Research Findings - Basic Behavioral Research

Nornicotine Enantiomers Decrease Nicotine Self-Administration in Rats

Dr. Michael Bardo and colleagues compared R(+) and S(-) enantiomers of nornicotine (a naturally occurring metabolite of nicotine) for their potency to decrease intravenous nicotine self-administration and sucrose-maintained responding. They also measured bioavailability in brain, effects on blood pressure and heart rate, and the development of tolerance. Given subcutaneously, both enantiomers dose-dependently decreased nicotine self-administration at the highest doses (5.6 and 10 mg/kg), however R(+)-nornicotine was more effective. In an intermediate dose (3 mg/kg), only R(+)-nornicotine reduced nicotine self-administration. Both enantiomers showed a similar magnitude of effect in decreasing nicotine self-administration; an effect that lasted up to 240 minutes. Repeated doses of R(+)- or S(-)-nornicotine did not change the number of nicotine infusions, indicating a lack of tolerance to this effect. Sucrose pellet-maintained behavior was also dose-dependently reduced by both enantiomers, however unlike their effects on nicotine self-administration, there were no significant differences between the enantiomers. Assessment of brain levels 60 min after systemic nornicotine enantiomer treatment revealed no difference in brain levels between R(+) and S(-)-nornicotine. Cardiovascular effects were assessed over a course of 9 treatment days. Both enantiomers increased heart rates and mean arterial pressure when given acutely, however tolerance to these effects only developed in the rats given chronic R(+)-nornicotine. These data suggest that, although both of these enantiomers of nornicotine might be useful in developing a pharmacotherapy for nicotine addiction, the R(+) enantiomer may hold more promise. Stairs, D.J., Neugebauer, N.M., Wei, X., Boustany, C., Hajahmat, M., Cassis, L.A., Crooks, P.A., Dwoskin, L.P. and Bardo, M.T. Effects of Nornicotine Enantiomers on Intravenous S(-)-Nicotine Self-Administration and Cardiovascular Function in Rats. Psychopharmacology, 190, pp. 145-155, 2007.

Chlordiazepoxide and Dizocilpine Selectively Impair Acquisition Learning in Rats

Dr. Joseph Galizio and colleagues tested the effects of the NMDA-antagonist dizocilpine (DZP), the opiate-agonist morphine (MOR), and the benzodiazepine chlordiazepoxide (CDP) using a novel repeated-acquisition and performance (RAP) task. This within-session procedure measures a rat's food-reinforced nose-poke response to one of six target locations on a computer touch screen. One location (target) is designated the correct location in the performance component of the task. Pretreatment with DZP, MOR or CDP increased the number of errors on this task. MOR increased the errors for both the acquisition and performance target locations. But interestingly, CDP, and some doses of DZP, increased errors only in the acquisition component, with little effect on the performance component. These data suggest that benzodiazepines and NMDA antagonists can selectively interfere with acquisition (learning) processes. The procedures used in the current task more closely resemble the RAP used in primates than those used in rodents. These results therefore shed some light on the controversy over whether or not species differences, or different RAP tasks, are responsible for different results on repeated-acquisition testing. Pitts, R.C., Buda, D.R., Keith, J.R., Cerutti, D.T. and Galizio, M. Chlordiazepoxide and Dizocilpine, but not Morphine, Selectively Impairs Acquisition under a Novel Repeated-Acquisition and Performance Task in Rats. Psychopharmacology, 189, pp. 135-143, 2006.

Mecamylamine Attenuates Responding for Nicotine and Cue-Induced Reinstatement

Drs. Xiu Liu, Anthony Cagguila, and colleagues tested the impact of noncompetitive nicotinic acetylcholine blockade (using mecamylamine) on cue-induced reinstatement of nicotine seeking. Rats were trained to self-administer intravenous nicotine, with a stimulus light accompanying the nicotine infusion. A second group was trained to respond on a lever for food reinforcement. The behavior was then extinguished, with lever pressing resulting in no food/light or drug/light consequences. Following extinction, rats were pretreated with either saline or mecamylamine prior to a test session in which pressing the drug or food- associated lever resulted in the light cue only. Mecamylamine dose-dependently attenuated cue-induced reinstatement for the nicotine-associated light cue, but not for the food-associated light cue. After the reinstatement test session, rats were again trained to self-administer nicotine or food, and behavior was re-established after 5-7 sessions. After retraining, mecamylamine was given as a challenge prior to a test session, when levers remained active. It significantly reduced nicotine self-administration. These data indicate that nicotine receptor blockade selectively attenuates both responding for nicotine and cue-induced reinstatement. Moreover, this is a specific effect, as reinstatement to the food-associated cue was unaffected. These findings suggest that mecamylamine might be clinically useful in promoting smoking cessation and for preventing relapse. Liu, X., Caggiula, A.R., Yee, S.K., Nobuta, H., Sved, A.F., Pechnick, R.N. and Poland, R.E. Mecamylamine Attenuates Cue-Induced Reinstatement of Nicotine Seeking Behavior in Rats. Neuropsychopharmacology, 21, pp. 710-718, 2007.

