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National Institute on Drug Abuse

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

May, 1996

Research Findings

Intramural Research

Psychobiology Section, Preclinical Pharmacology Laboratory, DIR

Benztropine Analogs Lack Cocaine-like Behavioral Effects Benztropine analogs bind to the dopamine transporter and inhibit dopamine uptake but do not produce behavioral effects similar to those of cocaine. It has been suggested that these compounds lack cocaine-like behavioral effects. Recent studies conducted in the Psychobiology Section show conclusively that antimuscarinic actions potentiate rather than interfere with the expression of cocaine-like behavioral effects. Therefore, the lack of cocaine-like effects of the benztropine analogs is not due to antimuscarinic actions, and may better be accounted for by an action at the dopamine transporter that is distinct from that of cocaine.

Brain Imaging Section, Neuroscience Branch, DIR

NOS Inhibitors as Potential Treatment Medications for Opiate Withdrawal Nitric oxide synthase (NOS) inhibitors and clonidine were compared for their effectiveness in attenuating signs of opiate withdrawal and affecting blood pressure in rats. Several signs of opiate withdrawal reduced by the NOS inhibitors were similarly attenuated by clonidine, which is used clinically to treat heroin withdrawal. Three NOS inhibitors, L-nitroarginine, L-nitroarginine methyl ester and LN(5)-(1-iminoethyl)-L-ornithine increased mean arterial pressure in awake morphine-naïve and morphine-dependent rats. 7-Nitroindazole, a selective inhibitor of neuronal NOS, did not elevate blood pressure and attenuated more withdrawal signs than other NOS inhibitors. Because hypertension is a component of opioid withdrawal in humans, the effectiveness of 7-nitroindazole to attenuate signs of morphine withdrawal without affecting blood pressure suggests that this drug may have human therapeutic potential.
DB Vaupel, AS Kimes, and ED London, Nitric oxide synthase inhibitors. Preclinical studies of potential use for treatment of opioid withdrawal. Neuropsychopharmacology 13: pp.315-322, 1995.

Interaction Between NMDA Antagonists and Opioids Studies utilizing the isolated spinal cord of the neonatal rat examined the role of glutamate in opioid tolerance. MK-801, a noncompetitive antagonist of the NMDA subtype of glutamate receptor, did not prevent the development of opioid tolerance. The results demonstrate that glutamate receptor antagonists act synergistically to enhance the potency of opioids, thus masking tolerance. JA Bell and CL Burgess, MK-801 blocks the expression but not the development of tolerance to morphine in the isolated spinal cord of the neonatal rat. Eur. J. Pharmacol. 294: pp.289-296, 1996.

Presynaptic Glutamate Receptors Contribute to Opiate Withdrawal
The isolated spinal cord of the neonatal rat and intact adult rats were used to examine the role of glutamate in the expression of opioid dependence. Chronic MK-801, a noncompetitive antagonist, enhanced withdrawal signs. MK-801, given acutely, diminished withdrawal in the isolated cord, but disrupted the behavioral expression of withdrawal in intact rats. The results demonstrated that a component of the opiate withdrawal syndrome is due to hyperactivity of presynaptic glutamatergic neurons. JA Bell and CL Burgess, Co-treatment with MK-801 potentiates naloxone-precipitated morphine withdrawal in the isolated spinal cord of the neonatal rat. Eur. J. Pharmacol. 294: pp. 297-301, 1996.

New 18F-labeled Ligand for PET Imaging of Nicotinic Acetylcholine Receptors A new radiotracer for the nicotinic acetylcholine receptor, (+/-)-exo-(2-[18F]fluoro-5-pyridyl)-7azabicyclo[2.2.1]heptane, was synthesized by Kryptofix(r) 222 assisted nucleophilic no-carrieradded [18F]fluorination of (+/-)-exo-(2-bromo-5-pyridyl)-7-azabicyclo[2.2.1] heptane. The 18Flabeled tracer may be developed for the noninvasive visualization of central nicotinic receptors using positron emission tomography (PET). A Horti, HT Ravert, ED London, and RF Dannals, Synthesis of a radiotracer for studying nicotinic acetylcholine receptors: (+/-)-exo-2-(2[18F]fluoro-5-pyridyl-7)-azabiocyclo[2.2.1]heptane. J Labeled Compds Radiopharm 38: pp.355366, 1996.

