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November 11, 2005 - 12:00am
Washington D.C.


Nora D. Volkow, M.D.

The 2005 Frontiers in Addiction Research mini-convention brought together participants from all over the world, representing a diverse array of scientific disciplines to share cutting-edge advances in research, and to discuss future directions in the neuroscience of drug abuse and addiction. Many of the discoveries and research advances discussed at the meeting hold great promise and may ultimately provide unprecedented opportunities to reduce drug abuse and addiction and their related health and social consequences.

Addiction and Obesity-Brain System Commonalities

What Marijuana Is Teaching Us About Food Intake and Body Weight Regulation
Daniele Piomelli, Ph.D.

Although it is well established that marijuana smokers eat more marshmallows than they should, exactly why this occurs is still largely a mystery. A few facts appear to be clear, however. Cannabinoid agonists stimulate food intake in animals, an effect that is likely due to the activation of CB1 receptors and is accompanied by enhanced food palatability. Moreover, CB1 antagonists, such as rimonabant, reduce food intake and body weight. Lastly, feeding status and feeding-regulating hormones, such as leptin, affect endocannabinoid synthesis in the hypothalamus and intestinal tissue. The neural substrates of these actions have not been fully elucidated yet, but their therapeutic potential is now being actively explored. Synthetic THC (Marinol®, dronabinol) is approved by the Food and Drug Administration to treat anorexia associated with AIDS, while rimonabant is in advanced clinical development for the treatment of obesity. In a recently completed Phase III trial, rimonabant produced a marked reduction of body weight in obese patients. Importantly, the drug is also under consideration as a treatment for tobacco abuse, a reminder of the common neural substrates that underlie drug and food rewards. Oleoylethanolamide, a natural endocannabinoid-like compound produced by cells in the upper intestine, inhibits feeding in rodents by binding with nanomolar affinity to the nuclear receptor PPAR-alpha; (peroxisome proliferator-activated receptor type-alpha;) which suggests that endocannabinoid and endocannabinoid-like lipid mediators play an important role in the regulation of feeding and energy balance.

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Neural Systems Recruited by Drugs and Food: Focus on Corticostriatal-Hypothalamic Integration
Ann E. Kelley, Ph.D.

Two of the greatest threats to public health in the United States in the 21st century are obesity and drug addiction including nicotine. Although these two health issues obviously are not related in terms of etiology or phenomenology, they share important commonalities and can be conceptualized as disorders of appetitive motivation. There is a growing realization that the neural pathways underlying the motivation for food and those affected by drugs of abuse share many commonalities. Both highly palatable food and rewarding drugs stimulate specific neurotransmitter systems in corticostriatal-hypothalamic circuits. Dr. Kelley has been particularly interested in how corticostriatal systems, involved with motivation, decisionmaking, and learning, interact with hypothalamic systems in both an upstream and downstream manner. Dr. Kelley's work has shown that these neurochemical systems play specific and dissociable roles in different aspects of food seeking, food intake, and reward learning. This study proposes that the striatum integrates information related to cognitive and emotional processing, with hypothalamic mechanisms mediating energy balance. The system as a whole enables complex hierarchical control of adaptive ingestive behavior, but its dysregulation underlies many compulsive aspects of both addiction and overeating.

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Brain Processing of Food-Related Stimuli With Relevance to the Control of Appetite: Taste, Olfactory, Texture, and Visual Representations of Food in the Brain
Edmund T. Rolls, D.Sc., D.Phil.