Adolescent Rats Show Reduced Nicotine Withdrawal

Dr. Athina Markou and colleagues compared the motivational and somatic signs of nicotine withdrawal in adolescent versus adult male rats. Motivational signs of nicotine withdrawal was measured using intracranial self-stimulation (ICSS) threshold measures. Results indicate that adolescent rats displayed less motivational and somatic effects of nicotine withdrawal, with no significant difference in ICSS threshold compared to baseline, and fewer total observed somatic signs during precipitated withdrawal. Adults, on the other hand, displayed a significant increase in the ICSS threshold (indicating withdrawal) and a dose-dependent increase in somatic signs. Thus, it appears that the negative effects of nicotine withdrawal are less severe in adolescent rats as compared to their adult counterparts. As adolescence is known to be a period of increased vulnerability to nicotine addiction, the current data suggest that adolescents may be not only more sensitive to the positive reinforcing effects of nicotine, but also less sensitive to the negative effects of withdrawal, and that both may underlie this enhanced vulnerability as well. O'Dell, L.E., Bruijnzeel, A.S., Smith, R.T., Parsons, L.H., Merves, M.L., Goldberger, B.A., Richardson, H.N., Koob, G.F. and Markou, A. Diminished Nicotine Withdrawal in Adolescent Rats: Implications for Vulnerability to Addiction. Psychopharmacology, 186, pp. 612-618, 2006.

MDMA ("Ecstasy") Self-Administration Is Abolished in Serotonin Transporter Knockout Mice

The rewarding properties of MDMA have been established in monkeys, rats, and mice, but the neurobiological mechanisms underlying MDMA's reinforcing effects remain unclear. MDMA increases the synaptic concentration of serotonin (5-HT), dopamine (DA) and norepinephrine as well as other neurotransmitters. Although some pharmacological studies have implicated DA in the reinforcing properties of MDMA, other data support a role for 5-HT in MDMA's rewarding effects, and in agreement with this MDMA binds with higher affinity to the 5-HT transporter (SERT) than to the DA transporter. The goal of this study was to evaluate the role of SERT in the reinforcing properties of MDMA using intravenous self-administration in SERT knockout (KO) and wild-type mice. The investigators used microdialysis to measure MDMA-evoked DA and 5-HT release in the nucleus accumbens (NAc) and prefrontal cortex (PFC), respectively. DA release in the NAc did not differ between KO and WT mice, whereas 5-HT release in the PFC was greatly reduced in the KO mice compared to WT. These results provide evidence for a key role for serotonin in MDMA's rewarding effects, and suggest that the SERT might be a fruitful target for the development of effective treatments for MDMA abuse, as has also been suggested for methamphetamine dependence in humans. Trigo, J.M., Renoir, T., Lanfumey, L., Hamon, M., Lesch, K.P., Robledo, P., and Maldonado, R. 3,4-Methylenedioxymethamphetamine Self-Administration is Abolished in Serotonin Transporter Knockout Mice. Biological Psychiatry [Epub ahead of print], 2007.

Methamphetamine Exposure Increases Synapse Formation in Striatal Regions Important for Habit Learning

Dr. Terry Robinson and his colleagues have been using anatomical methods to investigate structural changes in neuron morphology after treatment with a variety of drugs of abuse, mostly focused on brain regions that mediate the psychomotor activating and incentive motivational effects of drugs. However, repeated exposure to psychostimulant drugs also facilitates a transition in control of behavior guided by action-outcome associations, to behavior controlled by "automatized" stimulus-response habits. This transition is thought to be due to increasing engagement and control over behavior by the dorsolateral (but not dorsomedial) striatum. In this study, the PI hypothesized that repeated exposure to methamphetamine would differentially alter the density of dendritic spines on medium spiny neurons (MSNs) in the dorsolateral vs. dorsomedial striatum. Rats were treated with repeated injections of methamphetamine, and 3 months later dendrites were visualized using a technique in which green fluorescent protein can be expressed in vivo. Prior exposure to methamphetamine produced a significant increase in mushroom and thin spines on MSNs in the dorsolateral striatum and a significant decrease in mushroom spines in the dorsomedial striatum. These changes in spine densities may reflect differential alterations in glutamatergic innervation of these two subregions in dorsal striatum and indicate that, after drug exposure, the dorsolateral subregion receives more excitatory drive. The authors speculate that exposure to psychostimulant drugs may facilitate the development of stimulus-response habits by reorganizing patterns of synaptic connectivity in the dorsal striatum such that the dorsolateral subdivision has increased control over behavior. Behavior then would become more automatic and habitual, consistent with patterns of drug consumption behavior that have been observed in human addicts. Jedynak, J.P., Uslaner, J.M., Esteban, J.A., Robinson, T.E. Methamphetamine-Induced Structural Plasticity in the Dorsal Striatum. European Journal of Neuroscience, 25, pp. 847-853, 2007.

