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National Institute on Drug Abuse

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

May, 2000

Research Findings

Intramural Research

Treatment Section, Clinical Pharmacology and Therapeutics Research Branch

Methadone Dose Increase and Abstinence Reinforcement for Treatment of Continued Heroin Use in Patients Maintained on Methadone

Although methadone maintenance is an effective therapy for heroin dependence, some patients continue to use heroin and may benefit from therapeutic modifications. This study evaluated a behavioral intervention, a pharmacological intervention, and a combination of both. All patients received daily methadone maintenance (initially 50 mg/day PO) and weekly counseling throughout the study. Following baseline treatment patients who continued to use heroin were randomly assigned to one of four interventions: 1) contingent vouchers for opiate-negative urine specimens (N=29); 2) dose increase to 70 mg/day (N=31); 3) combined contingent vouchers and dose increase (N=32); 4) neither intervention (comparison standard; N=28). Methadone dose increases were double blind. Vouchers had monetary value and were exchangeable for goods and services. Groups not receiving contingent vouchers received matching vouchers independent of urine test results. Primary outcome measure was opiate-negative urine specimens (thrice weekly urinalysis). Contingent vouchers and a methadone dose increase each significantly increased the percentage of opiate-negative urines during the intervention phase. Contingent vouchers, with or without a dose increase, increased the duration of sustained abstinence as assessed by urine screens. Dose increase, with or without contingent vouchers, reduced self-reported frequency of use and self-reported craving. In methadone-maintained patients who continued to use heroin, abstinence reinforcement and a methadone dose increase were each effective in reducing use. When combined, they did not dramatically enhance each other's effects on any one outcome measure, but they did appear to have complementary benefits. Preston, K.L., Umbricht, A., and Epstein, D.H. Archives of General Psychiatry, 57, pp. 395-404, 2000.

Chemistry & Drug Metabolism Section, Clinical Pharmacology and Therapeutics Branch

Tobacco Craving is Associated with Craving for Other Drugs of Abuse

Two experiments were conducted to determine whether active imagery would elicit tobacco craving in smokers with histories of drug abuse who were not interested in quitting smoking. In Experiment 1, researchers used scripts that contained positive, negative, or neutral affective content with and without descriptions of smoking urge. Scripts with urge content and negative affect scripts increased subjective reports of tobacco craving. An interaction between affective manipulation and urge content was observed on self-reported mood. In Experiment 2, positive affect scripts that varied in amount of urge content produced an orderly increase in tobacco craving as a function of urge intensity, suggesting that changes were specific to the imagery manipulation. In both experiments, increases in tobacco craving were positively correlated with craving for drug of choice, suggesting that stimuli that engender smoking urges may occasion craving for other drugs of abuse. Taylor, R.C., Harris, N.A., Singleton, E.G., Moolchan, E.T., and Heishman, S.J. Tobacco Craving: Intensity-Related Effects of Imagery Scripts in Drug Abusers. Experimental and Clinical Psychopharmacology, 8, pp. 75-87, 2000.

Cellular Neurophysiology Section, Cellular Neurobiology Research Branch

Cellular Expression of the Immediate Transcription Factor Nurr1 Suggest a Gene Regulatory Role in Specific Dopaminergic Neurons

Nurr1, an orphan receptor of the nuclear receptor superfamily, is widely expressed in the central nervous system (CNS) including brain regions where dopaminergic neurons are abundant. Recent analyses of Nurr1 null mutant mice, have shown that Nurr1 is essential for the development and survival of midbrain dopaminergic neurons. However, other dopaminergic neuronal populations do not seem to be affected by ablation of the Nurr1 gene. The purpose of the present study was to investigate the degree of co-existence of Nurr1 mRNA and tyrosine hydroxylase (TH) immunoreactivity in the brain of adult mice to better characterize the selective effects of Nurr1 on catecholaminergic neurons. Results indicate that the majority of TH immunoreactive neurons in the substantia nigra (SN; 96%), ventral tegmental area (VTA; 95%), retrorubral field (91%), olfactory bulb (85%), linear nucleus raphe (91%) and central grey (61%) express Nurr1. In contrast, dopaminergic cells of the paraventricular and periventricular hypothalamic nucleus showed only a few Nurr1/TH double labeled neurons, while TH immunoreactive neurons in the arcuate nucleus and zona incerta did not express Nurr1 mRNA. Nurr1 expression was also excluded from (nor)adrenergic neurons of the brain stem. In conclusion, Nurr1 transcripts were not found in all CNS catecholaminergic neurons. Nurr1 expression was confined to periglomerular and midbrain dopaminergic neurons. These results suggest that within the adult mouse brain, Nurr1 may participate in dopaminergic functions of the olfactory bulb and midbrain. Manipulation of Nurr-1 expression may allow modulation of dopaminergic circuits critical for substance abuse and addiction. BŠckman, C., Perlmann, T., Wallen, A., Hoffer, B.J., and Morales, M. Brain Research, 851, pp. 125-132, 1999.

