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Director's Report to the National Advisory Council on Drug Abuse
May, 2002

Research Findings

Intramural Research

Clinical Pharmacology Section, Clinical Pharmacology & Therapeutics Research Branch

Open-Label Pilot Study of Bupropion plus Bromocriptine for Treatment of Cocaine Dependence

Combinations of medications are often used in neuropsychiatry to enhance treatment efficacy. This 8-week, open-label study tested the combination of bupropion (< 300 mg) and bromocriptine (< 7.5 mg) daily in 34 cocaine-dependent (DSM-IIIR) outpatients also receiving weekly individual counseling. The first 18 subjects spent 1 week at maximum dose; the next 16 spent 3 weeks. Both groups showed significant reductions in self-reported cocaine use, with no significant change in proportion of urine toxicology tests positive for cocaine. There were no significant differences in outcome between groups. These results suggest that the combination of bupropion and bromocriptine is safe in cocaine addicts, but provide ambiguous evidence of its efficacy. Montoya, I.D., Preston, K.L., Rothman R., and Gorelick D.A. American Journal of Drug and Alcohol Abuse, 28, pp. 1-8, 2002.

Chemistry & Drug Metabolism Section, Clinical Pharmacology & Therapeutics Research Branch

Marijuana Craving Questionnaire: Reliability and Validity

The purpose of this study was to determine the reliability and validity of the Marijuana Craving Questionnaire (MCQ), using active imagery of auditorily presented scripts. Current marijuana users (n = 48) imaged scripts that varied in amount of descriptors of desire to smoke marijuana, from no-urge to high-urge content. Self-reported marijuana craving significantly increased as a function of script urge intensity on Factors 1, 3, and 4 of the MCQ. Homogeneity of items comprising each MCQ factor was examined, indicating no significant departures from unidimensionality. These results verify and extend the reliability and validity of the MCQ as a multidimensional measurement of marijuana craving. The data also suggest that drug craving is not an all-or-none phenomenon. Singleton, E.G., Trotman, A.J.-M., Zavahir, M., Taylor, R.C. and Heishman, S.J. Experimental and Clinical Psychopharmacology, 10, pp. 47-53, 2002.

Brain Imaging Section, Neuroimaging Research Branch

Cue-Induced Cocaine Craving Likely Activates Neural Systems that Process Memories and Emotions

NIDA IRP scientists have extended their pioneering work investigating the neural correlates of cue-induced cocaine craving through the use of positron emission tomography with greater spatial resolution (<4.6 mm), an evocative script, and a pixel-by-pixel analysis. Craving and cerebral glucose metabolism were measured after presentation of cocaine-related or neutral cues to 11 cocaine abusers. Cocaine cues, consisting of visual cues and an evocative script, elicited a higher degree of craving than has been previously reported and resulted in left hemispheric activation of lateral amygdala, lateral orbitofrontal cortex, and rhinal cortex and right hemispheric activation of dorsolateral prefrontal cortex and cerebellum. The intensity of activation representing increased brain metabolism in these areas (except cerebellum), as well as in the left insula, was also correlated with craving. A remarkably consistent pattern of regional brain activation during the subjective state of cocaine craving has emerged from our original study, this, and other studies. The results suggest that induction of drug craving involves a neural network that assigns incentive motivational value to environmental stimuli through the coactivation of cortical and subcortical brain regions that process information about memories and emotions. Bonson, K.R., Grant, S.J., Contoreggi, C.S. Links, J.M., Metcalfe, Weyl, H.L, Kurian, V., Ernst, M., and London, E.D. Neuropsychopharmacology, 26, pp. 376-386, 2002.

Evaluation of Risk-Taking Using PET Identifies Unique Neural Networks Associated with Decision-making and Guessing

As decision-making is central to motivated behavior, understanding its neural substrates can help elucidate the deficits that characterize various maladaptive behaviors, including drug abuse. Twenty healthy, normal adults performed a risk-taking task during positron emission tomography with [O-15]-labeled water. The task, a computerized card game, tests the ability to weigh short-term rewards against long-term losses. A control task matched all components of the risk-taking task except for decision-making and the difference between responses to contingent and non-contingent reward and punishment. Decision-making (2 runs of the active task minus 2 runs of the control task) activated orbital and dorsolateral prefrontal cortex, anterior cingulate, insula, inferior parietal cortex and thalamus predominantly on the right side, and cerebellum predominantly on the left side. In an exploratory analysis, guessing (run 1 minus run 2 of the active task) accompanied activation of sensory-motor associative areas, and amygdala on the left side, whereas informed decision-making (run 2 minus run 1) activated areas that subserve memory (hippocampus, posterior cingulate) and motor control (striatum, cerebellum). The findings provide a framework for future investigations of decision-making in maladaptive behaviors based upon the apparent involvement of a right lateralized neural network for decision-making whereas guessing activated left-sided structures involved in sensory, motor and emotional coding and did not recruit structures subserving executive functions. Ernst, M., Bolla, K., Mouratidis, M., Contoreggi, C., Matochik, J.A., Kurian, V., Cadet, J-L., Kimes, A.S., and London, E.D. Neuropsychopharmacology, 26, pp. 682-691, 2002.