The Subthalamic Nucleus (STN) and Control of Impulsive Behavior in the Rat

Recent evidence suggests that the STN is involved in mediating the effects of drugs of abuse and in impulse control. In animal models, lesions of the STN alter the behavioral and reinforcing effects of cocaine and either increase or decrease impulsive responding, depending on the exact nature of the behavioral task. The goals of the current study were (a) to determine the effects of STN lesions on behaviors indicative of "impulsive action" (or behavioral disinhibition) and "impulsive choice" (or impulsive decision making); and (b) to examine the effects of amphetamine and food restriction on these behaviors in animals with STN lesions. To test for impulsive action, the investigators used differential reinforcement of low rates of responding (DRL). In the DRL task, the rat is rewarded only if it restrains from pressing the reward lever for a specified time period (30 s in these experiments). Impulsive choice was measured by performance on a delay discounting task in which the rat has a choice between a lever that delivers one banana-flavored pellet immediately vs. another lever that delivers four pellets, but only after a delay (delay times varied from 3 to 24 s). Food restriction and acute amphetamine exposure, which are known to affect impulsivity, were tested in both tasks after STN lesions to determine if they augmented the lesions' effects. The investigators found that STN lesions increased impulsive action in the DRL task but decreased impulsive choice in the delay discounting task. Amphetamine and food restriction each increased impulsive action and decreased impulsive choice to a greater extent in STN-lesioned animals than in sham-lesioned controls. The authors speculate that these apparently discrepant effects may be because STN lesions enhance the incentive salience assigned to rewards, rather than having a more general effect on impulsivity or ability to measure time. In the DRL task, enhanced incentive salience could produce premature responding because the subjects are overly eager to receive the reward; in the delay discounting task, such enhancement could favor willingness to wait for the larger reward. The results of these experiments, and the authors' thoughtful discussion of the underlying psychological processes, provide a theoretical framework for understanding the role of STN and its viability as a potential target for treating disorders characterized by deficits of behavioral control, such as drug addiction and attention deficit hyperactivity disorder. Uslaner, J.M. and Robinson, T.E. Subthalamic Nucleus Lesions Increase Impulsive Action and Decrease Impulsive Choice--Mediation by Enhanced Incentive Motivation? European Journal of Neuroscience, 24, pp. 2345-2354, 2006.

Orbitofrontal Neurons of Rats Treated with Chronic Cocaine Fail to Efficiently Encode Cues Associated with Negative Outcomes

