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National Institute on Drug Abuse

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

February, 1999

Research Findings

Basic Research

Normally Silent Synapses in Spinal Cord Become Active to Produce Chronic Pain

Silent glutamatergic synapses have been reported in various portions of the central nervous system (CNS) and are believed to underlie some nervous system plasticity. Using patch-clamp techniques in a slice preparation, NIDA grantee Min Zhou (University of Washington in St. Louis, St. Louis, Missouri) has found silent glutamatergic synapses in the spinal pain pathways of rats. This research suggests it is likely that the recruitment of these synapses contributes to chronic pain both by increasing the intensity of noxious sensory input (hyperalgesia) and by allowing normally non-noxious stimuli to activate pain pathways (allodynia). This research may help in the development of technologies to diminish chronic pain. Li, P., Zhuo M. Nature, 393, pp. 695-698, 1998.

Controlling for the Effect of Hair Color in Drug Tests

The ratio of eumelanin (brown-black pigment) to pheomelanin (reddish-yellow pigment) was recently shown to provide a good control for variations in PCP concentration found by hair color. PCP was found in the hair of multiple strains of rats and mice to whom PCP had been administered and who differed in the pigment composition of their hair. If these results were replicated in humans, this ratio could help eliminate the effect of hair color on drug test results for at least some drugs of abuse. Slawson, M.H., Wilkins, D.G., Rollins, D.E. J. Anal. Tox., 22, pp. 406-413, 1998.

Endothelial Cells and Abused Drugs

Dr. George Stefano and his colleagues have demonstrated recently that both morphine and anandamide stimulated endothelial cNOS and inhibit LPS- and IFN-stimulated iNOS. Inhibition of the adenylate cyclase cascade was also noted due to simultaneous generation of NO. These findings provide information regarding the relationship between cNOS and iNOS as well as the functional significance of cAMP cascade in the regulation of NOS activity that may contribute to a better understanding of endothelial regulatory activities. Stefano, G.B., Salzet, M., Magazine, H.I., et al., J. Cardiovascular Pharmacology, 31, pp. 813-820, 1998.

Neurotoxic Doses of Methamphetamine Induced Reactive Gliosis

Reactive microglia have been shown to play an active role in some models of cell damage. Dr. Teresa Hastings of the University of Pittsburgh and her research team have investigated whether reactive glial changes occur in the striatum following neurotoxic administration of methamphetamine (METH) in rats. They demonstrated a temporally organized reactive gliosis throughout the striatum in these rats. Hyperplastic responses by reactive glia were maximal at two days post-METH and resolved to near control levels by six days. Furthermore, the magnitude of this response was greatest in the ventrolateral striatum, a subregion previously shown to undergo the greatest pathology. Inspection of other brain regions of the neuraxis revealed focal hyperplastic changes of microglia in piriform cortex, parietal cortex, periaqueductal gray and red nucleus that were of greater magnitude than those observed in the striatum. Collectively, these data demonstrate a robust activation of glial cells in regions known to exhibit METH-induced pathology and identify other brain regions at risk among METH abusers. LaVoie, M.J., Hastings, T.G., Card, J.P. Soc. Neuroscience Abstract, 24, p. 1243, 1998.

Associations to Rewarding Events are Not Dopaminergic

A major problem in the development of medications to prevent relapse to drug abuse is that our understanding of the reinforcing properties of drugs of abuse is based on the brain reward model. The brain reward model suggests that the dopaminergic nucleus accumbens plays a major role in mediating the reinforcing effects of drugs. However, clinical trials based on this model have been disappointing because dopaminergic antagonists do not seem to prevent relapse. For this reason, the Institute is encouraging studies to examine mechanisms beyond the nucleus accumbens to determine if there are non-dopaminergic mechanisms playing a major role in relapse. Recently, Dr. Ettenberg reported that dopamine receptor antagonism did not reduce subjects' motivation to seek food. Rats were trained to discriminate between two olfactory cues predicting either the presence or absence of food reinforcement in a goal box of a straight-arm runway. Rats learned to run the alley rapidly in the presence of the cue associated with food. A dopamine antagonist (halperdol) pretreatment did not alter this pattern of behavior. Thus the same dopamine antagonist treatments that disrupt food reinforcement do not prevent the food-seeking behavior produced by food-predictive cues. These findings are most likely applicable to the failure of dopamine antagonists to prevent drug relapse since relapse is generally accepted to result from environmental cues related to the drug experience. McFarland, K. Ettenberg, A. Behavioral Neuroscience 112(3), pp. 630-635, 1998.