Effects of Triazolam on Brain Activity During Episodic Memory Encoding: A PET Study

It is well documented that acute administration of the benzodiazepine hypnotic drug triazolam (Halcion¨) impairs episodic memory encoding. We examined the neuroanatomical substrates of this effect in healthy adult volunteers using a double-blind, within-subject design. Following oral capsule administration (0.25 mg/70 kg triazolam or placebo), regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) with [O-15]-H2O during the performance of semantic categorization, orthographic categorization, and visual fixation (resting) tasks. rCBF associated with episodic memory encoding was measured by the difference in rCBF during the orthographic categorization task relative to that during the semantic categorization task. Results in the placebo condition (n = 9) replicated those of previous nonpharmacological encoding studies (activation in the left prefrontal cortex, cerebellum, anterior cingulate cortex, temporal cortex, and occipital cortex). Relative to placebo, results in the triazolam condition (n = 6) revealed significantly impaired memory performance, and deactivation during encoding in a subset of areas shown previously to be associated with encoding (anterior cingulate, cortex, cerebellum, and precuneus). Results are discussed in relation to triazolam's effects on mnemonic versus attentional processes. Mintzer, M.Z., Griffiths. R.R., Contoreggi, C., Kimes, A.S., London, E.D., and Ernst, M. Neuropsychopharmacology, 25, pp. 745-756, 2001.

Development of a Potential Single Photon Emission Computed Tomography (SPECT) Imaging Agent for the Corticotropin-Releasing Hormone Receptor Type-1

Corticotropin-releasing hormone (CRH) is secreted in response to stress and overstimulation of CRH type-1 receptors (CRHR-1) may be the underlying factor in the pathogenesis of a variety of mental disorders that include major depression, anxiety, and substance abuse. A high-affinity, nonpeptide radioligand for CRHR-1 has been prepared that can serve as a template for the development of SPECT imaging agents. 5-chloro-N-cyclopropylmethyl-N-(2,6-dichloro-4-iodophenyl)-2-methyl-N-propylpyrimidine-4,6-diamine (Ki=14 nM), and the corresponding 4-bromophenyl analogue (Ki=21 nM), were synthesized in four steps. The high binding affinity exhibited by the iodo analogue (Ki=14 nM), makes its I-125 analogue an intriguing template for further development of the SPECT imaging agent for the CRHR-1. In summary, IRP investigators have developed the synthesis of the first nonpeptide potential SPECT ligand for CRHR-1. This ligand holds great potential as a selective nonpeptide radioligand for the CRHR-1 binding assay, replacing the currently used peptide radioligands. The development a specific radioligand to label CRHR-1s in vivo would be a valuable diagnostic and prognostic tool for important illnesses, such as those cited above. Tian, X., Hsin, L-W. , Webster, E.L., Contoreggi, C., Chrousos, G.P., Gold, P.W., Habib, K., Ayala, A., Eckelman, W.C., Jacobson, A.E., and Rice, K.C. Bioorg. Med. Chem. Lett. 11, pp. 331-333, 2001.

PET Imaging of Nicotinic Acetylcholine Receptors: A Method to Test Hypotheses on the Role of Nicotinic Receptors in Facilitating Drug Abusing Behavior