Recent evidence has linked exposure to addictive drugs to an inability to use information about adverse consequences, or outcomes, to control behavior. For example, drug-experienced animals often fail to adapt their behavior to avoid adverse outcomes in reversal tasks or after changes in the value of expected rewards. These deficits are similar to those caused by damage to the orbitofrontal cortex (OFC), suggesting that addictive drugs may cause long-lasting changes in the representation of outcome associations in a circuit that includes the OFC. In the present study, the investigators tested this hypothesis by recording from OFC neurons during a discrimination task in rats previously treated with cocaine (30 mg / kg i.p. for 14 days) and in saline treated controls. Rats were trained to associate one odor with sucrose reward and a second odor with a bitter quinine solution. Activity of neurons in OFC was recorded while animals were learning the discrimination. All rats learned the odor discrimination, but the behavior of the two groups during learning differed. Even before reaching criterion, control rats made fast responses towards the fluid well when they anticipated sucrose, but when they made incorrect approaches after sniffing quinine-associated odors, they approached slowly. By contrast, cocaine-treated rats, failed to appropriately slow responses made towards the quinine well during learning. OFC activity was analyzed first during this learning phase, when animals were still making some incorrect responses. Firing rate was quantified in the interval between odor cue presentation and fluid delivery, during which time OFC responses would indicate neural encoding of expected outcomes (i.e., not a response to odor or taste per se). In both groups of rats, the investigators found that different subsets of neurons fired selectively in anticipation of the sucrose vs. quinine in this delay interval. Therefore, OFC neurons in both groups were capable of signaling the expected outcome after the animal had made a behavioral response towards the fluid well. They then saw that as the animals learned the task to criterion, neurons began responding to the odor cues themselves (i.e., began firing earlier in the trial). In control animals, sucrose-expectant neurons (i.e. those that had fired more during the delay interval on a sucrose trial) also fired more intensely to the sucrose-associated odor, and quinine-expectant neurons fired more to the other odor. That is, in control animals, OFC neurons developed selective responsivity to conditioned stimulus associated with appetitive or aversive events. In the cocaine-treated rats sucrose-expectant neurons also developed a preference for the CS associated with sucrose, but these animals also showed impaired encoding of aversive outcomes: quinine-expectant neurons did not develop selective responses to the odor that signaled quinine in this group. Therefore, these neurons would be ineffective in guiding appropriate behavioral responses to stimuli that signal an aversive event, as was also evident by the inability of cocaine-treated animals to slow their approach to the quinine well. These results provide direct neurophysiological evidence that exposure to cocaine can cause behaviorally relevant changes in the processing of associative information in a circuit that includes the OFC, and that encoding of adverse outcomes is particularly vulnerable. Stalnaker, T.A., Roesch, M.R., Franz, T.M., Burke, K.A. and Schoenbaum, G. Abnormal Associative Encoding in Orbitofrontal Neurons in Cocaine-Experienced Rats During Decision-Making. European Journal of Neuroscience, 24, pp. 2643-2653, 2006.

Animal Study Indicates that the ADHD Medication, Atomoxetine, May Help Alleviate Nicotine Withdrawal

Nicotine withdrawal symptoms are an important target for medications development because they are a major indicator of smoking relapse following cessation. The cognitive symptoms of nicotine withdrawal and attention deficit hyperactivity disorder (ADHD) are similar and may share neural correlates. Thus, therapeutics that ameliorate ADHD symptoms may also ameliorate nicotine-withdrawal symptoms. The present research tested this hypothesis in an animal model of nicotine withdrawal-associated cognitive deficits using atomoxetine, a norepinephrine reuptake inhibitor that is approved to treat the symptoms of ADHD. Mice were administered nicotine (or saline in control animals) for 12 days. Twenty-four hours after nicotine administration ceased, the animals were trained in fear conditioning by pairing two presentations of an auditory conditioned stimulus (CS) with a footshock in a specific training environment (context) to examine the effects of nicotine withdrawal on learning. One day after training, the animals were tested for freezing behavior in response to either the context or the tone CS. Fear conditioning is useful because it can be rapidly acquired and it involves two types of learning that engage different brain areas. Associations between context and shock require the hippocampus, while associations between tone and shock do not. Consistent with previous research, mice withdrawn from chronic nicotine had lower levels of contextual fear conditioning than mice that were not withdrawn from chronic nicotine, but showed no differences in response to the CS. Atomoxetine dose-dependently reversed this deficit, suggesting that nicotine withdrawal may be associated with changes in noradrenergic function, acetycholinergic function, and/or with changes in cell signaling cascades in the hippocampus or its associated circuits that are activated by both nicotine and norepinephrine. These data suggest that atomoxetine may be efficacious for treating nicotine withdrawal-associated cognitive deficits that promote relapse in abstinent smokers. Davis, J.A. and Gould, T.J. Atomoxetine Reverses Nicotine Withdrawal Associated Deficits in Contextual Fear Conditioning. Neuropsychopharmacology, 2007 [Epub ahead of print].

Combined Inhibition of Dopamine and Serotonin Transporters Reduces Cocaine Self-Administration

The dopamine transporter (DAT) is now acknowledged as a critical recognition site for cocaine and is a major factor in cocaine's significant abuse liability. Dr. Leonard Howell and his associates at Yerkes National Primate Research Center are studying DAT inhibitors because this class of compounds show promise in effectively treating cocaine abuse. They studied effects of a selective DAT inhibitor, RTI-336, in rhesus monkeys self-administering the drug, and examined the ability of the RTI-336 to substitute for cocaine in this paradigm. In addition, Dr. Howell used PET imaging to quantify the DAT occupancy of RTI-336 in the range of doses tested in the other studies. He reports that RTI-336 produces a dose-related decrease in cocaine self-administration, with approximately 90% DAT occupancy. RTI-336 did substitute for cocaine, i.e. the compound was self-administered, though with lower rates of responding that those associated with cocaine. Interestingly, when RTI-336 was given along with an inhibitor of the serotonin transporter, cocaine self-administration was completely eliminated. Dr. Howell and his colleagues propose that inhibiting both dopamine and serotonin transporters may represent a new approach to treating cocaine abuse in humans. Howell, L.L., Carroll, F.I., Votaw, J.R., Goodman, M.M., and Kimmel, H.L. Effects of Combined Dopamine and Serotonin Transporter Inhibitors on Cocaine Self-Administration in Rhesus Monkeys. Journal of Pharmacology and Experimental Therapeutics, 320, pp. 757-765, 2007.