Molecular Neuropsychiatry Section, Cellular Neurobiology Research Branch

Chronic Exposure to Antibodies Directed Against Anti-Opiate Peptides Alters Delta-Opioid Receptor Levels

The development of addictive states in response to chronic opioid use may be regulated partially by the release of endogenous peptides. These anti-opiate peptides (AOP) are secreted or released into the CNS and produce diverse actions that counterbalance the effects of prolonged opiate exposure. Though the mechanism(s) by which these peptides exert their physiological properties remain largely unknown, there is some indication that AOP's modulate opioid receptor levels. In this study, IRP researchers investigated the effects of chronically infused alpha-melanocyte stimulating hormone (alpha-MSH), dynorphin(1-8) (DYN(1-8)), dynorphin A (DYNA), and NPFF antibodies on delta-opioid receptor expression in rat brains. Quantitative autoradiographic experiments revealed that antibodies directed against alpha-MSH and DYNA produced significant increases in delta receptor levels in the caudate, claustrum, and cingulate cortex of the rat brain. Conversely, NPFF monoclonal antibodies caused significant decreases in the caudate, nucleus accumbens, olfactory tubercle, and cingulate cortex. These results suggest that the density of delta-opioid receptors is affected by changes in the levels of the anti-opioid peptides in the extracelluar fluid in the rat brain. Goodman, C.B., Heyliger, S., Emilien, B., Partilla, J.S., Yang, H.Y., Lee, C.H., Cadet, J.L. and Rothman, R.B. Peptides, 20(12), pp. 1419-24, 1999.

Caffeine Withdrawal Increases Cerebral Blood Flow Velocity and Alters Quantitative Electroencephalography (EEG)

Cessation of daily caffeine consumption produces a withdrawal syndrome comprised of subjective symptoms and functional impairment. Few controlled studies have examined the physiological effects of caffeine withdrawal. The present study examined the effect of caffeine withdrawal on cerebral blood flow velocity and quantitative EEG. Ten volunteers reporting moderate caffeine intake (mean 333 mg/day) participated in this double-blind study. Subjects completed several tests when maintaining their normal diet (baseline period) and during two 1-day periods during which they consumed caffeine-free diets and received capsules containing placebo (placebo test session) or caffeine (caffeine test session) in amounts equal to their baseline daily caffeine consumption. Blood flow velocity was determined for four arteries: right and left middle (MCA), and right and left anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded for 3 min from eight scalp sites while subjects sat, with eyes closed, in a sound-attenuated electronically shielded chamber. Subjective effects were assessed with questionnaires. Results showed an effect of the placebo (21-h withdrawal) condition compared to the caffeine condition. Placebo significantly increased the mean velocity, systolic velocity and diastolic velocity (cm/s) in all four cerebral arteries. In the MCA, the pulsatility index was significantly decreased following placebo. Placebo significantly increased EEG theta power. Placebo also produces subjective effect changes, including increases in heavy feelings in arms and legs and decreases in ability to concentrate. The caffeine and baseline conditions produced similar results on both the physiological and subjective measures. Cessation of daily caffeine consumption produced changes in cerebral blood flow velocity and quantitative EEG. These changes may be related to classic caffeine withdrawal symptoms of headache, drowsiness and decreased alertness. Jones, H.E., Herning, R.I., Cadet, J.L., Griffiths, R.R., Psychopharmacology (Berl) 147(4), pp. 371-377, 2000.