Reduction of the demand for illicit drugs can be approached from different directions, such as interdiction or treatment. Our focus is on the potential role of nicotine-induced changes in the brain as a predisposing factor for drug abusing behavior and the development of a promising radiolabelled compound that, with positron emission tomography (PET), can be useful for non-invasively examining the role of nicotinic acetylcholine receptors (nAChRs) in drug abuse. Nicotine exposure may result in brain chemistry changes that lead to greater vulnerability to illicit, addicting drugs. Smokers exhibit greater densities of nAChRs than non-smokers and chronic nicotine upregulates alpha4beta2 nAChRs, the receptor subtype that appears responsible for nicotine addiction. Among four promising compounds that IRP investigators have developed for imaging and quantifying nicotinic receptors using PET, 2-[F-18]fluoro-A-85380 has been this group's primary focus. Its high affinity and selectivity for these receptors, the distribution of its radioactivity in the mouse and non-human primate brain in proportion to the known densities of alpha4beta2 nAChRs, a reasonably high binding potential (a measure describing the specificity of receptor binding for an in vivo ligand), and the absence of pharmacological activity at radiotracer doses indicate its suitability for quantitative analysis of receptor binding in vivo. These advances indicate that PET studies of alpha4beta2 receptors in the brains of human volunteers are imminent. This tool will allow us to examine the role of nicotinic receptors in the initiation and progression of drug dependence, and therefore, to find new, more effective ways of preventing and treating drug addiction. Kimes, A.S., Chefer, S.I, Vaupel, D.B., Pavlova, O., Koren, A.O., Contoreggi, C., London, E.D. and Mukhin, A. Proceedings of ONDCP Symposium, San Diego, California, June 25 - 28, 2001.

Neuroimaging and Substance Abuse Disorders in the Year 2000

Basic and clinical research have contributed to the fundamental principle that substance abuse is a brain disorder. Advances in the neurobiology of this disorder have evolved primarily from investigations in animals. Now with the development of neuroimaging tools, particularly functional imaging, findings from preclinical and clinical research can be integrated into testable hypotheses. Not only does neuroimaging provide a unique tool to bridge bench to bedside research, it also spurs new approaches, such as cognitive neuroscience, to study brain disorders in humans. The three critical aspects of substance abuse disorder that permeate all research questions and designs are: (1) cycle of addiction (intoxication, dependence, withdrawal, long-term abstinence, relapse), (2) direct pharmacological impact (long-term and short-term) of the addictive drugs not necessarily related to the addictive effects, and (3) polysubstance use by most substance abusers. Publications over the year of 2000 related to substance abuse research that have been targeted by neuroimaging techniques is reviewed in this paper. They include (1) brain morphometry, (2) neural connectivity and neural tracks, (3) integrated brain activity at rest (i.e., regional cerebral blood flow [rCBF] or regional cerebral metabolic rates of glucose [rCMRglc]), (4) cognitive activation, and (5) neurochemical systems. These domains of investigation converge to address the questions of (1) neural mechanisms of addiction (i.e., neural circuits, neurochemical substrates), (2) neural substrates of influential factors (e.g., sex, age, comorbidity, genetics), (3) therapeutic mechanisms (e.g., treatment development, predictors of therapeutic response), and (4) identification of risk and protective factors underlying substance abuse disorder. Ernst, M., and Chefer S.I. Current Opinion in Psychiatry, 14, pp. 179-185, 2001.

Cellular Neurophysiology Section, Cellular Neurobiology Research Branch

Bone Morphorgenetic Protein-6 Reduces Ischemia-induced Brain Damage In Rats

Bone morphogenetic protein-6 (BMP6) and its receptors are expressed in adult and fetal brain. Receptors for BMP6 are upregulated in adult brain after injury, leading to the suggestion that BMP6 is involved in the physiological response to neuronal injury. The purpose of this study was to determine if there was a neuroprotective effect of BMP6 in vivo and in vitro. Lactate dehydrogenase (LDH) and microtubule-associated protein-2 (MAP-2) activities were used to determine the protective effect of BMP6 against H2O2 in primary cortical cultures. The neuroprotective effects of BMP6 were also studied in chloral hydrate-anesthetized rats. BMP6 or vehicle was injected into right cerebral cortex before transient right middle cerebral artery (MCA) ligation. Animals were sacrificed for tri-phenyl-tetrazolium chloride staining, caspase-3 immunoreactivity and enzymatic assays, and TUNEL assay. A subgroup of animals was used for locomotor behavioral assays. Application of H2O2 increased LDH activity and decreased the density of MAP-2(+) neurons in culture. Both responses were attenuated by BMP6 pretreatment. Complementary in vivo studies showed that pretreatment with BMP6 increased motor performance, and generated less cerebral infarction, induced by MCA ligation/reperfusion in rats. Pretreatment with BMP6 did not alter cerebral blood flow or physiological parameters. There was decreased ischemia-induced caspase-3 immunoreactivity, caspase-3 enzymatic activity, and density of TUNEL(+) cells in ischemic cortex in BMP6 -treated animals. BMP6 reduces ischemia/reperfusion injury, perhaps by attenuating molecular events underlying apoptosis. Wang, Y., Chang, C.F., Morales, M., Chou, J., Chen, H.L., Chiang, Y.H., Lin, S.Z., Cadet, J., Deng, X., Wang, J.Y., Chen, S.Y., Kaplan, P.L., and Hoffer, B.J., Stroke, 32, pp. 2170-2178, 2001.

