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National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse
September, 1998

Research Findings

Intramural Research

Behavioral Neuroscience Section, Behavioral Neuroscience Branch

An Antagonist of the Psychotomimetic Effects of Phencyclidine (PCP) has been Identified

PCP is a drug of abuse which produces bizarre behavioral and toxic effects. A selective agonist for dopamine D3 receptors, PD 128,907, has recently been shown to prevent the psychotomimetic-like effects of PCP in animal models. Interestingly, PD 128,907 also demonstrates the pharmacological profile of an atypical antipsychotic agent. This is the first report that has identified a D3 receptor drug as a potential antipsychotic drug candidate and an antagonist of effects of PCP. Likewise, the pharmacological management of schizophrenia, a disorder affecting about 1% of the general population, is not well-advanced. IRP researchers demonstrated that the PCP-blocking effects of PD 128,907 are due to effects of the drug on a very specific class of dopamine receptors that has precise localization in the brain. This paper is also the first to report on a new antagonist for these receptors that is the most selective agent known to date. These data will be useful for understanding the pathophysio-logical states of schizophrenia and the effects of PCP. This knowledge may result in the ultimate development of clinically useful drugs based upon this novel strategy. Witkin, J.M., Acri, J., Beekman, M., DeBoer, P., Wikstrom, H., and Dijkstra, D. Atypical Antipsychotic-like Effects of the Dopamine D3 Receptor Agonist, (+)-PD 128,907. Eur. J. Pharm. 347, R1-R3, 1998.

Pharmacotherapy Section, Treatment Branch

Sociodemographic Characteristics of Subjects in Cocaine Studies

Intramural scientists have reviewed the English-language, peer-reviewed literature on clinical studies of cocaine abuse pharmacotherapy to evaluate the sociodemographic characteristics of research subjects. Their major findings were that (1) many published studies do not fully report the sociodemographic characteristics of their subjects, and (2) research subjects are fairly comparable in basic sociodemographic characteristics to the larger population of treatment-seeking individuals with cocaine-related problems (assessed in the National Comorbidity Survey), except for race/ethnicity (African-Americans over represented) and geographic location (Northeast region over represented). Gorelick, D.A., Montoya, I.D., & Johnson, E.O. Sociodemographic Representation in Published Studies of Cocaine Abuse Pharmacotherapy. Drug and Alcohol Dependence, 49, pp. 89-93, 1998.

Behavioral Pharmacology Section, Preclinical Pharmacology Laboratory

Upregulation of Nicotine Receptors following Chronic Nicotine is Mediated by NMDA Receptor Activation

Chronic exposure to nicotine can result in sensitization to the stimulant effects of nicotine and produce an increase in the number of CNS nicotine receptors. A number of studies have shown that activation of NMDA receptors mediates the behavioral adaptations that occur following psychomotor stimulant administration. IRP investigators have recently shown that NMDA receptors also mediate the behavioral and neurochemical adaptations observed following chronic nicotine. Rats treated chronically with nicotine showed clear evidence of sensitization to the locomotor activating effects of nicotine. This sensitization could be blocked by pretreatment with the NMDA receptor antagonist MK801. The same treatment regimen of chronic nicotine upregulated nicotine receptors, as shown by [3H]-cystine binding. The upregulation of nicotine receptors was also attenuated by MK-801 treatment. These results suggest that, like other drugs of abuse, sensitization following chronic nicotine exposure is mediated, at least in part, through NMDA receptors. Shoaib, M., Schindler, C.W., Goldberg, S.R. and Pauly, J.A. Behavioural and Biochemical Adaptations to Nicotine in Rats: Influence of MK801, an NMDA Receptor Antagonist. Psychopharmacology, 134, pp. 121-130, 1997.