The orbitofrontal cortex (OFC) contains the secondary taste and olfactory cortices, in which the reward value of taste and smell and the texture and temperature of food in the mouth is represented, as shown by neuronal recordings in macaques. Human functional neuroimaging studies have shown that activation of the OFC and adjoining anterior cingulate cortex (ACC) by odors and liquid food is hunger-dependent, and that the pleasantness of the food is correlated with the degree of activation found. Also, it has been shown that the modulation is sensory-specific so that sensory-specific satiety is implemented in the OFC. The viscosity of food is represented in the human taste and nontaste insula and in the OFC. Fat in the mouth is detected by its texture, and this is represented in the ACC and OFC. The pleasantness of odors is represented in the OFC and flavor representations are formed by combining taste and olfactory inputs in the OFC. Cognitive influences, such as a word label, can influence activations produced by olfactory stimuli in the OFC. This neurophysiological and human functional neuroimaging evidence thus shows that the OFC is involved in decoding some primary reinforcers, such as taste, odor, texture, touch, and temperature; learning and reversing associations of visual and other stimuli to these primary reinforcers; and representing the subjective pleasantness of food in a way that correlates directly with whether food is eaten. The OFC and connected areas play key roles in representing the sensory qualities and affective value of oral sensory stimuli and, thus, in controlling intake. Moreover, the OFC is involved with other types of reward, including reward produced by amphetamine, and damage to the OFC impairs affective responses and can produce impulsive behavior.

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Common Brain Mechanisms in Addiction and Obesity
Nora D. Volkow, M.D.

The reinforcing effects of food are mediated in part by its ability to increase dopamine (DA) in brain reward and motivation circuits. Brain imaging studies in humans have shown that increases in dopamine induced by a display of food are associated with the desire and the motivation to consume the food. Since the reinforcing effects of drugs of abuse are also mediated by their ability to increase DA in the same circuits as food, why does food not produce addiction? This is likely to reflect the fact that, when compared with the increases in DA induced by drugs of abuse, those induced by food are smaller, of shorter duration, and habituate with repeated administration. Despite these differences, in some obese individuals the loss of control and compulsive food-taking behavior shares characteristics with the compulsive drug intake observed in drug-addicted subjects. We have used brain imaging in obese individuals to investigate both the brain DA system as well as regional brain metabolism, and to compare these with the changes seen in drug-addicted individuals. These studies have shown that morbidly obese subjects have significant reductions in striatal DA D2 receptor availability, which are equivalent to those we have previously reported in drug-addicted subjects. However, obese subjects showed enhanced activity of somatosensory cortical regions involved with processing palatability, which is a variable that contributes to the hedonic properties of food. Decreased levels of D2 receptors may make addicted subjects less sensitive to natural reinforcers at the expense of more powerful reinforcers; in the case of obese individuals, the enhanced sensitivity to palatability would make food a stronger reinforcer, driving its preference over that of other reinforcers.

Keynote Speech: Jacob P. Waletzky Memorial Award Recipient

Welcoming Remarks
Timothy P. Condon, Ph.D., Deputy Director, NIDA

Robert Malenka, M.D., Ph.D., Chair of the 2005 Jacob P. Waletzky
Memorial Award Selection Committee, SfN

Established in 2003, the Society for Neuroscience Jacob P. Waletzky Memorial Award is given for innovative research in drug addiction and alcoholism. This year's award recipient was William A. Carlezon Jr., Ph.D.

Experience-Dependent Alterations in the Function of Brain Reward Systems: The Role of CREB
William A. Carlezon Jr., Ph.D.

Drugs of abuse and stress each have profound effects on the NAc, including enhanced activation of CREB. We examined the consequences of altering CREB function and one of its targets (dynorphin, an endogenous opioid that acts at kappa receptors in the brain) on complex behavior, and found that elevations of CREB function within the NAc reduce the rewarding effects of cocaine, sucrose, and hypothalamic brain stimulation. Conversely, reductions in CREB activity within the NAc increase the rewarding effects of cocaine and morphine, and produce antidepressant-like effects. This pattern of behavioral effects can be attributed to changes in the expression of a single CREB-regulated protein: dynorphin. 

Administration of kappa-selective agonists produces effects that are qualitatively similar to those produced by increased CREB function in the NAc. Many of these same effects are produced by microinjections of the kappa-selective agonists directly into the NAc, suggesting that dynorphin-mediated activation of kappa-receptors in this region triggers depressive-like effects. In contrast, kappa-selective antagonists produce an antidepressant-like phenotype resembling that seen in animals with disrupted CREB function in the NAc. These findings indicate that a biologically important consequence of drug- or stress-induced activation of CREB within the NAc is increased transcription of dynorphin, which triggers certain features of depression. The fact that stress and drugs trigger common molecular cascades in the NAc may contribute to the high incidence of co-morbidity of addiction and depressive conditions in humans. A better understanding of these cascades will lead to improved treatments for addiction and other psychiatric conditions.