Behavioral Neuroscience Section, Behavioral Neuroscience Research Laboratory

Brain Hyperthermia and Arousal

Stress and drugs of abuse cause brain and body hyperthermia, and hyperthermia plays an important role in the neurotoxicity associated with drugs of abuse. To determine the degree of brain hyperthermia associated with stress and other aspects of behavioral testing, we recorded brain temperature from the dorsal and ventral striatum and compared it with that of neck muscle. Animals were subjected to the stress of cage transfer, mild tail-pinch, exposure to another male rat, a female rat, and a mouse, and presentation of a novel light-tone combination. Each challenge elevated brain temperature, with cage transfer, tail pinch, and social interactions causing 1-2¡C elevations in brain and muscle temperature. Brain temperature was generally higher and increased more quickly than muscle temperature, suggesting neuronal activation as a source of the hyperthermia. These findings suggest that brain hyperthermia is not restricted to conditions of stress and that it may offer an alternative for fMRI for assessing general brain activation in small unanesthetized animals. Kiyatkin, E.A. and Wise, R.A., Brain Research, 918, pp. 141-152, 2001.

Brain Hyperthermia During Heroin Self-administration

Self-administered intravenous heroin caused and maintained elevations of brain temperature to approximate 39¡C in the dorsal striatum, dorsomedial thalamus, and temporalis muscle and to 39.6¡C in the nucleus accumbens. Temperature began to rise during the period of activation prior to the first injection, rose to peak levels with the first 2-3 injections, and remained at peak levels until drug availability was terminated. The initial rise was more closely time-locked to the initial lever-press than to the light-tone stimulus that signaled initial drug availability. Temperatures returned to normal in about 2 hours when drug availability was simply terminated and returned in about 20 minutes when heroin action was terminated by the opiate antagonist naloxone. This action of self-administered doses of heroin could exacerbate methamphetamine neurotoxicity when methamphetamine and heroin are taken concurrently. Kiyatkin, E.A. and Wise, R.A., Journal of Neuroscience, 22, pp. 1072-1080, 2002.

Contribution of the Norepinephrine Transporter in the Clearance of Brain Dopamine

While dopaminergic, noradrenergic, and serotonergic neurons each express unique transporters that clear their respective transmitter from the extracellular space, and while drugs selective for the different transporters are available, the transporters are rather promiscuous in that each can clear the other monoamines. Which transporter clears a given monoamine depends on both the selectivity of the transporter for the substrate and the relative density of the three transporters. IRP investigators confirmed this by assessing synaptosomal uptake of dopamine in dopamine and norepinephrine transporter knockout mice. Dopamine uptake into frontal cortex synaptosomes was normal in dopamine transporter knockout mice and minimal in norepinephrine transporter knockout mice. Conversely, dopamine uptake into striatal synaptosomes was normal in NET knockout mice and nil in DAT knockout mice. These findings confirm pharmacological studies that implicate NET in dopamine clearance from frontal cortex and suggest that NET may be involved in dopamine clearance from other structures, like the shell of nucleus accumbens, where DAT density is low. Mor—n, J.A., Brockington, A., Wise, R.A., Rocha, B.A. and Hope, B.T. Journal of Neuroscience, 22, pp. 389-395, 2002.

A Cannabinoid Mechanism in Relapse to Cocaine Seeking

Treatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine, by re-exposure to stimuli previously associated with cocaine or by exposure to stress. In laboratory rats, similar events reinstate cocaine seeking after prolonged withdrawal periods, thus providing a model to study neuronal mechanisms underlying the relapse to cocaine. The endocannabinoid system has been implicated in a number of neuropsychiatric conditions, including drug addiction. The active ingredient of marijuana, Delta9- tetrahydrocannabinol, activates the mesolimbic dopamine (DA) reward system and has rewarding effects in preclinical models of drug abuse. IRP investigators report here that the synthetic cannabinoid agonist, HU210, provokes relapse to cocaine seeking after prolonged withdrawal periods. Furthermore, the selective CB1 receptor antagonist, SR141716A, attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself, but not relapse induced by exposure to stress. These data reveal an important role of the cannabinoid system in the neuronal processes underlying relapse to cocaine seeking, and provide a rationale for the use of cannabinoid receptor antagonists for the prevention of relapse to cocaine use. De Vries, T.J., Shaham, Y., Homberg, J.R., Crombag, H., Schuurman, K., Dieben, J., Vanderschuren, L.J. and Schoffelmeer, A.N., Nature Medicine, 7, pp. 1151-1154, 2001.