Cocaine Infusion Rate Can Influence Self-administration in Rhesus Monkeys

Substitution therapy has proven to be one of the most effective treatments for drug abuse. Typically, substitution drugs are delivered slowly over period of time (like a nicotine patch) or have a much longer duration of action (like methadone). The slow infusion or long duration of action are thought to mitigate against the abuse of the treatment agent. It follows then that the slow infusion of cocaine at a non-reinforcing dose may well block cocaine self-administration. To test this hypothesis, investigators varied the infusion rate of cocaine delivery to rhesus monkeys lever pressing for cocaine. As infusion rate decreased, self-administration rate also decreased to placebo levels. However, when this non-reinforcing infusion rate of cocaine was delivered throughout a self administration session, responding for cocaine was not affected. If fact, there was evidence to suggest that this slow infusion actually primed or reinstated drug seeking rather than decreased it. Thus, to be successful, substitution therapy for cocaine will likely require dosage levels well above those which are themselves not reinforcing. Panlilio, L.V., Goldberg, S.R., Gilman, J.P., Jufer, R., Cone, E.J., & Schindler, C.W. Effects of Delivery Rate and Noncontingent Infusion of Cocaine on Self-administration in Rhesus Monkeys. Psychopharmacology, 137, pp. 253-258, 1998.

Brain Imaging Section, Neuroimaging Branch

The Enantioselective Radiotracer [11C]A-84543 May Have Utility for the Noninvasive Imaging of Nicotinic Acetylcholine Receptors using PET

[11C]A-84543, 3-[(1-[11C] methyl-2(S)-pyrrolidinyl)methoxy]pyridine, is a specific and enantioselective neuronal nicotinic acetylcholine receptor (nAChR) radiotracer. The in vivo biodistribution of this radiotracer in mice showed high brain uptake and a distribution consistent with the density of nAChRs. The nAChR agonists (-)nicotine, cytisine, and (+) epibatidine reduced the radioactivity due to [11C]A-84543 in the superior colliculus by 41%, 38%, and 27%, respectively. The noncompetitive nAChR ligand, mecamylamine displayed no inhibitory effect. Ketanserin (5-HT2/5-HT2C), scopolamine (mAChR antagonist), (+)butaclamol (DA receptor antagonist), and haloperidol (D2/sigma) also displayed no inhibitory effect. The pharmacologically less active (R) enantiomer, also exhibited a high brain uptake, but had a low thalamus/cerebellar ratio of 1.4 which contrasts with a higher value of 2.3 for the more active (S) enantiomer. Since [11C]A-84543 displays enantioselectivity for nAChRs, it may deserve further investigation as a possible PET radiotracer. Kassiou, M., Scheffel, U.A., Ravert, H.T., Mathews, W.B., Musachio, J.L., London, E.D., and Dannals, R.F. Pharmacological Evaluation of [11C]A-84543: An Enantioselective Ligand for In Vivo Studies of Neuronal Nicotinic Acetylcholine Receptors. Life Sci. 63(1), PL13-8, 1998.

Cue-Elicited Craving for Cocaine Does Not Represent a Simple State of Cortical Arousal as Assessed by Signs of EEG Activation

Relationships between the spontaneous electro- encephalogram (EEG), self-reports of cocaine craving, and cerebral glucose metabolism, determined using 2-[18F]fluoro-2-deoxy-D-glucose and positron emission tomography, were assessed during the presentation of either neutral or cocaine-related environmental stimuli. In cocaine users but not non-drug-abusing controls, EEG power in the alpha1 and alpha2 frequency bands was significantly lowered during presentation of the drug-related stimuli when compared to the neutral test session. Decreases in alpha1 power were negatively correlated with increases in global glucose metabolism but were not correlated with either the time course or the magnitude of craving throughout the 30-min test session. Although EEG desynchron-ization is related to global brain metabolism, the difference in the time courses between EEG power and craving suggests that self-reports of cue-elicited cocaine craving do not simply reflect increases in the state of cortical arousal. Liu, X., Vaupel, D.B., Grant, S. and London, E.D. Effect of Cocaine-Related Environmental Stimuli on the Spontaneous Electroencephalo-gram in Polydrug Abusers. Neuropsychopharmaoclogy 19, pp. 192-199, 1998.