Neurobiological Basis for Co-Occurring Substance Abuse and Mental Illness

Human Genetic Determinants of Schizophrenia and Nicotine Addiction
Sherry Leonard, Ph.D.

This study investigated the relationship between smoking, schizophrenia, and a candidate gene, the α7 nicotinic receptor (CHRNA7). The CHRNA7 receptor is decreased in expression in the hippocampus, cortex, and reticular nucleus of the thalamus in schizophrenic subjects. Promoter mutations in the CHRNA7 gene are associated with both schizophrenia and abnormal auditory-evoked potential responses (P50 deficit). A microarray comparison of gene expression in postmortem hippocampus of control and schizophrenic smokers and nonsmokers shows that smoking significantly changes the expression of 277 genes. In the schizophrenic hippocampus, smoking differentially regulated more than 70 genes. The gene groups most significantly changed by smoking were genes expressed in the NMDA postsynaptic density (NMDA-PSD) and in the immune complex. Expression for many of the genes in these two groups was differentially regulated in the schizophrenic brain. The CHRNA7 receptor, which plays a role in the regulation of the NMDA-PSD, is one of the genes differentially regulated by smoking in schizophrenia, at both the mRNA and protein levels. Generally, the expression of differentially regulated genes was abnormal in schizophrenic nonsmokers and was brought to control levels by smoking, suggesting that smoking is normalizing gene expression in the patients. This is consistent with self-medication. We have also completed a haplotype analysis of 2 kb of upstream regulatory DNA sequence in the CHRNA7 gene. The regulatory region haplotypes seem to be related to both smoking and schizophrenia. A single haplotype was strongly associated with abnormal auditory gating (P50). Two haplotypes were associated with both smoking and schizophrenia, but the association was strongest with smoking. The data suggest that the CHRNA7 genotype may regulate smoking behavior.

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Animal Models of Schizophrenia and Depression: Studies on the Neurobiological Basis for Comorbidity With Drug and Alcohol Abuse
R. Andrew Chambers, M.D.

Substance use disorders involving addictive drugs of differing psychoactive profiles are frequently comorbid across a broad spectrum of psychiatric disorders. Combining animal models of psychiatric disorders with preclinical addiction paradigms is a route toward understanding the fundamental brain mechanisms underlying dual-diagnosis phenomena and their heterogeneous presentations. Investigations using neurodevelopmental models of schizophrenia and adult lesion models of affective disorders suggest the unitary nature of mental illness and addiction vulnerability on the levels of major limbic neurocircuits and clinical phenomenology. Further investigations using animal models of dual diagnosis will specify how environmental and genetic determinants may conspire to alter neural networks commonly involved with psychiatric disorders and the addiction process.

Nicotine-Induced Sensitization in ADHD
Jean A. King, Ph.D.

Recent findings have shown that a disproportionate number of individuals diagnosed with attention deficit hyperactivity disorder (ADHD) are smokers. It has been hypothesized that individuals with ADHD may smoke as a means of self-medication. This study was conducted to examine the effects of nicotine administration in an animal model of ADHD. It was hypothesized that exposure to nicotine would alter behavior, monoamine levels, and neuronal activation in the ADHD animal model.

Dr. King found that nicotine differentially altered all parameters examined in the ADHD animal model, compared with controls. On behavioral indices that assessed ADHD, levels of hyperactivity decreased with chronic nicotine administration, while pain sensitivity increased in ADHD animals with nicotine administration. Meanwhile, serotonin and dopamine levels in the frontal cortex (an area implicated in ADHD) showed enhanced basal levels of both monoamines; however, nicotine differentially altered the release of these transmitters. Although nicotine induced consistent increases in dopamine levels, similar increases in serotonin levels were not observed. Finally, functional brain imaging studies support a dosage-dependent increase in neuronal activation in the brain reward circuitry, with larger increases observed in the ADHD animal model. These studies support the premise that animals exhibiting ADHD features differ in their sensitivity to nicotine.

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Use Increases Risk of Adult Psychosis Only in Those With Specific COMT Genotypes
Robin M. Murray, M.D., D.Sc.