Renewal of Speedball Seeking after Prolonged Extinction by Reexposure to Drug-Associated Contextual Cues

Contextual stimuli associated with drug exposure can modulate the behavioral effects of drugs, but little is known about the role of these stimuli in relapse to drug seeking in laboratory animals. Using a renewal procedure we report here that drug-associated contextual stimuli play a critical role in relapse to drug-seeking behavior previously maintained by a heroin-cocaine mixture (speedball). Rats were trained for 10 days to self-administer speedball after which drug-reinforced behavior was extinguished over 20 days, either in the self-administration context or in a different context. On the test day rats exposed to the drug-associated context, following extinction in a different context, renewed drug seeking to levels observed prior to extinction training. Authors suggest that the present renewal procedure can be used to study mechanisms underlying relapse to drug seeking induced by exposure to drug-associated contextual stimuli. Crombag, H.S. and Shaham, Y. Behavioral Neuroscience, 116, pp. 169-173, 2002.

Neurobiology of Relapse to Heroin and Cocaine: A Review

The objective of this article was to review data from studies that used a reinstatement model in rats to elucidate the neural mechanisms underlying relapse to heroin and cocaine seeking induced by exposure to the self-administered drug (drug priming), conditioned drug cues, and stressors. These factors were reported to contribute to relapse to drug use in humans following prolonged abstinence periods. In the reinstatement model, the ability of acute exposure to drug or nondrug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. Authors reviewed studies in which pharmacological agents were injected systemically or intracranially to block (or mimic) reinstatement by drug priming, drug cues, and stressors. They also reviewed studies in which brain lesions, in vivo microdialysis and electrochemistry, and gene expression methods were used to map brain sites involved in relapse to drug seeking. Subsequently, they discussed theoretical issues related to the processes underlying relapse to drugs and address methodological issues in studies on reinstatement of drug seeking. Finally, the implications of the findings from the studies reviewed for addiction theories and treatment were discussed. The main conclusion of this review is that the neuronal mechanisms involved in relapse to heroin and cocaine seeking induced by drug priming, drug cues, and stressors are to a large degree dissociable. The data reviewed also suggest that the neuronal events mediating drug-induced reinstatement are to some degree dissociable from those mediating drug reinforcement. Shalev, U., Grimm, J.W. and Shaham, Y., Pharmacological Review, 54, pp. 1-42, 2002.

Preclinical Pharmacology Section, Behavioral Neuroscience Research Laboratory

Lack of Persistent Changes in the Dopaminergic System of Rats Withdrawn from Methamphetamine Self-Administration

IRP investigators previously reported that rats that had actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed marked decreases in somatodendritic dopamine D2 autoreceptor levels in the ventral tegmental area and median and dorsal part of the substantia nigra zona compacta with a corresponding down-regulation of dopamine D1 receptors in the shell of the nucleus accumbens. The purpose of the present study was to determine whether neuroadaptive changes in dopamine receptors or transporters in the brains of of rats withdrawn for 24 h from chronic methamphetamine self-administration are persistent changes that can be demonstrated long after withdrawal. A "yoked" procedure was used in which rats were tested simultaneously in groups of three, with only one rat actively self-administering methamphetamine while the other two received yoked injections of either methamphetamine or saline. in vitro quantitative autoradiography was used to determine densities of dopamine uptake sites and dopamine D1 and D2 receptors in different brain regions following 7- and 30-day periods of withdrawal from chronic methamphetamine self-administration. No changes in dopamine transporter and dopamine receptor numbers were detected in any brain region examined in rats self-administering methamphetamine compared with littermates receiving yoked infusions of either methamphetamine or saline. Thus, neuroadaptive changes in densities of dopamine receptors or transporters in certain brain areas may contribute to the reinforcing effects of methamphetamine during the acquisition and maintenance phases of self-administration, but do not appear to contribute to the long-lasting neuroadaptive effects of chronic methamphetamine self-administration which may trigger craving and relapse. Stefanski, R., Hee, S-H., Yasar, S., Cadet, J.L., and Goldberg, S.R. European Journal of Pharmacology, 439, pp. 59-68, 2002.

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