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Director's Report to the National Advisory Council on Drug Abuse
February, 1996

Research Findings

Basic Research

Cocaine Immunization

Kim Janda, Ph.D., Rocio Carrera, M.A., George Koob, Ph.D. and colleagues at the Scripps Research Institute have demonstrated, for the first time, the ability to immunize rats against some of the stimulant effects of cocaine. The animals were treated for 35 days with a conjugated analog of cocaine that is more resistant to metabolism by esterases and that is recognized by the body as a foreign substance. Antibodies were produced in the rats which prevented the subsequent administration of cocaine from producing its CNS stimulatory effects. Cocaine levels in the brains of these animals were reduced from 50 to 75% from those of rats not subjected to the 35-day pretreatment regimen. Suppression of Psychoactive Effects of Cocaine by Active Immunization. Nature, 378: pp. 727-730, 1995.

The biotechnology company ImmuLogic Pharmaceutical Corp., also recently announced having developed a cocaine vaccine. The details are proprietary, and as yet unpublished. Dr. Barbara S. Fox of ImmuLogic discussed some of the company's findings in Chemistry and Engineering News, December 18, 1995, and at a January 18, 1996 meeting of the Maryland Bioscience Alliance at the request of NIDA's Medications Development Division.

Cocaine and Cardiovascular Toxicity

NIDA supported researchers, Drs. Patrick Abrahams, Kurt Varner and their associates have reported recently that the sympathoinhibitory responses elicited by cocaine and amphetamine are centrally-mediated and involve, in large part, an alpha2 adrenergic mechanism in the rostral ventrolateral medulla. The local anesthetic actions of cocaine appear to have little, if any, role in the sympathetic nerve responses. These findings provide new insights into the site(s) and mechanism(s) by which cocaine and other sympathomimetic stimulants affect sympathetic and cardiovascular function. Abrahams, TP, Cuntapay, MC and Varner, KJ. Physiol Behav, in press; Abrahams, TP, Faust, ML and Varner, KJ. J Auto Nerv Sys, in press.

Prenatal Cocaine: Effects on the Offspring

Dr. Michael Lidow (Yale University) has been investigating the effects of prenatal cocaine in rhesus monkeys on the offspring. Dr. Lidow has found that prenatal cocaine, in doses that produce blood levels approximately equal to those producing a euphoriant dose in humans, resulted in histological changes in the 2-month-old offspring. He reported that 20 mg/kg/day (PO) from days 40 to 102 of gestation resulted in significantly altered lamination of the primate cerebral cortex, in some cases completely blending distinction between individual layers. In addition, autoradiographic analysis revealed that [3H]thymidine labeling occurred in cortical white matter as well as layers IV, V, and VI while control animals showed no labeling in the white matter or in layer IV. These data suggest an inability of cortical cells to reach proper cortical layers. The number of labeled cells was also much lower in the cocaine-treated offspring. Finally, immunocytochemical studies with antisera directed toward glial fibrillary acidic protein showed that prenatal exposure to cocaine had dramatic effects on the glial fibers normally observed in the upper cortical layers.

In many regions, no such fibers were observed. Lidow, M.S. Prenatal Cocaine Exposure Adversely Affects Development of the Primate Cerebral Cortex. Synapse 21:332-341, 1995.

Understanding the Central Cannabinoid Receptor

The cannabinoid antagonist SR141716A and its corresponding radioligand are expected to be valuable tools in basic research leading to an understanding of the biochemical mechanisms of action of the central cannabinoid receptor, CB1. The use of such tools may lead to the identification of receptor types, mapping of receptor types in brain, and addressing the pathophysiological role of CB1. To date, the synthesis of this compound is not reported from Sanofi Recherche. The first published synthesis of this compound was by NIDA grantees and their colleagues. The publication is entitled "The Synthesis and Pharmacological Evaluation of the Cannabinoid Antagonist SR141716A ", Med Chem Res, 5: pp. 54-62, 1994, by Dutta et al. Another paper that appeared recently was from Seltzman et al., "Synthesis, Spectral Studies and Tritiation of the Cannabinoid Antagonist", J Chem Soc., Chem Commun, 1995. This work was supported by NIDA and this paper describes a simple procedure for making the radiolabeled ligand. Both the cold and the radiolabeled compounds are in the NIDA Drug Supply System.