MDMA, MDA, and Methamphetamine Produce Hyperthermia in Nonhuman Primates

Dr. Michael Taffe and his colleagues at the Scripps Research Institute have been studying the thermoregulatory effects of several structurally distinct amphetamine compounds in rhesus monkeys. A better understanding of these effects is important because severe and malignant hyperthermia is an often reported effect in MDMA abusers when seen by emergency medical personnel. Dr. Taffe compared the body temperature and locomotor effects of MDMA, MDA, and methamphetamine in monkeys outfitted with radiotelemetric devices that allowed continuous and unobtrusive monitoring. All three compounds were found to elevate temperature significantly, though the time course and duration of these effects varied and did not depend on increased activity. These studies are important in extending our knowledge of the hyperthermia-inducing effects of these compounds in that all three are commonly found in samples of the abused street drug ecstasy. Crean, R.D., Davis, S.A., Von Huben, S.N., Lay, C.C., Katner, S.N., and Taffe, M.A. Effects of (+/-)3,4-Methylenedioxymethamphetamine, (+/-)3,4-Methylenedioxyamphetamine and Methamphetamine on Temperature and Activity in Rhesus Macaques. Neuroscience, 142, pp. 515-525, 2006.

Acquistion of i.v. Cocaine Self-Administration in Adolescent and Adult Male Rats Selectively Bred for High and Low Saccharin Intake

Animal studies have explored numerous variables that confer vulnerability to the reinforcing effects of drugs of abuse. A growing number of studies are pointing to greater vulnerability to the reinforcing effects of abused drugs in adolescents compared to adults. Another factor shown to confer vulnerability to the reinforcing effects of drugs is the propensity for high saccharin consumption. Recent work by Dr. Marilyn Carroll and her colleagues revealed heightened vulnerability to the reinforcing effects of cocaine in female rats selectively bred for high (HiS) versus low saccharin intake (LoS). HiS rats exhibited faster escalation of cocaine intake, self-administered more cocaine, and exhibited more cocaine-associated lever pressing during maintenance, extinction, and cocaine-primed reinstatement than LoS rats (Perry, J.L., Morgan, A.D., Anker, J.J., Dess, N.K., and Carroll, M.E. Escalation of I.V. Cocaine Self-administration and Reinstatement of Cocaine-Seeking Behavior in Rats Bred for High and Low Saccharin Intake. Psychopharmacology, 186, pp. 235-245, 2006). Given the growing body of animal research demonstrating greater adolescent vulnerability to the reinforcing effects of drugs (e.g., nicotine, alcohol, and morphine), Dr. Carroll and her colleagues compared the role of HiS versus LoS in cocaine self-administration in adult and adolescent male rats. In each of the four groups, faster acquisition of cocaine self-administration was correlated with higher cocaine intake during the last five days of acquisition. Acquisition was faster and in a greater percentage of rats in the LoS adolescents than LoS adults, but not HiS adolescents versus HiS adults, possibly indicating an age-independent ceiling effect among HiS rats. These results extend those from other rodent studies indicating greater vulnerability to the reinforcing effects of drugs (e.g., nicotine, alcohol, and morphine) in adolescent versus adult rats, and suggest that genetic background (saccharin avidity) modulates this effect. Perry, J.L., Anderson, M.M., Nelson, S.E, and Carrroll, M.E. Acquistion of I.V. Cocaine Self-Administration in Adolescent and Adult Male Rats Selectively Bred for High and Low Saccharin Intake. Physiology and Behavior, [epub ahead of print], 2007.