Chronic Running Activity Decreases Sensitivity to Morphine-Induced Analgesia

The effects of exercise on morphine-induced analgesia were examined in male and female rats. Male rats housed in activity wheels (active group) for 20 days were more sensitive to pain than rats housed in standard laboratory cages (inactive group). Additionally, both active male and female rats displayed decreased morphine-induced analgesia relative to inactive controls. Moreover, females that had been inactive and then were permitted to run showed less morphine-induced analgesia relative to inactive rats, and to their own nociceptive responses when sedentary. In contrast, morphine-induced analgesia in initially active females who were housed in standard cages for 17 days prior to a second nociceptive test was enhanced relative to their first nociceptive test and to presently active rats. These observations showed that the attenuation of morphine analgesia induced by running is reversible and not permanent. Short term exposure to exercise (24 h running) had no significant effect on morphine-induced analgesia. These results indicate that chronic activity can decrease morphine's analgesic properties. These effects may be due to cross tolerance between endogenous opioid peptides released during exercise and exogenous opioids. Kararek, R.B., Gerstein, A.V., Wildman, R.P., Mathes, W.F., D'Anci, K.E. Pharm. Biochem. and Behav., 61(1), pp. 19-27, 1998.

Homer Regulates Metabotropic Glutamate Receptors-induced Intracellular Calcium Release

Homer (or Homer 1a) is a neuronal immediate early gene that is enriched at excitatory synapses and binds group 1 metabotropic glutamate receptors. Homer modulates the activity and assembly of the metabotropic receptor. NIDA grantee Dr. Paul Worley and his coworkers at the Johns Hopkins University School of Medicine recently characterized a family of Homer-related synaptic proteins derived from 3 distinct genes (Homer 1b/c, 2a/b, and 3). Like Homer immediate early gene (Homer 1a), all new members bind group 1 metabotropic glutamate receptors. In contrast to Homer 1a, new members are constitutively expressed and encode a C-terminal coiled-coil domain that mediates self-multimerization. Coiled-coil-Homers form natural complexes that cross-link metabotropic glutamate receptors and are enriched at the post synaptic density. Homer 1a does not multimerize, and blocks the association of metabotropic glutamate receptors with Coiled-coil-Homer complexes. Group 1 metabotropic glutamate receptors activate phosphatidylinositol turnover and trigger intracellular calcium release. Dr. Worley and his coworkers discovered that Homer-related synaptic proteins (Homer 1b/c, 2a/b, or 3) form a physical tether linking metabotropic glutamate receptors with inositol trisphosphate receptors. A novel proline rich "Homer ligand" (PPXXFr) is identified in group 1 metabotropic glutamate receptors and inositol trisphosphate receptors and these receptors co-immunoprecipitate as a complex with Homer-related synaptic proteins from brain. Expression of Homer 1a, which lacks the ability to cross-link, modulates metabotropic glutamate receptors-induced intracellular calcium release. These studies identify a novel mechanism in calcium signaling and provide evidence that an immediate early gene, whose expression is driven by synaptic activity, can directly modify a specific synaptic function. Xiao, B., Tu, J.C., Petralia, R.S., Yuan, J.P., Doan, A., Breder, C.D., Ruggiero, A., Lanahan, A.A., Wenthold, R.J., Worley, P.F. Neuron 21, pp. 707-716, 1998; Tu, J.C., Xiao, B., Yuan, J.P., Lanahan, A.A., Leoffert, K., Li, M., Linden, D.J., Worley, P.F. Neuron, 21, pp. 717-726, 1998.

Alpha7 Subunit and Subtypes of Receptors in Embryonic Sympathetic Neurons

Previous work has shown the presence of the a7 subunit of the nicotinic acetylcholine receptor to be present in the brain. Yu and Role recorded from sympathetic neurons in order to determine the physiological role of a7 nicotinic receptors in the brain. They report evidence that the a7 subunit contributes to three distinct heteromeric nicotinic acetylcholine receptors in chick embryonic sympathetic neurons. The currents evoked by nicotinic agonists in embryonic sympathetic neurons are different than the currents evoked by nicotinic agonists in the hippocampus in the brain where the nicotinic receptors appear to be composed only of homomeric a7 subunits and are highly permeable to calcium. The three different currents evoked by nicotinic agonists differ with respect to their sensitivities to a-bungarotoxin and methyllycaconitine, single channel conductances, and open times. This work suggests that alternative processing and trafficking of the a7 nicotinic acetlylcholine receptors subunit in neurons profoundly affects the functioning and pharmacology of nicotinic receptors. Yu, C.R., Role, L.W. Physiology (Lond), 509, pp. 651-65, 1998.

Stress and Adolescent Development

In a recent paper, Dr. Carol Kellogg and her associates report that restraint, as a form of stress, induced Fos in a broader spectrum of neurons in young adult than in juvenile male rats. The Fos protein, a product of an immediate early gene, is transiently expressed in neurons after stimulation. The lack of Fos-positive cells in specific areas of juveniles may relate to maturation of specific brain nuclei as age-related differences were observed in Fos production. These findings provide insight into the temporal regulation of the nuclei activated by the stressors as well as into the adolescent development of brain regions involved in mediating various stress responses. Kellogg, C.K., Awatramani, G.B., Piekut, D.T. Neuroscience, 83(3), pp. 681-689, 1998.

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