The Regulation of Cerebral Blood Flow During Intravenous Cocaine Administration in Cocaine Abusers

Cocaine abuse is associated with heightened risk of life-threatening neurological complications such as strokes, seizures, and transient ischemic attacks. We used transcranial Doppler (TCD) sonography, a continuous measure of cerebral blood flow velocity, to better understand the changes in cerebral hemodynamics produced by cocaine administration, which may lead to an increased risk for stroke in cocaine abusers. Heart rate and blood pressure were also measured. Blood flow velocity of seven cocaine abusers was studied during placebo, 10-, 25-, and 50-mg intravenous (i.v.) injections of cocaine. A significant increase in mean and systolic velocity that lasted for about two minutes was observed with all doses of cocaine, with no change in the placebo condition. This increase in systolic velocity indicates that cocaine produces an immediate and brief period of vasoconstriction in large arteries of the brain. The present results elucidate the time course of cocaine's acute cerebrovascular effects and provide a better understanding of the etiology of cocaine-related stroke and transient ischemic attacks. Herning, R.I., Better, W., Nelson, R., Gorelick, D., and Cadet, J.L. Ann N Y Acad. Sci., 890, pp. 489-494, >

Methamphetamine Administration Causes Overexpression of nNOS in the Mouse Striatum

The accumulated evidence suggests that the overproduction of nitric oxide (NO) is involved in methamphetamine (METH)-induced neurotoxicity. Using NADPH-diaphorase histochemistry, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) antibody immunohistochemistry, the possible overexpression of nNOS and iNOS was investigated in the brains of mice treated with METH. The number of positive cells or the density of positive fibers was assessed at 1 h, 24 h and 1 week after METH injections. There were no clear positive iNOS cells and fibers demonstrated in the brains of mice after METH treatment. In contrast, METH caused marked increases in nNOS in the striatum and hippocampus at 1 and 24 h post-treatment. The nNOS expression normalized by 1 week. There were no statistical changes in nNOS expression in the frontal cortex, the cerebellar cortex, nor in the substantia nigra. These results provide further support for the idea that NO is involved in the neurotoxic effects of METH. Deng, X. and Cadet, J.L. Brain Res. 851(1-2), pp 254-257, 1999.

Null Mutation of c-fos Causes Exacerbation of Methamphetamine-Induced Neurotoxicity

Methamphetamine neurotoxicity has been demonstrated in rodents and nonhuman primates. These neurotoxic effects may be associated with mechanisms involved in oxidative stress and the activation of immediate early genes (IEG). It is not clear, however, whether these IEG responses are involved in a methamphetamine-induced toxic cascade or in protective mechanisms against the deleterious effects of the drug. As a first step toward clarifying this issue further, the present study was thus undertaken to assess the toxic effects of methamphetamine in heterozygous and homozygous c-fos knock-out as well as wild-type mice. Administration of methamphetamine caused significant reduction in [(125)I]RTI-121-labeled dopamine uptake sites, dopamine transporter protein, and tyrosine hydroxylase-like immunohistochemistry in the striata of wild-type mice. These decreases were significantly exacerbated in heterozygous and homozygous c-fos knock-out mice, with the homozygous showing greater loss of striatal dopaminergic markers. Moreover, in comparison with wild-type animals, both genotypes of c-fos knock-out mice showed more DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled nondopaminergic cells in their cortices and striata. In contrast, wild-type mice treated with methamphetamine demonstrated a greater number of glial fibrillary acidic protein-positive cells than did c-fos knock-out mice. These data suggest that c-fos induction in response to toxic doses of methamphetamine might be involved in protective mechanisms against this drug-induced neurotoxicity. Deng, X., Ladenheim, B., Tsao, L. and Cadet, J.L. J. Neurosci. 19(22), pp. 10107-10115, 1999.

