 or 70-74 to conduct dialysis studies. Cocaine was administered i.v. in three successive doses from 0.37 to 2.92 mg/kg following by dialysate collection to quantify dopamine levels and cocaine concentrations in the nucleus accumbens. In the i.p. injection group, animals received 20 mg/kg prior to dialysate collection. On the measure of locomotor behavior, PA and A groups were no different in their response to acute cocaine. With repeated administration of 10 mg/kg, both age groups showed evidence of psychostimulant sensitization, but under different conditions (i.e., dose and day). Rate of acquisition and amount of drug self-administered was no different between the two age groups. Also, both basal DA and DA in vivo recovery revealed no difference between groups. However, i.v. cocaine produced higher brain cocaine concentrations in the A group after mid- and high-dose injections; (no difference was noted following the i.p. injection). The results suggest PA hyposensitivity to i.p. cocaine's effects on motor activity, even though levels of extracellular DA were no different. Thus, age differences were seen on drug-induced locomotor activation but not on measures of drug reward, which suggest a developmental dissociation between the locomotor activating versus reinforcing effects of cocaine. Collectively, this and other studies that attempt to probe mechanisms for developmental differences in drug response suggest that the differences are complex, may depend on the psychostimulants used, the behaviors that are measured, and the developmental period. Frantz, K.J., O'Dell, L.E. and Parsons, L.H. Behavioral and Neurochemical Responses to Cocaine in Periadolescent and Adult Rats. Neuropsychopharmacology, 32, pp. 625-637, 2007.

Noradrenergic Transport Inhibitors Reinstate Cocaine-Seeking Behavior

The present study examined the ability of selective NE transport inhibitors to mimic or modulate the relapse-inducing effects of cocaine in the reinstatement model in squirrel monkeys. Twelve animals acquired i.v. cocaine self administration and maintained stable responding for 6-8 months. After responding was extinguished, tests for cocaine-primed (plus cue presentation) reinstatement were conducted and cycles of cocaine self-administration followed by repeated extinction were imposed between drug tests. The following tests for reinstatement were conducted: priming with cocaine (0.1 to 1.0 mg/kg), the selective dopamine transport inhibitor GBR 12909 (GBR), and selective NE transport inhibitors (nisoxetine and talsupram). Antagonism experiments were conducted to evaluate the degree to which DA and/or NE receptor mechanisms contribute to the cocaine-like priming effects of GBR and nisoxetine. Priming with GBR dose-dependently reinstated cocaine seeking. Both NE transport inhibitors also reinstated cocaine seeking but only to 36-55% of the maximal rates engendered by cocaine or GBR. All three drugs also enhanced the ability of cocaine to prime reinstatement; however the NE transport inhibitors were without effect on the ability of GBR to induce reinstatement. Antagonist tests with the DA receptor antagonist flupenthixol (flu), an alpha1 NE antagonist, or the alpha2 NE agonist clonidine, before priming doses of GBR or nisoxetine produced the following results: flu reducing priming effects of GBR only, while the alpha1 antagonist, the alpha2 agonist, and a beta NE antagonist all blocked nisoxetine priming only. Priming effects of cocaine were reduced by flu and clonidine only. The finding that NE transport inhibitors can reinstate cocaine seeking, (albeit only one half as effectively as the DA transport blocker), contrasts with observations for a relatively minor role of NE transmitter systems in rodent relapse models. The results suggest that NE receptors systems involving both alpha and beta NE receptor subtypes may be involved in relapse to cocaine seeking, possibly via DA modulation by NE in the frontal cortex. Alternatively, these receptor systems may be involved as a function of their role in endogenous stress mechanisms. Platt, D.M., Rowlett, J.K. and Spealman, R.D. Noradrenergic Mechanisms in Cocaine-Induced Reinstatement of Drug Seeking in Squirrel Monkeys. Journal of Pharmacology and Experimental Therapeutics, 322, pp. 894-902, 2007.

Methamphetamine Self-Administration and Voluntary Exercise Have Opposite Effects on Neuroplasticity

George Koob and his colleagues tested the effects of methamphetamine self-administration and running wheel activity on cell proliferation, survival and death in the medial prefrontal cortex (mPFC) of the rat. Different group of rats had either intermittent 1 hr access to methamphetamine (I-ShA), or daily 1hr (ShA) or 6 hr (LgA) access to methamphetamine self-administration. Separate groups of rats had either access to running wheels in the home cage (voluntary exercise) or no access (exercise controls). Results showed that self- administration of methamphetamine was at a stable and low level for Group I-ShA. Groups ShA and LgA both showed escalation of methamphetamine self-administration over sessions with LgA showing the largest increase in self-administration. Therefore, the self-administration data from the I-ShA, ShA, and LgA groups provide evidence for distinct patterns of methamphetamine intake that may be related to human patterns of use: recreational, chronic abuse, and dependence. Histological results indicated that Group I-ShA showed an increase in cell proliferation and survival, but that ShA and LgA showed decreases in proliferation and survival. All groups showed increased cell death. Voluntary exercise enhanced proliferation and survival but, in contrast to methamphetamine exposure, did not alter cell death or mature cell phenotypes. Furthermore, enhanced cell survival by I-ShA and voluntary exercise had profound effects on gliogenesis with differential regulation of oligodendrocytes versus astrocytes. In addition, new cells in the adult mPFC were detected, although enhanced cell survival by I-ShA and voluntary exercise did not result in increased neurogenesis. These findings demonstrate that mPFC gliogenesis is vulnerable to psychostimulant abuse and physical activity with distinct underlying mechanisms. The susceptibility of mPFC gliogenesis to even modest doses of methamphetamine could account for the pronounced pathology linked to psychostimulant abuse. Mandyam, C.D., Wee, S., Eisch, A.J. Eisch, Richardson, H.N., and Koob, G.F. Methamphetamine Self-Administration and Voluntary Exercise Have Opposing Effects on Medial Prefrontal Cortex Gliogenesis. Journal of Neuroscience, 27, pp. 11442-11450, 2007.