Cocaine Sensitization is Prevented by K-opioid Agonists Studies conducted in the rat demonstrated that K-opioid receptor agonists prevented sensitization to the conditioned rewarding effects of cocaine. TS Shippenberg, A Le Fevour, and C Heidbreder. K-opioid agonists prevent sensitization to the conditioned rewarding effects of cocaine. J Pharmacol Exp Ther, 276: pp. 545554, 1996.

Molecular Neuropsychiatry Section, Neuroscience Branch, DIR

Chronic Cocaine Use as a Neuropsychiatric Syndrome In humans, chronic cocaine abuse is associated with neuropathological changes in the central nervous system. Acute administration of cocaine is associated with acute psychoactive episodes and paranoid states, while withdrawal from the drug is often associated with depressed mood. DIR investigators propose that the chronic, heavy use of cocaine may result in a neuropsychiatric syndrome, the disconnection syndrome, which because of its subtlety may have deleterious effects on both the acute and longterm therapeutic interventions with these subjects. JL Cadet and KI Bolla, Chronic cocaine use as a neuropsychiatric syndrome: a model for debate. Synapse 22: pp. 28-34, 1996.

A Role for Superoxide Radicals in the Chronic Effects of Methamphetamine Methamphetamine (METH)-induced neurotoxicity is thought to involve release of dopamine (DA) in presynaptic DA terminals, which is associated with increased formation of oxygen-based free radicals. In CuZn-superoxide dismutase expressing transgenic mice, the loss of DA terminals caused by METH was attenuated in a gene dosage-dependent manner, with female mice being more resistant than male mice against the deleterious effects of METH. These results suggest a role of superoxide radicals in the long-term effects of METH. H Hiroshi, B Ladenheim, E Carlson, E Epstein, and JL Cadet, Autoradiographic evidence for methamphetamine-induced striatal dopaminergic loss in mouse brain: attenuation of CuZn-superoxide dismutase transgenic mice. Brain Research 714: pp. 96-103, 1996.

Sigma Ligand PRE-084 as an Anti-Amnesic Agent In both long-term and short-term memory retrieval tests in mice, a selective sigma receptor ligand PRE-084, identified at the DIR, NIDA, was found to block the impairment of learning and memory induced by MK-081, mecamylamine, and nimodipine. PRE-084 may have a unique property to act as a anti-amnesic agent. T Maurice, T-P Su, DW Parish and A Privat, Prevention of nimodipine-induced impairment of learning by the F selective phencyclidine derivative PRE-084. J. Neural Transmission, 102: pp.1-18,1995.

Lung Survives Longer with Delta Opioid Peptide DADLE Delta opioid peptide DADLE worked in an as yet to be investigated manner to prolong lung preservation. In this study DIR investigators demonstrated that the DADLE-preserved lung functioned perfectly when transplanted into the host animal. PR Oeltgen, ND Horton, SF Bolling and T-P Su, Extended lung preservation with the use of hibernation trigger factors. The Annuals of Thorac. Surg., In Press.

A Hibernation Specific Protein is Purified and Partially Sequenced A protein enriched in winter-hibernating animal has been purified and partially sequenced. It is a 88 kDa protein with a sequence which does not exhibit homology with any known protein. ND Horton, PR Oeltgen, DJ Kaftani, T-P Su, DS Bruce, AS Krober and JF Jones, Biochemical characterization of a hibernation-specific 88 kDa protein derived from the plasma of deeply hibernating woodchucks. In: "Adaptations to the Cold - Tenth International Hibernation Symposium", Ed: F. Geiser, Univ. New England Press, Armidale, Australia, In Press.

An Original Opioid/Sigma Receptor? In an attempt to purify non-opioid sigma receptors, we have instead purified a protein which resembles the opioid/sigma receptors originally proposed by Martin and coworkers. This protein binds benzomorphans, naloxone, morphine, and haloperidol with high affinities. The protein showed three bands in SDS/PAGE. L-I Tsao and TP Su, A naloxone-sensitive, haloperidol-sensitive, [3H](+)SKF-10047-binding protein partially purified from rat liver and rat brain membranes: An opioid/sigma receptor? Synapse, In Press, 1996.

Sigma Ligand PRE-084 as an Anti-Amnesic Agent for Aging and Alzheimer's Patients? Scientists at DIR found that PRE-084 reverses the amnesia in Senescence Accelerated Mice (SAM) both in short-term memory and long-term memory tests. Sigma ligands may represent a new class of drugs for targeting amnesia due to aging or Alzheimer's disease. T Maurice, FJ Roman,,T-P Su and A Privat, Beneficial effects of sigma ligands on the age-related learning impairment in the senescence accelerated mouse (SAM). Brain Res., In Press.

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