Brain Imaging Section, Neuroimaging Research Branch

In Vivo Labeling nAChRs with 6-[F-18]Fluoro-A85380

A new tracer for positron emission tomography (PET), 6-[F-18]fluoro-3-(2(S)-azetidinylmethoxy)-pyridine (6-[F-18]fluoro-A-85380 or 6-[F-18]FA), was synthesized by no-carrier-added [F-18]fluorination of 6-iodo-3-((1-tert-butoxycarbonyl-2(S)-azetidinyl)methoxy)pyridine followed by acidic deprotection. Radioactivity as 6-[F-18]fluoro-A-85380 reflects the regional densities of brain nAChRs reported in the literature. Evidence of binding to nAChRs and high specificity of the binding in vivo was demonstrated by inhibition with nAChR selective ligands, as well as with unlabeled 6-fluoro-A-85380. A preliminary toxicology study of the 6-fluoro-A-85380 showed a relatively low biological effect. Scheffel, U., Horti, A.G., Koren, A.O., Ravert, H.T., Banta, J.P., Finley, P.A., London, E.D. and Dannals, R.F. Nuclear Medicine and Biology, 27, pp. 51-56, 2000.

Kinetic Modeling Study with PET and [C-11]Iomazenil

Quantification of the PET benzodiazepine receptors using the antagonist, [C-11]Iomazenil, at low specific activity was previously described. The current study presents quantitative benzodiazepine receptor binding in human subjects using PET imaging and high specific activity [C-11]Iomazenil. Values for the kinetic rate constants and measures of benzodiazepine receptor binding, including binding potential and volume of distribution, were similar to results obtained with the single photon emission computed tomography (SPECT) radioligand [I-123]Iomazenil, and the prior report with low specific activity [C-11]Iomazenil. Kinetic modeling using the three compartment model with PET and high specific activity [C-11]Iomazenil provides a reliable measure of benzodiazepine receptor binding. Bremner, J.D., Horti, A., Staib, L.H. Zea-Ponce, Y., Soufer, R., Charney, D.S. and Baldwin, R. Synapse, 35, pp. 68-77, 2000.

5-Iodo-A-85380, an Alpha4 Beta2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

In an effort to develop selective radioligands for in vivo imaging of neuronal nAChRs, we synthesized 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380) and labeled it with I-125 and I-123. The affinity of 5-iodo-A-85380 for alpha4 beta2 nAChRs in rat and human brain is defined by Kd values of 10 and 12 pM, respectively, similar to that of epibatidine (8 pM). In contrast to epibatidine, however, 5-iodo-A-85380 is more selective in binding to the alpha4 beta2 subtype than to other nAChR subtypes. In rat adrenal glands, 5-iodo-A-85380 binds to nAChRs containing alpha3 and beta4 subunits with 1/1000th the affinity of epibatidine, and exhibits affinities of 1/60th and 1/190th those of epibatidine for alpha7 and muscle-type nAChRs, respectively. Moreover, in contrast to epibatidine and cytisine, 5-iodo-A-85380 exhibits no binding to brain regions in mice homozygous for a deletion mutation of the beta2 subunit of nAChRs. Binding of 5-iodo-A-85380 in rat brain is reversible, and is characterized by high specificity and a slow rate of dissociation of the receptor-ligand complex (t1/2 for dissociation ca. 2 h). These properties, along with other features observed previously in vivo (low toxicity, rapid penetration of the blood-brain barrier, and a high ratio of specific to nonspecific binding), suggest that this compound, labeled with I-125 or I-123 is superior to other radioligands available for in vitro and in vivo studies of alpha4 beta2 nAChRs, respectively. Mukhin, A.G., GŸndisch, D., Horti, A.G., Koren, A.O., Tamagnan, G., Kimes, A.S., Chambers, J., Vaupel, D.B., King, S.L., Picciotto, M.R., Innis, R.B. and London, E.D. Molecular Pharmacology, 57, pp. 642-649, 2000.

Orbitofrontal Cortex and Drug Abuse

The orbitofrontal cortex (OFC) plays a central role in human behavior. Anatomically connected with association areas of all sensory modalities, limbic structures, prefrontal cortical regions that mediate executive function, and subcortical nuclei, this brain region can serve to integrate the physical and emotional attributes of a stimulus-object and to establish a motivational value based on estimation of potential reward. To the extent that addictive disorders reflect a dysregulation of the ability to evaluate potential reward against harm from drug self-administration, it would be anticipated that substance abuse disorders might reflect dysfunction of the OFC. With the application of brain imaging techniques to the study of human substance abuse, evidence has been obtained that activity in the OFC and its connections plays a role in several components of the maladaptive behavior of substance abuse, including expectancy, craving, and impaired decision-making. London, E.D., Ernst, M., Grant, S., Bonson, K., and Weinstein, A. Cerebral Cortex, 10, pp. 334-342, 2000.