Locus Coeruleus Neurons from Morphine-treated Rats Do Not Show Opiate Withdrawal Hyperactivity In Vitro - A Challenge to Current Theory of Opiate Withdrawal

In vitro studies have not consistently demonstrated naloxone-precipitated opiate-withdrawal hyper-activity of locus coeruleus neurons, possibly because some withdrawal may occur during the locus coeruleus slice preparation. NIDA scientists measured opiate withdrawal-related hyperactivity in neurons recorded from locus coeruleus slices while ensuring the maintenance of dependence by keeping morphine present in all solutions to which the tissue is exposed until naloxone-precipitated withdrawal. The firing rate of the drug-naive controls was 0.93 Hz. Bath application of morphine almost completely suppressed firing in drug naive controls (0.058 Hz), whereas in solutions containing morphine the cell firing rate from morphine-treated rats averaged 0.71Hz indicating considerable, but incomplete tolerance. In the same slices, naloxone increased the spontaneous firing to 0.96 Hz. Thus, naloxone did not produce withdrawal hyperactivity even when dependence was maintained, but returned the cells from morphine-treated rats to control rates. It was concluded that locus coeruleus cells in slice preparations from morphine-treated rats do not demonstrate withdrawal-related hyperactivity. Thus, the results do not support a role for adaptations intrinsic to locus coeruleus neurons in withdrawal hyperexcitability, but instead imply the necessity of functional afferent activity. Bell, J.A. and Grant, S.J. Locus Coeruleus Neurons from Morphine-treated Rats Do Not Show Opiate-withdrawal Hyperactivity In Vitro. Brain Res., 788(1-2), pp. 237-244, 1998.

A New High Affinity Ligand for Nicotinic Acetylcholine Receptors, [125I]5-I-A-85380, has Excellent Potential as a Noninvasive Imaging Radioligand Using SPECT

5-[125I]iodo-3-(2(S)-azetidinylmethoxy)pyridine, [125I]5-I-A-85380, was evaluated in the mouse as a potential in vivo imaging ligand for central nicotinic acetylcholine receptors (nAChRs). After intravenous administration of [125I]5-I-A-85380, peak brain levels of radioactivity were measured within 1 h and declined slowly over 4 h. [125I]5-I-A-85380 binding was saturable, and both its pharmacology, based upon inhibition studies, and its pattern of accumulation in brain regions having high nAChR densities were consistent with an interaction at (4(2 nAChR agonist binding sites. The thalamus:cerebellum radioactivity ratio, a measure of specific labeling, reached 37. Therefore, radiolabeled 5-I-A-85380 has excellent potential as an imaging radiotracer for nAChRs, particularly with single photon emission computed tomography (SPECT), when 123I is incorporated into the molecule. Vaupel, D.B., Mukhin, A.G., Kimes, A.S., Horti, A.G., Koren, A.O. and London, E.D. In Vivo Studies with [125I]5-I-A-85380, A Nicotinic Acetylcholine Receptor Radioligand. NeuroReport, 9, pp. 2311-2317, 1998.

Atrophy in the Gray Matter of the Prefrontal Cortex of Substance Abusers may Contribute to the Neuropathology of Functional Impairments Associated with Substance Abuse Disorder

Volumes of the prefrontal lobe in subjects with histories of polysubstance abuse (n = 25) were measured and compared with those in normal volunteers (n = 14), using high-resolution volumetric magnetic resonance imaging (MRI). The total volumes of the prefrontal lobes were significantly smaller in the substance abuse group than in controls. When the prefrontal lobe was segmented for gray and white matter, the deficit in the substance abusers was seen as significantly smaller volumes of gray but not of white matter. These results indicate that hypoplasia and/or atrophy in the prefrontal cortex accompany substance abuse and suggest that structural deficits in the prefrontal cortex may play an essential role in the neuropathological basis of functional impairments in substance abuse disorder, as demonstrated by functional brain imaging and cognitive studies. Liu, X., Matochik, J.A., Cadet, J.L. and London, E.D. Smaller Volume of Prefrontal Lobe in Polysubstance Abusers: A Magnetic Resonance Imaging Study. Neuropsychopharmacology. 18, pp. 243-252, 1998.