Until recently, it was suggested that individuals with psychosis used cannabis as self-medication to alleviate the distressing symptoms of schizophrenia. However, recent studies have focused on determining whether cannabis use is causal or consequential to the development of schizophrenia.

This study followed 759 individuals from age 11 (before cannabis use began), showing that individuals using cannabis at ages 15 and 18 had increased rates of developing psychotic symptoms, even with children who appeared unlikely to be predisposed by virtue of their personality and childhood. Using cannabis by age 15 was associated with increased risk for being diagnosed with schizophreniform psychosis at age 26.

Although studies investigating the interaction between cannabis use and psychosis have suggested that cannabis increases the risk of later schizophrenia, cannabis use alone does not appear to be a sufficient or necessary cause for the development of schizophrenia. The harmful effects of cannabis use appear to occur in a minority of users, suggesting that underlying factors, such as a genetic liability to psychosis, may make individuals susceptible. An obvious susceptibility gene to study in relation to cannabis use and the development of schizophrenia is catechol-O-methyltransferase (COMT), which forms part of the dopamine metabolism pathway in the prefrontal cortex. A functional polymorphism appears to moderate the effect of adolescent cannabis use on the risk for adult psychosis.

Overall, these findings support the model of schizophrenia that suggests there is a genetic background predisposing individuals to psychosis, upon which a complex constellation of factors act to trigger the development of schizophrenia. These factors include early hazards to the development of the brain; certain types of social adversity; and the abuse of such drugs as amphetamines, cocaine, and cannabis.

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mGluR: A Substrate in the Neurobiology of Addiction

Metabotropic Glutamate 5 Receptors: Role in Drug Self-Administration and in Regulating the Activity of Brain Reward Systems
Paul J. Kenny, Ph.D.

Emerging evidence suggests that glutamate-mediated transmission, particularly in metabotropic glutamate (mGlu) receptors, plays an important role in regulating the physiological and behavioral actions of drugs of abuse. This study shows that the mGlu5 receptor antagonist MPEP (2-methyl-6-[phenylethynyl]-pyridine hydrochloride) decreased intravenous cocaine and nicotine self-administration in rats. These observations, together with similar findings from other laboratories, provide strong evidence that mGlu5 receptors regulate the reinforcing effects of drugs of abuse. Little is currently known about the mechanisms by which mGlu5 receptors regulate drug reinforcement. Drugs of abuse, such as nicotine and cocaine, increase the sensitivity of brain reward systems, as measured by the drug-induced lowering of intracranial self-stimulation (ICSS) thresholds. Such drug-induced increases in reward sensitivity likely contribute to the reinforcing effects of addictive drugs. This study shows that in contrast to the actions of addictive drugs, the mGlu5 receptor antagonist MPEP decreased the sensitivity of brain reward systems, as measured by MPEP-induced elevations of ICSS thresholds in rats. When MPEP was administered in combination with nicotine or cocaine, the antagonism of mGlu5 receptors resulted in attenuation of the magnitude by which nicotine or cocaine lowered reward thresholds. These observations demonstrate that mGlu5 receptors play an important role in regulating drug consumption. In addition, mGlu5 receptors regulate the baseline sensitivity of brain reward systems. It is likely that the antagonism of mGlu5 receptors decreases the consumption of drugs of abuse by attenuating the stimulatory effects of these drugs on brain reward systems.

mGluR-Homer Interactions: A Cellular Mediator of Alcohol Reward
Karen K. Szumlinski, Ph.D.