Preclinical Pharmacology Section, Behavioral Neuroscience Research Laboratory

Alteration of the Behavioral Response to Nicotine by Caffeine Exposure

Nicotine and caffeine are among the most widely used licit drugs and their consumption is often characterized by concurrent use. Some epidemiological reports suggest that smokers consume caffeine to enhance the effects of nicotine. In a series of recent experiments on rats, the effects of chronic exposure to caffeine in the drinking water on behavioral responses to nicotine or other psychomotor stimulants were assessed. Using a two-lever drug-discrimination procedure in rats, there was a significant increase in the speed of acquisition of the nicotine discrimination at the lowest caffeine concentration, while at the highest concentration there was a tendency for caffeine to retard acquisition of the nicotine discrimination. Interestingly, the dopamine component of the discriminative stimulus effects of nicotine was not present in caffeine-drinking rats at the high concentration, but it appeared to be enhanced at the lowest concentration (as evidenced by shifts to the left in the dose-response curves for generalization to amphetamine and cocaine). In rats exposed to the above oral caffeine regimens, caffeine dose dependently facilitated the increase of dopamine release in the nucleus accumbens shell after injection of nicotine using in-vivo microdialysis procedures. These studies provide evidence that the behavioral propeties of nicotine and other psychomotor stimulants can be modified by chronic caffeine exposure. The pharmacological basis for any putative interaction between these drugs remains to be established. Goldberg, S.R., Jaszyna, M., Gasior, M., Tanda, G., Poster, 2000. Society for Research on Nicotine and Tobacco Annual Meeting, Arlington, VA, February 18-20, 2000.

Behavioral Neuroscience Section, Behavioral Neuroscience Research Laboratory

Role of Noradrenaline in Stress-Induced Relapse to Heroin Seeking

Using a reinstatement procedure, it has been shown that intermittent footshock stress reliably reinstates extinguished drug-taking behavior in rats. Here we studied the role of noradrenaline (NE), one of the main brain neurotransmitters involved in responses to stress, in reinstatement of heroin seeking. We first determined the effect of clonidine, an alpha-2 adrenergic receptor agonist that decreases NE cell firing and release, on stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin (0.1 mg/kg/infusion, IV, three 3-h sessions/day) for 9-10 days. Extinction sessions were given for up to 11 days during which saline was substituted for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30 min, 0.5 mA). During testing, clonidine was injected systemically (0.01-0.04 mg/kg, IP) or directly into the lateral or fourth ventricles (0.001-0.003 mg/rat). Clonidine (0.001-0.002 mg/site) or its charged analogue, ST-91 (0.0005-0.001 mg/site), was also injected bilaterally into the locus coeruleus (LC), the main noradrenergic cell group in the brain. Clonidine blocked stress-induced reinstatement of drug seeking when injected systemically or into the cerebral ventricles. In contrast, neither clonidine nor ST-91 consistently altered stress-induced reinstatement when injected into the locus coeruleus. We, therefore, studied the effect of lesions of the lateral tegmental NE neurons on stress-induced reinstatement. 6-Hydroxydopamine lesions performed after training for heroin self-administration had no effect on extinction of heroin-taking behavior, but significantly attenuated reinstatement induced by intermittent footshock. These data suggest that (1) clonidine prevents stress-induced relapse to heroin seeking by its action on neurons other than those of the locus coeruleus, and (2) that activation of the lateral tegmental NE neurons contributes to stress-induced reinstatement of heroin seeking. Shaham, Y., Highfield, D., Delfs, J., Leung, S., and Stewart, J. Clonidine Blocks Stress-Induced Reinstatement of Heroin Seeking in Rats: An Effect Independent of the Locus Coeruleus Noradrenergic Neurons. European Journal of Neuroscience, 12, pp. 292-302, 2000.

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