Personality and Gender Moderate Amphetamine's Effects on Risk Taking

Dr. Harriet de Wit and her colleagues examined how gender and personality (temperament) moderate the effects of d-amphetamine on risk taking, measured by performance on the BART (Balloon Analogue Risk Task). Previous research indicates that stimulant drugs can either increase or decrease impulsive behavior, depending upon a number of factors including gender and variation in personality traits related to reward and punishment sensitivity. The present study assessed personality using the Multidimensional Personality Questionnaire Brief Form, because this questionnaire is an empirically derived measurement instrument that assesses three orthogonal factors related to reward sensitivity, behavioral impulsivity, and negative affect. These include the personality dimensions of Agentic Positive Emotionality (AgPEM), which is thought to reflect individual differences in the function of ascending VTA dopamine projections that modulate behavioral approach and incentive motivation; Constraint (CON), which measures impulsive spontaneity and approach-versus-avoidance of physical harm, which could be relevant to drug-induced changes in the relative frequency of impulsive choices versus successful impulse control; and Negative Emotionality (NEM), which measures anxiety proneness, interpersonal alienation and aggression, which could be relevant to drug-induced changes in aggressive impulsive behavior. Forty healthy men and women, aged 18 to 35, completed the BART after ingesting placebo or d-amphetamine (10, 20 mg). There were three main findings. First, for male participants, there were strong, positive correlations between the personality trait of AgPEM and amphetamine-induced increases in risk taking on the BART risk task. Second, there was evidence of discriminant validity, as correlations between AgPEM and drug-induced risk behavior were significantly greater than correlations with trait CON and trait NEM in the same participants. Third, 20 mg d-amphetamine significantly decreased risk behavior in men with scores in the lower half of the distribution for AgPEM, and significantly increased risk behavior in men with scores in the upper half of the distribution on AgPEM. The drug did not affect risk taking in women. Overall, the current findings suggest that the personality trait of AgPEM could constitute a preexisting risk factor (neural, metabolic, or behavioral characteristics) for amphetamine-induced changes in risk-taking in healthy young adult males, and could affect behavioral responses to stimulant drugs when used recreationally or therapeutically. White, T.L., Lejuez, C.W., and de Wit, H. Personality and Gender Differences in Effects of d-Amphetamine on Risk Taking. Experimental and Clinical Psychopharmacology, 15, pp. 599-609, 2007.

Emotional Environments Can Retune the Valence of Appetitive Versus Fearful Motivations Mediated by Nucleus Accumbens

In drug abuse research, the nucleus accumbens (NAc) is commonly thought of as part of "reward" circuitry, but in fact, it is well known that NAc mediates both appetitive motivation for rewards and fearful, defensive motivation towards threats. Appetitive and defensive motivations are generated in a graded manner along the rostral to caudal axis of the NAc shell, as shown by studies in Kent Berridge's and Anne Kelley's laboratories. Microinjections of the AMPA glutamate receptor inhibitor DNQX near the rostral pole of NAc elicit intense feeding and other appetitive behaviors and conditioned place preference; whereas such injections near the caudal pole evoke fearful behaviors such as distress vocalizations, defensive burying, and conditioned avoidance. Injections in more central areas produce a mixture of appetitive and fearful behaviors corresponding to their relative rostral-caudal position. In the current study, Reynolds and Berridge tested whether or not the valence of the behaviors generated at locations along the gradient could be retuned, or shifted, by the emotional valence of the external environment. They tested three different environments in a three chambered apparatus. One was a home-like environment (dark and quiet), the second was a conventional laboratory environment, and the third was stressful and over-stimulating (bright light and unpredictable presentations of loud punk-rock music). First they confirmed the rats' preference for the home environment and avoidance of the stressful one in an experiment where rats could self-administer selected pairs of environments (home vs. standard and standard vs. stressful). Rats could turn on the light and sound components of a specified environment by entering one end compartment, and then turn these off and another environment on by going to the opposite end. As expected, the animals preferred to turn on the dark, quiet home condition over the standard condition, and they preferred the standard over the stressful environment. Next, they microinjected DNQX at various locations along the rostro-caudal axis of NAc, while rats were confined in one of the three environments, and observed the amounts of appetitive (eating) vs. fearful (defensive burying) behaviors. They found that environmental exposure shifted the gradient along the rostro-caudal axis of NAc shell. In the home environment, sites that elicited appetitive behaviors extended much more caudally than in the standard environment, and the 'fearful zone' shrank to about one-third of its original size. The opposite was true for exposure to the stressful environment, which extended sites that elicited fearful behaviors much more rostrally, confining sites that evoked purely appetitive behaviors to the rostral pole. Thus, at many intermediate sites, remapping by environmental ambience completely switched the appetitive vs. fearful valence of DNQX-motivated behaviors. These data suggest that corticolimbic circuits that involve NAc can flexibly retune affective-generating functions from moment to moment as the external environment changes. This remapping has implications for understanding how these circuits tune adaptive motivations and how these can be altered in disorders of pathological motivation such as addiction. Reynolds, S.M. and Berridge, K.M. Emotional Environments Retune the Valence of Appetitive Versus Fearful Functions in Nucleus Accumbens. Nature Neuroscience, 11(4), pp. 423-425, 2008.


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