A Simple Radiosynthesis of a High Specific Activity Radiofluorinated Ligand for Labeling Nicotinic Acetylcholine Receptors in the Brain is Suitable for In Vivo PET Imaging Studies

NIDA IRP radiochemists have used a new chemical series of 3-pyridyl ethers synthesized by Abbott Laboratories and having subnanomolar affinity for the nAChR to develop a new fluorinated radioligand. The radiosynthesis of 2-[18-F]A-85380 has yielded a radiotracer with a high specific activity (1050 mCi/(mol). It is noteworthy that the parent compound, A-85380, has a substantially wider margin of safety than epibatidine-type compounds in animal studies. Therefore, a high specific activity combined with the potential for a wider margin of safety suggest that of 2-[18-F]A-85380 that may be an excellent positron emission tomography (PET) imaging radiotracer for nAChRs. Horti, A.G., Koren, A.O., Ravert, H.T., Musachio, J.L., Mathews, W.B., London, E.D. and Dannals, R.F. Synthesis of a Radiotracer for Studying Nicotinic Acetylcholine Receptors: 2-[18F]fluoro- 3-(2(S)-azetidinylmethoxy)-pyridine (2-[18F]A-85380). J. Label Compds. Radiopharm. XLI, pp. 309-318, 1998.

Molecular Neurobiology Section, Molecular Neurobiology Branch

Conditioned Place Preference Established in Dopamine- and Serotonin-Transporter Knockout Mice

Cocaine and methylphenidate block uptake by neuronal plasma membrane transporters for dopamine, serotonin, and norepinephrine. Cocaine also blocks voltage-gated sodium channels, a property not shared by methylphenidate. Several lines of evidence have suggested that cocaine blockade of the dopamine transporter (DAT), perhaps with additional contributions from serotonin transporter (5-HTT) recognition, was key to its rewarding actions. Investigators now report that knockout mice without DAT and mice without 5-HTT establish cocaine-conditioned place preferences. Each strain displays cocaine-conditioned place preference in this major mouse model for assessing drug reward, while methylphenidate- conditioned place preference is also maintained in DAT knockout mice. These results have substantial implications for understanding cocaine actions and for strategies to produce anticocaine medications. Sora, I., Wichems, C., Takahashi, N., Li, X.F., Zeng, Z., Revay, R., Lesch, K.P., Murphy, D.L., and Uhl, G.R. Cocaine Reward Models: Conditioned Place Preference Can Be Established in Dopamine- and in Serotonin-Transporter Knockout Mice. Proc. Natl. Acad. Sci. USA 95, pp. 7699-7704, 1998.

Cellular Neurophysiology Section, Cellular Neurobiology Branch

Trophic Factors in Neurodegeneration

Intranigral transplantation of fetal ventro- mesencephalic grafts and nigrostriatal administration of GDNF from nigra to striatum regenerates the nigrostriatal dopaminergic pathway and restores striatal dopamine release in 6-hydroxydopamine lesioned rats. In addition, ischemic brain injury elicits an upregulation of GDNF and GDNF receptors. Exogenous GDNF administration markedly attenuates ischemic brain injury, suggesting an endogenous neuroprotective role for this trophic factor. Tang, F.I., Tien, L.T., Zhou, F.C., Hoffer, B.J., and Wang, Y. Intranigral Ventral Mesencephalic Grafts and Nigrostriatal Injections of Glial Cell Line-Derived Neurotrophic Factor Restore Dopamine Release in the Striatum of 6-hydroxydopamine-lesioned Rats. Exp. Brain Res., 119, pp. 287-296, 1998.

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