Nicotine Withdrawal Effects Differ in Adolescent and Adult Male Rats

Most smokers initiate smoking during adolescence. Adolescent initiation is associated with faster development of symptoms of dependence, greater severity of dependence, and greater difficulty quitting. Studies employing animal models of nicotine use suggest that adolescents are more sensitive than adults to the reinforcing effects of nicotine. Drs. Carrie Wilmouth and Linda Spear recently reported differences in adolescent and adult withdrawal effects. After seven days of chronic exposure to nicotine via implanted osmotic minipumps, nicotine withdrawal was induced via the nicotine antagonist mecamylamine, and anxiety-producing effects of withdrawal were assessed via behavior in open versus closed arms of the elevated plus maze (EPM). Following removal of the minipumps, spontaneous withdrawal was assessed by prepulse inhibition (PPI, i.e., inhibition of the acoustic startle response by presentation of a lesser intensity acoustic stimulus immediately prior to the startle stimulus), as a measure of withdrawal-related cognitive effects. Evaluation of behavior in the EPM indicated that withdrawal from chronic nicotine produced anxiety-like behavior in adults, but not in adolescents. Withdrawal from chronic nicotine had no effect on PPI in adults, but disrupted PPI in adolescents. These differences in adult versus adolescent withdrawal effects may contribute to understanding the enhanced vulnerability to nicotine during adolescence. Wilmouth, C.E. and Spear, L.P. Withdrawal From Chronic Nicotine in Adolescent and Adult Rats. Pharmacology, Biochemistry and Behavior, 85, pp. 648-657, 2006.

Nociceptive Threshold and Analgesic Response to Morphine in Aged and Young Adult Rats

Dr. Conan Kornetsky and colleagues conducted experiments to determine whether there are differences between young (5 mos) and aged (24 mos) rats in their sensitivity to pain (nociception) and in their analgesic response to morphine. When nociception was assessed peripherally using a standard tail-flick response to nociceptive stimulation, aged rats exhibited a higher nociceptive threshold than young rats (i.e., less sensitivity to pain); however, when nociception was assessed by delivering nociceptive stimulation directly to a pain pathway in the brain (the mesencephalic reticular formation), there were no differences in pain sensitivity between the two age groups. These outcomes suggest that registration of peripheral nociceptive stimulation (as measured in the tail-flick procedure, which is commonly used to assess nociception in rodents), may be compromised in the aged rat. Assessment of morphine's analgesic effects revealed that at the higher two of the three morphine doses tested, both the young and the aged rats exhibited morphine analgesia; however, at the lowest dose, only the young rats exhibited analgesia. To the extent to which these data can be extrapolated to humans, the authors conclude these data suggest that "...the belief that the aged patient feels less pain and requires less analgesic medication than the young patient needs to be re-examined." Crosby, S.J., Knapp, C.M., and Kornetsky, C. Nociceptive Threshold and Analgesic Response to Morphine in Aged and Young Adult Rats as Determined by Thermal Radiation and Intracerebral Electrical Stimulation. Pharmacology Biochemistry and Behavior, 84, pp. 148-157, 2006.

Racial Discrimination, Conduct Disorder and Subsequent Drug Use: A Critical Period Hypothesis

The present study provided a test of a critical period hypothesis that links early experiences with both racial discrimination and conduct disorder (CD) to subsequent drug use. The hypothesis was examined in a longitudinal study of 889 African American adolescents selected from the Family and Community Health Study (FACHS), which is a study of environmental factors associated with health (mental and physical) in African American families. The first phase, time 1 (T1), conducted in 2004 when the children were on average, 10.5 years of age, examined both the children and their parents through self-report measures that included substance use, conduct disorder and a host of other factors. A second wave, T2, examined the same relationships when the children were 12.5 years of age. The current study of 606 families (average age of adolescents 15.5 years), at T3, continued the examination of the relation between CD, discrimination and substance use. Results examined to date have revealed a number of interesting relationships: For example, early onset CD was associated with earlier use of marijuana and more drug use 5 years later. The amount of use was higher by those who manifested behavioral problems early on as opposed to at age 12.5. Also interesting was the finding that almost every child (77%) manifesting diagnosable CD symptoms was above the median in discriminatory experience, and 54% of the T1 CD cases were in the top 20% of self-reported discrimination. Early discrimination was also related to earlier use of marijuana, and it predicted drug use 5 years later, through its relation with friends who were using. Moreover, the combination of discrimination and conduct problems was particularly influential, as those CD-diagnosed adolescents who were in the top quarter of the discrimination distribution were more likely to report using than was any other group. In short, it appears that early discriminatory experiences can have an aversive effect on Black children that can last for a while and, for some, may precipitate behaviors that are harmful to their health. Finally, the impact of discrimination was not limited to the adolescents: the relation between the parents' T1 reports of discrimination and their T1 use was also very strong. These results suggest that identification of behavioral problems as well as distress associated with discriminatory experience at an early age among African Americans is very important. Preventive interventions aimed at helping Black parents prepare their children for the difficulties they are likely to face as a result of discrimination from others, may be particularly effective, especially if presented to children under the age of 12 or 13. Gibbons, F.X., Yeh, H-C, Gerrard, M., Cleveland, M.J., Cutrona Carolyn, Simons, R.L., and Brody, G.H. Early Experience with Racial Discrimination and Conduct Disorder as Predictors of Subsequent Drug Use: A Critical Period Hypothesis. Alcohol and Drug Dependence, 88S, S27-S87, 2007.