Dr. Karen Szumlinski discussed a potential therapeutic target for the treatment of alcoholism, Group 1 metabotropic glutamate receptors (mGluRs), which are indirectly inhibited by alcohol via a protein kinase C-dependent mechanism. There is an important role for Group 1 mGluRs in mediating the rewarding and motor-sensitizing effects of opiate and psychomotor-stimulant drugs. Pharmacological blockade of either the mGluR5 or mGluR1 (a subtype of Group 1 mGluRs) reduces both the conditioned and unconditioned aspects of alcohol reward in rodents and abolishes alcohol-induced increases in extracellular dopamine and glutamate within the nucleus accumbens - two neural substrates implicated in addiction-related behaviors. The trafficking, localization, and signaling of Group 1 mGluRs depend on interactions with members of the Homer family of postsynaptic scaffolding proteins. Recently, a series of behavioral and neurochemical studies revealed an active and necessary role for Homer2 expression in the accumbens in alcohol-induced neural plasticity. Similar to the effects of mGluR blockade on alcohol-related behaviors, Homer2 knockout mice exhibit an alcohol-avoiding and -intolerant phenotype that is associated with a lack of alcohol-induced neurochemical sensitization in the accumbens. Intra-accumbens, virus-mediated overexpression of the Homer2b isoform enhances the expression of alcohol reward in alcohol-preferring B6 mice and facilitates alcohol-induced locomotor and neurochemical sensitization. As manipulations of either Group 1 mGluR or Homer function alter sensitivity to the behavioral effects of other drugs of abuse (including cocaine and PCP), these data pose the physical interaction between Group 1 mGluRs and constitutively expressed Homer proteins within the nucleus accumbens as one cellular mediator of addiction to alcohol and perhaps other drugs of abuse.

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mGluR Regulation of Endocannabinoid Release From Midbrain Dopamine Neurons
Carl R. Lupica, Ph.D.

Mesolimbic dopamine (DA) neurons are involved in mediating the rewarding effects of virtually every abused drug. The cell bodies of these neurons are found in the ventral tegmental area (VTA), and their afferent axons target a variety of forebrain structures, including the nucleus accumbens and prefrontal cortex. In addition, the DA neurons are targeted by both excitatory and inhibitory axons, which strongly regulate their activity and their involvement with drug abuse and addiction. Recent work in the laboratory of Dr. Lupica indicates that presynaptic metabotropic glutamate autoreceptors (mGluRs), located on the axon terminals of glutamatergic afferents to the VTA DA neurons, can strongly control the strength of excitatory input to these cells and, consequently, the degree of DA neuron activation. This mGluR regulation of the level of DA neuron activity can then modulate the release of endogenous cannabinoid molecules (endocannabinoids) from the DA neurons, which then act on cannabinoid CB1receptors to limit both inhibitory and excitatory neurotransmitter release onto these cells. Through this mechanism, mGluRs and endocannabinoids can interact to modify the integration of synaptic inputs to the DA neurons, presenting an additional neurobiological mechanism that may be involved with reward and addictive processes.

Reconsolidation of Memory: A New Approach to Treat Drug Addiction?

The Labile Nature of Consolidation Theory
Karim Nader, Ph.D.

Memory consolidation theory posits that new memories initially enter a labile or sensitive state, during which they can be disrupted, called short-term memory (STM). Over time, this STM is converted to a fixed long-term memory (LTM) state, which is resistant to being disrupted. For memories to enter the LTM, the neurons mediating the memory must produce new proteins that will be used for LTM storage. Recently, this study showed that when a consolidated LTM is remembered or reactivated, it returns to a labile state similar to STM, in that neurons must synthesize new proteins for the memory to persist. If protein synthesis is inhibited after the reactivation of a consolidated auditory fear memory, that memory could be erased from the brain. This phenomenon is called reconsolidation. The findings from these studies have significant clinical implications for disorders such as posttraumatic stress disorder and drug addiction. In the case of drug addiction, if drug-related memories could be reactivated and prevented from being restored, then drug seeking behavior could in principle be greatly reduced in one session. Theoretically, reconsolidation challenges the foundation on which memory consolidation theory rests.

Disrupting Memories Induced by Drugs of Abuse
Christina M. Alberini, Ph.D.

In human addicts, craving and relapse are frequently evoked by the recall of memories connected to a drug experience. Established memories can become labile if recalled or disrupted by several interfering events and pharmacological treatments, including the administration of protein synthesis inhibitors. Thus, the reactivation of mnemonic traces provides an opportunity for disrupting memories that contribute to pathological states. This study tested whether inhibiting consolidation-like processes could weaken or eliminate memories induced by drugs of abuse. Dr. Alberini found that, like conventional memories, both a new and an established morphine-conditioned place preference (mCPP) are persistently disrupted if protein synthesis is inhibited either during conditioning or following reactivation. Importantly, the disruption of an established mCPP requires that reactivation evokes a concomitant re-experience of both the conditioned context and the internal state induced by the drug. The established CPP can be abolished by selectively inhibiting protein synthesis in the hippocampus, basolateral amygdala, or nucleus accumbens, but not in the ventral tegmental area. The loss of mCPP appears to be permanent, as it does not return after further conditioning. Thus, memories induced by a drug of abuse can be persistently disrupted following reactivation.