Conformational Analysis of a Cannabinoid Ligand

CP-55, 940 is one of the high-affinity non-classical cannabinoid receptor ligands. Dr. Makriyannis and colleagues, using a combination of solution NMR and computer modeling methods, studied the conformational properties of the ligand to obtain information on stereoelectronic requirements at the cannabinoid receptor active site. Their manuscript is in press (J Biol Chem). Their data indicates that for the most energetically favored conformation, 1) the aromatic A-ring is perpendicular to the cyclohexane ring, and the phenolic O-H bond is coplanar with the aromatic ring and points away from the cyclohexyl ring; 2) the dimethylheptyl chain adapts one of the four preferred conformations in all of which the chain is almost perpendicular to the A-ring; and 3) an intramolecular H-bond between the phenolic and hydroxypropyl groups allows all three hydroxyl groups to be oriented toward the upper face of the molecule. Such an orientation by the OH groups may be a characteristic requirement for cannabimimetic activity.

Do Endogenous Opioids Play a Role in Nicotine Dependence?

Smokers' ability to quit is compromised by the nicotine abstinence syndrome. Dr. David Malin of the University of Houston, a NIDA Shannon awardee, developed a rat model of this syndrome, useful for (1) elucidating the neurobiological mechanisms of the syndrome, and (2) screening putative interventions to ease smoking cessation. Nicotine was infused subcutaneously via osmotic minipump. The pump was removed after 7 days, and the rats were observed for characteristic withdrawal signs (with experimenters blind as to treatment). The signs resembled those of moderate opiate abstinence, and were precipitated by a nicotine antagonist or by the opiate antagonist naloxone, suggesting a major role of the endogenous opioid peptides in nicotine dependence. In nicotine dependent rats, signs were reversed by morphine as well as nicotine itself. Naloxone prevented nicotine alleviation of nicotine abstinence syndrome. These results further support the hypothesis that the release of endogenous opioids plays a role in nicotine dependence. David H. Malin et al., Pharmacol. Biochem. Behav. 53(2), in press.

Morphine Inhibits Spontaneous and Cytokine Enhanced Natural Killer Cell Cytotoxicity in Volunteers

Opioids are used by patients who have conditions ranging from the acute pain of surgery and chronic cancer pain to substance abuse. This study was designed to evaluate the in vivo effect of morphine on human peripheral blood immune functions. {Animal studies indicate that the naive subject's immune system may be affected more initially than after days to weeks of opiate administration (see Bayer et al. below)}. This study was conducted on healthy volunteers. Subjects underwent continuous exposure to morphine for 36 hr. including a 24 hr. intravenous infusion in the hospital. Peripheral blood was drawn for immune function studies at five measurement times before, during, and after morphine exposure. Suppression of g-interferon stimulated natural killer cell cytotoxicity [NKCC] was observed at 2 and 24 hr. after the onset of intravenous morphine exposure. Suppression of NKCC persisted for 24 hr. after termination of morphine infusion in the higher dose study group; g-interferon-stimulated NKCC and antibody dependent cell cytotoxicity were also decreased after 24 hr. of morphine exposure. These results suggest that morphine administration, at doses within the range of analgesic use, can cause measurable suppression of some components of the human cellular immune system. The potential impact of this suppression on disease progression remains to be evaluated. Mark Yeager, Thomas A. Colacchio, Cecelia T. Yu, Laurie Hildebrandt, Alexandra L. Howell, Julie Weiss, Paul M. Guyre.

Membrane Potential and Morphine Tolerance

Dr. William W. Fleming of West Virginia University has been investigating if (1) the state of partial depolarization of morphine-responsive S myenteric neurons is the result of altered function of the Na/K pump and (2) the adaptation of myenteric and brainstem neurons induced by chronic treatment with morphine is nonspecific and due to changes in resting membrane potential.