Effects of 1 Receptor Blockade on Cocaine Seeking

Sigma1 (_1) receptors have been implicated in cognitive function, anxiety, depression, and regulation of stress responses. In addition, _1 receptors have been found to modulate several neurobehavioral effects of cocaine, including the drug's subjective, psychomotor stimulant, rewarding, and toxic actions. Moreover, pharmacological blockade of this receptor attenuates expression of cocaine-conditioned place preference (CPP), suggesting that _1 receptors participate in mediating the conditioned incentive effects of cocaine-related environmental stimuli. The present study was designed to investigate the role of _1 receptors in cocaine-seeking by testing the effects of a potent, selective _1 receptor antagonist, BD1047, on conditioned stimulus elicited reinstatement of cocaine self-administration. To establish whether BD1047 preferentially modifies drug-directed behavior or exerts general suppressant effects on motivated behavior, BD1047 effects were tested also on responding induced by stimuli conditioned to a potent conventional reinforcer, sweetened condensed milk (SCM). Because _1 receptors have been implicated not only in the expression but also acquisition of cocaine CPP, tests of BD1047 effects on self-administration of cocaine and SCM were conducted as well. BD1047 (1-30 mg/kg) reversed response reinstatement induced by the cocaine SD at 20 and 30 mg/kg but only modified SCM SD-induced responding at the highest (30 mg) dose, when responding was reversed to extinction levels. BD1047 did not modify responding reinforced directly by SCM or cocaine. The findings support a role for _1 receptors in regulating conditioned responses to cocaine-related contextual stimuli and identify this receptor as a potential treatment target for the prevention of craving and relapse. Martin-Fardon, R., Maurice, T., Aujla, H., Bowen, W.D., and Weiss, F. Differential Effects of 1 Receptor Blockade on Self-Administration and Conditioned Reinstatement Motivated by Cocaine vs Natural Reward. Neuropsychopharmacology advance online publication 31 January 2007.

Behavioral Regulation in Individuals Co-morbid for both Cocaine and Alcohol Abuse

Neuronal integrity of frontal cortical regions may be compromised in chronic psychostimulant abusers. These frontal regions show a hypoactivity that persists after drug use is discontinued and long-term abusers show functional deficits on cognitive tasks that involve evaluating outcomes and taking risks. Human subjects with lesions to these frontal regions have similar difficulty with risk taking tasks and it appears that these deficits are due to an inability to inhibit prepotent responses, especially those that are environmentally triggered. Animal studies have mimicked these deficits in rats and monkeys with lesions of the orbitofrontal cortex (OFC). OFC lesions produce a behavioral inflexibility that manifests as a deficit in reversal learning. Recently, Drs. Fillmore and Rush at the University of Kentucky have been studying cognitive flexibility in cocaine abusers who are also moderate or heavy drinkers of alcohol. Previous investigations from this laboratory had revealed that subjects with a history of cocaine + alcohol abuse have difficulty inhibiting responses on a go/no-go task to measure control of behavioral activation and inhibition. The present study was conducted to determine if this drug abuse history can be associated with more general deficits of stimulus-response learning, which also depends on a complex neurocircuitry involving the OFC, amygdala and striatal regions. In this study authors used a cued go/no-go task where cocaine abusers or controls who were only light drinkers were tested for their speed of learning to respond to a "go" cue and withhold responding in the presence of a "no go" cue. Subjects earned monetary rewards for correct responses. Results indicate that individuals who abuse both cocaine and alcohol may have deficits of behavioral control that can be linked to perturbations of this circuit. Fillmore, M.T. and Rush, C. R. Polydrug Abusers Display Impaired Discrimination-Reversal Learning in a Model of Behavioural Control. Journal of Psychopharmacology, 20, pp. 24-32, 2006.