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Disrupting Reconsolidation of Drug Memories: Potential Treatment Target for Attenuating Drug-Seeking and Relapse Elicited by Drug-Associated Stimuli
Barry J. Everitt, Sc.D.

Drug-associated conditioned stimuli (CSs) elicit memories of prior drug experiences, induce craving, and precipitate relapse in abstinent drug addicts. In experimental animals, drug-associated conditioned CSs can similarly underpin drug seeking, reinstate previously extinguished drug seeking, and also support the learning of new instrumental drug seeking responses by acting as conditioned reinforcers. We investigated whether the impact of drug-associated conditioned stimuli on drug seeking could be reduced by knocking down the zif268 gene in the amygdala - a site known to be involved with conditioned reinforcing influences on drug seeking - thereby preventing the reconsolidation of a CS-cocaine association. Zif268 knockdown in the basolateral amygdala prevented relapse to drug seeking both early and late into a period of withdrawal, but the learning of a new drug seeking response could not be supported. The results of this study demonstrate that appetitive, drug-related, CS-US associations undergo reconsolidation; that this reconsolidation process depends on the expression of zif268 in the amygdala; and that it can be disrupted to reduce drug seeking behavior in the long term, even in animals that have undergone hundreds of pairings of a CS with self-administered cocaine. These results also suggest a novel approach to the prevention of addictive behavior, including relapse, especially as the neurochemical basis of reconsolidation is elucidated.

Reconsolidation, Cocaine, and Matrix Metalloproteinases
Barbara A. Sorg, Ph.D.

Repeated cocaine exposure induces neural plasticity, as implied by the development of behavioral sensitization and drug dependence. A critical aspect of cocaine-dependent plasticity is the impact of cocaine on proteins involved with synaptic remodeling during drug seeking and drug taking behaviors. This study focused on proteins that regulate the extracellular matrix (ECM), which are critical for the dynamic physical processes involved with synaptic reorganization during neural development, long-term potentiation, and learning. Dr. Sorg's research team hypothesized that the formation of the original memory (consolidation) and reconsolidation processes require shifts in the expression of ECM proteins. One of the major regulators of the ECM is a family of proteins called matrix metalloproteinases (MMPs). MMPs are zinc metalloendopeptidases that are produced as zymogens and are secreted by cells. MMPs have been implicated in neural plasticity via degradation of the ECM, ultimately resulting in the restructuring of the ECM.

It has been proposed that drug addiction is a result of drug-induced learning and the formation of a long-term memory. With each drug use, the memory for the drug may be reactivated (retrieved) and reconsolidated to maintain the original memory. During reactivation, the memory is thought to be temporarily labile and susceptible to disruption so that reconsolidation of the memory may be prevented. Molecules involved with plasticity may therefore influence the process of reconsolidation. Dr. Sorg's laboratory demonstrated through animal testing that intracerebroventricular (ICV) injection of an MMP inhibitor (FN-439) can attenuate the learning (consolidation) of cocaine-induced conditioned place preference (CPP) when FN-439 is administered prior to each training session. The researchers tested whether MMPs also play a critical role in memory reconsolidation. Their findings suggest that both the context (CPP chambers) and unconditioned stimulus (cocaine) were needed to reactivate the memory for cocaine and to disrupt the memory for the cocaine-paired chamber.

Adolescent Drug Abuse: Brain Development, Cognition, and Vulnerability

Evidence for Enhanced Neurobiological Vulnerability to Nicotine During Periadolescence in Rats
Pier Vincenzo Piazza, M.D., Ph.D.