During the past year Dr. Fleming has shown that: (1) There is no decrease in the percent of S myenteric neurons which are hyperpolarized by morphine in tolerant vs placebo preparations. (2) Approximately 2/3 of tested S neurons were hyperpolarized by 0.1 µM morphine. (3) Only neurons which responded to morphine acutely demonstrated a lesser resting transmembrane potential in tolerant vs control preparations (a mean depolarization of 7.2 mV). (4) The acute hyperpolarizing effects of morphine 0.l µM, clonidine 0.3 µM, and 2-CADO (2-chloro-adenosine) 0.1 µM were equivalent (6-8 mV) on the same S neurons and not different between tolerant and placebo preparations. This is important because these concentrations produce 50-60% inhibition of the neurogenically induced twitch in control LM/MP but less than 10% in tolerant preparations. (5) The hyperpolarizing effects of morphine and clonidine are accompanied by reductions in input resistance while the hyperpolarizing effect of 2-CADO is not. And (6) effects of these agonists on input resistance do not differ between tolerant and placebo preparations. Preliminary experiments with cardiac glycosides are consistent with the S neurons of tolerant preparations having depressed electrogenic function of the Na/K pump.

It was concluded that: (1) The receptors for the three agonists are co-localized on S neurons, the motor neurons to the longitudinal muscle. (2) The transduction process for 2-CADO is different from that of morphine and clonidine. (3) Cross tolerance (subsensitivity) among the agonists is not a function of altered receptors or transduction processes. And (4) the hypothesis that the de polarized state of S neurons is responsible for tolerance in the LM/MP preparation is strongly supported.

In brainstem, the morphology and pharmacology of the guinea pig nucleus of the Tractus Solitarius (nTS) have been defined. The sensitivity of spontaneously firing nTS neurons to several agonists has been quantified and compared between brainstem slices from guinea pigs implanted seven days before with morphine pellets ("tolerant") and slices from placebo implanted guinea pigs. Sensitivity to the inhibitory actions of morphine, muscimol (GABAA-selective agonist) and 2-CADO was significantly reduced in the tolerant preparations. Sensitivity to the excitatory effects of potassium ion was increased. Thus, the working hypothesis that the adaptation of these neurons induced by chronic treatment with morphine will be nonspecific (i.e., not confined to opioids), just as in the LM/MP, has been confirmed.

Orphanin FQ: A Neuropeptide That Activates an Opioid Receptor-like Orphan Receptor

During the arduous pursuit of the molecular cloning of opioid receptors, several laboratories have identified an orphan receptor with a sequence similar to the mu, delta and kappa opioid receptors, yet incapable of high affinity binding of the known ligands.

Now NIDA grantee David Grandy and other investigators at the Vollum Institute in Oregon and Hoffman-La Roche in Switzerland have discovered the natural ligand for this novel receptor. This natural ligand, named orphanin FQ by Grandy and his coworkers, is a heptadecapeptide which shares the greatest sequence similarity with dynorphin A. It inhibited adenylate cyclase in transfected cells expressing the orphan receptor. After intracerebroventricular administration, orphanin FQ caused a decrease in locomotor activity in mice but did not induce analgesia in the hot-plate test. It produced hyperalgesia in the tail-flick assay. Future studies on orphanin FQ will likely enhance our understanding of pain mechanisms as well as tolerance and dependence associated with opioid drugs. Science, Vol. 270, p. 792, November 3, 1995. Dr. Lei Yu of Indiana University School of Medicine, recently reported that dynorphins are the endogenous ligands for the orphan receptor. JBC, Vol. 270, p. 22772, 1995.

Opiates and Pain Fibers

Pain is carried to the brain by two classes of fibers: A-delta and C fibers. A-delta fibers generally mediate acute sharp pain, whereas chronic aching pain is mediated by C fibers. Dr. David Yeomans (University of Illinois) has recently established a non-invasive method for exclusively activating either fiber class in rats. Dr. Yeomans has found that pain produced by C-fiber activation is mediated by substance P or NMDA receptors. Conversely, pain produced by A-delta fibers is mediated by the release of excitatory amino acids. Despite this pharmacological difference, both types of fibers could be inhibited by endogenously released opioids. This research has important significance to pain control. Whereas opioids are effective on both acute and chronic pain, there are significant drawbacks of chronic opioid administration. The methods established by Dr. Yeomans will be valuable in the study of the pharmacological differences between acute and chronic pain, and perhaps will lead to improved treatments for chronic pain. These findings were presented at the 1995 Society for Neuroscience annual meeting (Dimethyl Sulfoxide Sensitizes A-delta and Desensitizes C-fiber Nociceptors, Soc. Neurosci Abs, 21: p. 649, 1995; Differential Pharmacology of Raphe Magnus Stimulation Produced Antinociception for Rat Foot Withdrawal Response Evoked by Different Rates of Radiant Heating, Soc. Neurosci Abs, 21: p. 1415, 1995) and are in press in the journal Pain.