Accuracy of the Expectancy Valence Model for Predicting Drug Induced Impairments in Risky Decision Making

It is important to understand how drugs of abuse might alter decision making under conditions of variable risk. For example, in evaluating situations that expose drug abusers to risk of acquiring or transmitting HIV and other STDs, drugs may affect various components of a decision making process - from reward evaluation, to sensitivity for aversive consequences, expectations, or use of prior learned information, etc. NIDA-funded investigators have been applying formal mathematical models to data from acute drug tests in the laboratory, in an attempt to deconstruct the processes influenced under conditions of risk and uncertainty. Recently Dr. Scott Lane and colleagues evaluated the ability of the expectancy valence model (EVM) to predict changes in risk taking while volunteers are under the influence of marijuana, alcohol or the benzodiazepine alprazolam. The model includes three parameters that relate to putatively independent factors in a decision making process: (a) valence (affective reaction to the outcome of each trial, weighted as an index of salience); (b) learning/memory (updating or the influence of recent outcomes on expectancies); and (c) consistency (sensitivity of the decision maker's choices to the expectancies). Learning from the consequences of each decision should increase this last, consistency parameter, whereas effects on concentration, motivation and attention might be expected to decrease this value. Theoretically, these three constructs represent motivational, learning/memory, and sensitivity components of decision making. When all drug data were collapsed, investigators noted that the learning/memory parameter was the only one that was statistically different from placebo. The authors suggest that perhaps this component of decision making is the most sensitive to influence by drugs of abuse, but additional drugs should be examined. They also suggest that the EVM might be applied to assess populations with known deficits in decision making and evaluate these components as possible targets for intervention. Lane, S.D., Yechiam, E. and Busemeyer, J.R. Application of a Computational Decision Model to Examine Acute Drug Effects on Human Risk Taking. Experimental and Clinical Psychopharmacology, 14, pp. 254-264, 2006.

Rat Prenatal or Adolescent THC Exposure is Associated with Greater Heroin Intake in Adulthood

Brain cannabinoid and opioid systems are intimately connected. Cannabinoids stimulate release of enkephalin in the nucleus accumbens (NAS).They also stimulate PENK - the precursor gene for this endogenous opioid. Cannabinoid and opioid mu receptors are found on the same VTA neurons. Dr. Yasmin Hurd and colleagues have been conducting NIDA-supported studies to model (1) prenatal effects of clinically relevant gestational THC exposure and (2) adolescent marijuana abuse, to determine effects on the vulnerability for opiate self-administration in adulthood. In the prenatal study, rats were implanted for i.v. THC administration and then bred. THC was administered (.15 mg/kg) from gestational day 5 to postnatal day (PND) two (corresponding to mid-gestation in the human). Results showed that THC rats administered more drug and emitted more responses after stress, and had more drug-seeking behavior during extinction, but resembled controls on reinstatement tests with a heroin "prime" (return to bar-pressing on the drug-associated lever). Other groups were used to measure opioid peptide mRNA expression. The authors report that PENK mRNA in the NAS core and medial shell, and in the amygdala, was significantly increased in THC exposed animals at PND 62, suggesting a hyperactivity of the mesocorticolimbic enkaphalinergic system that may mediate greater sensitivity for heroin reinforcement seen on some measures of these behavioral paradigms. Spano, M.S, Allgren, M., Wang, X. and Hurd, Y.L. Prenatal Cannabis Exposure Increases Heroin Seeking with Allostatic Changes in Limbic Enkephalin Systems in Adulthood. Biological Psychiatry, 61, pp. 554-563, 2007. In the adolescent study, THC exposed adolescents took significantly more opiate (greater number of infusions on the active lever, with no differences on an inactive lever) than adults. During dose response testing, they also self-administered significantly more heroin at this dose, and at 60 _g/kg/inf. Interestingly, THC treated animals did not exhibit more drug-seeking behavior during extinction. In a separate group sacrificed at PND 57, THC treatment was associated with significant increases of PENK mRNA expression in the NAC shell. There was also a significant positive correlation between the heroin self-administration and DAMGO-stimulated [35S]GTP_S binding in the shell suggesting that THC increases opiate _ receptors in this region, and a significant correlation between heroin self-administration and CB-1 (cannabinoid receptor) binding in the substantia nigra. Ellgren, M., Spano, S.M. and Hurd, Y.L. Adolescent Cannabis Exposure Alters Opiate Intake and Opioid Limbic Neuronal Populations in Adult Rats. Neuropsychopharmacology, (Epub ahead of print) May 22, 2006, pp. 1-9. Findings from these studies suggest that developmental exposure to the active pharmacological ingredient in marijuana, THC, may enhance subsequent vulnerability for opiate abuse, and shed light on potential neurobiological mechanisms responsible for this effect.