Epidemiological studies indicate that there is an increased likelihood for the development of nicotine addiction when cigarette smoking starts during early adolescence. These observations suggest that adolescence could be a critical ontogenetic period during which drugs of abuse have distinct effects responsible for the development of dependence later in life. The long-term behavioral and molecular effects of repeated nicotine treatment were compared during either periadolescence or postadolescence in rats. It was found that exposure to nicotine during periadolescence, but not postadolescence, increased the intravenous self-administration of nicotine and the expression of distinct subunits of the ligand-gated acetylcholine receptor in adult animals. Both these changes indicated an increased sensitivity to the addictive properties of nicotine. In conclusion, adolescence seems to be a critical developmental period characterized by enhanced neurobehavioral vulnerability to nicotine.

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Adolescent Brain and Behavior: Age-Related Sensitivities to Natural Rewards and Drugs 
Linda P. Spear, Ph.D.

Adolescence is associated with certain age-typical behaviors evident across species, including increases in novelty-seeking/risk-taking and elevated peer-directed social interactions, along with highly conserved transformations in a variety of brain regions. Prominent brain regions sculpted during adolescence include the mesocorticolimbic regions critical for attributing motivational incentives, affective relevance, and hedonic value to natural rewards as well as drugs of abuse. These ontogenetic changes in the brain may contribute to the unique behavioral characteristics of adolescents by influencing the reward value of the stimuli they encounter. Using conditioned place preference (CPP) paradigms, the responses to and relative preferences for social stimuli, novel objects, and nicotine were examined in adolescent and adult rats. Exploration of novel objects during conditioning was greater in adolescent rats, with adolescent males showing stronger novel object CPP than adult males. Social CPP also was stronger in adolescents, emerging in both group- and isolate-housed adolescents, while only being evident in isolate-housed adults. Nicotine-induced CPP was evident only in adolescent animals at the training dose used (0.6 mg/kg), with the stimulatory effects of nicotine likewise emerging during conditioning only in adolescents. Although some dissociations between reward value (as indexed by CPP preference scores) and seeking behaviors (e.g., the time spent with stimuli during conditioning) emerged in these data sets, social stimuli, novel objects, and nicotine generally were found to be more rewarding for adolescents than adults.

Vulnerabilities in Neurocognitive Processes in Adolescence
Beatriz Luna, Ph.D.

Risk-taking behavior is one of the primary causes for health problems and mortality in adolescence, due in great part to flawed decisionmaking. Decisionmaking requires the ability to choose and implement the responses that best fit goal-directed behavior. Adolescence is the period of initial transition to mature cognitive control of behavior that is supported by important brain maturation processes, such as synaptic pruning and myelination. The interaction between cognitive development and brain maturation, however, is poorly understood. Dr. Luna presents studies that characterize the changes in behavior and brain function that underlie the maturation of cognitive control of behavior, as measured by the ability to voluntarily inhibit responses and to use working memory for goal-directed behavior.

Behavioral results indicate that by midadolescence adult levels of cognitive control become evident, while the mature use of working memory is not evident until late adolescence. fMRI results from Dr. Luna's team indicated that the brain function supporting adult-level cognitive control in adolescents is different from that of adults. Although adolescents and adults recruited a similar brain network, adolescents relied primarily on the prefrontal cortex, while adults recruited the promoter-response planning regions and the hippocampus, freeing up valuable prefrontal executive processes.

Results suggest that although adolescents can appear to have mature cognitive control of behavior in a well-controlled environment, they need to exhaust brain resources used for high-level computation to a greater degree than adults. Using resources needed for cognitive control of behavior, as is provided by the prefrontal cortex, may set a system that is more vulnerable to the lack of cognitive control.

Brain Development in Healthy and Impulsive-Inattentive Children
Judith L. Rapoport, M.D.

Dr. Rapoport presented a prospective, longitudinal, anatomic brain MRI study that revealed considerable changes during childhood and adolescence and the influences of these changes. The study showed the relationship of brain developmental trajectories to age, gender, genetics (including some individual candidate risk genes), and IQ. For all these factors, the effect on the trajectory itself, rather than just regional volume, was striking - indicating that these periods of great change may also be periods of greatest vulnerability.

She also presented prospective anatomic and functional studies of children with attention deficit hyperactivity disorder that suggest important disorder-related changes at baseline and a plastic response, predicting a good outcome at followup.

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