Tolerance and Crosstolerance to the Suppressive Effects of Cocaine and Morphine on Lymphocyte Proliferation

The effects of acute or daily exposure to either cocaine or morphine on lymphocyte proliferative responses and NK cytolytic activity were determined. Two hours following the IV infusion of cocaine, blood lymphocyte proliferative responses were found to be suppressed by 75%. Cocaine had no effect on proliferative responses of thymic or splenic lymphocytes or cytolytic activity of splenic NK cells following acute or 5 day repetitive dosing. Similar to the effects of cocaine, morphine administration was also accompanied by a suppressed blood lymphocyte response, which was no longer apparent 8 days following repeated morphine injections. Animals that had received daily injections of either morphine or cocaine were also found to be resistant to the inhibitory effect of a single dose of morphine or cocaine respectively. These data suggest that repeated exposure to either morphine or cocaine results in the development of an apparent crosstolerant state to further suppression of blood lymphocyte proliferative responses by either drug. Barbara M. Bayer, Monica C. Hernandez and Xuan Z. Ding, Pharmacol Biochem Behav 52: pp. 227-34, 1995.

A Primate Model of Polydrug Abuse: Cocaine and Heroin Combination

NIDA grantees at the Alcohol and Drug Abuse Research Center at McLean Hospital have developed a primate model for studying cocaine-opiate combinations ("speedballs") using self-administration and drug discrimination procedures. This model should prove to be valuable in developing pharmacotherapies for concurrent cocaine and opiate abuse. A Primate Model of Polydrug Abuse: Cocaine and Heroin Combination, Mello et al., J. Pharmacol. Exp. Therap., 274: pp. 1325-1337, 1995.

Anabolic-androgenic Steroids and Brain Reward

Dr. Ann Clark and her associates have recently found that in rodents, two weeks of exposure to anabolic-androgenic steroid (AAS), methandrostenolone produced no significant changes in the rewarding properties of brain stimulation reward. On the other hand, their data also suggested that AAS may influence the sensitivity of brain reward systems as the rate-frequency curve-shift observed in response to a systemic dose of amphetamine was significantly greater in animals after 15 weeks on a mixture of commonly abused AAS compounds. Clark, AS, Lindenfeld, RC, and Gibbons, CH. Pharmacol Biochem and Behavior, in press.

A Simple Genetic Basis for a Complex Psychological Trait in Laboratory Mice

Anxiety, either pre-existing or drug induced, is often associated with chronic use and abuse of psychoactive drugs. Understanding the biological bases of anxiety may provide insight into the mechanisms underlying substance abuse. This philosophy guided a study carried out as part of a NIDA funded research Center (DeFries: Behavioral Genetic Studies of Drug Abuse Vulnerability) in the laboratory of NIDA Research Scientist Allan C. Collins. The study used the Quantitative Trait Locus (QTL) methodology to identify QTLs associated with emotionality in the mouse. The QTL methodology provides a first step towards identifying the genes that regulate emotionality or anxiety. Emotionality was inferred in mice by a covariation of behavioral measures that included open field activity, defecation in the open field activity on an elevated plus-maze and Y-maze activity. Quantitative measures of each of these behaviors were assessed in over 800 F2 crosses derived from two mouse lines that were selectively bred for differences in activity and defecation in an open field arena.

The mice were genotyped and a linkage analysis was performed. Three QTLs were identified, on mouse chromosomes 1, 12, and 15, that are common to the four behaviors that were measured. The results suggest that these loci are, at least in part, the genetic basis of emotionality. Reasons for expecting that the genetic basis of emotionality is similar in other species and that it may underlie the psychological trait of susceptibility to anxiety in humans is suggested by the behavioral effects of anxiolytic drugs in rodents together with results of electrophysiological and lesion experiments. While the nature of these genes is unknown, the results suggest that they may influence emotional response to a wide variety of anxiogenic stimuli and may provide new approaches towards understanding the association between anxiety and psychoactive drug use. Jonathan Flint (Institute of Psychiatry, London, UK funded by Wellcome Trust), Robin Corley, John C. DeFries, David W. Fulker, Jeffrey A. Gray, Stacey Miller, Allan C. Collins (Funded by NIDA Center Grant to DeFries and K-Award to Collins) Science, 269: pp. 1432-1435, September 8, 1995.

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