Readings

The readings listed below are the foundation of this course. Where available, journal article abstracts from PubMed (an online database providing access to citations from biomedical literature) are included.

Introduction

Cooper, Bloom, and Roth. "Cellular Foundations of Neuropharmacology." Chap. 2 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 9-48.

------. "Introduction." Chap. 1 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 3-8.

------. "Molecular Foundations of Neuropharmacology." Chap. 3 in The Biochemical Basis of Neuropharmacology. 7th ed.
New York: Oxford University Press, 1996, 75-81.

Neurochemical Systems in the Central Nervous System in Basic Neurobiology. 20-24.

Tobin, A. "Gene Expression in the Mammalian Nervous System." In Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. Edited by G. J. Siegel. New York: Raven Press Ltd., 1994, 493-513.

Lipids

Agranoff, B. W., and A. K. Hajra. Lipids in Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. Edited by G. J. Siegel. New York: Raven Press Ltd., 1994, 97-116.

Betz, A. L. "Transport of Ions Across the Blood-Brain Barrier." Federation Proc. 45, no. 7 (1986): 2050-2054.

PubMed abstract:  Capillaries in the brain are formed by a uniquely specialized endothelial cell that regulates the movement of substances between blood and brain. Although they provide an impermeable barrier to some solutes, brain capillary endothelial cells facilitate the transcapillary exchange of others. In addition, they contain specific enzymes that contribute to a metabolic blood-brain barrier by limiting the movement of compounds such as neurotransmitters across the capillary wall. Studies of sodium and potassium transport by brain capillaries indicate that the endothelial cell contains distinct types of ion transport systems on the two sides of the capillary wall, i.e., the luminal and antiluminal membranes of the endothelial cell. As a result, specific solutes can be pumped across the capillary against an electrochemical gradient. These transport systems are likely to play a role in the active secretion of fluid from blood to brain and in maintaining a constant concentration of ions in the brain's interstitial fluid. In this way, the brain capillary endothelium is structurally and functionally related to an epithelium.

Brownlees, J., and C. H. Williams. "Peptidases, Peptides, and the Mammalian Blood-Brain Barrier." J. Neurochem. 60, no. 3 (1993): 793-803.

Pardridge, W. M. "Regulation of Amino Acid Availability to the Brain." In Nutrition and the Brain. Vol. 1. Edited by R. J. Wurtman, and J. J. Wurtman. New York: Raven Press, 1977, 142-175.

Temburni, M. K., and M. H. Jacob. "New Functions for Glia in the Brain." Proc. Natl. Acad. Sci. USA 98, no. 7 (2001): 3631-3632.

Acetylcholine

Blusztajn, J. K., and R. J. Wurtman. "Choline and Cholinergic Neurons." Science 221 (1983): 614-620.

PubMed abstract:  Mammalian neurons can synthesize choline by methylating phosphatidylethanolamine and hydrolyzing the resulting phosphatidylcholine. This process is stimulated by catecholamines. The phosphatidylethanolamine is synthesized in part from phosphatidylserine; hence the amino acids methionine (acting after conversion to S-adenosylmethionine) and serine can be the ultimate precursors of choline. Brain choline concentrations are generally higher than plasma concentrations, but depend on plasma concentrations because of the kinetic characteristics of the blood-brain-barrier transport system. When cholinergic neurons are activated, acetylcholine release can be enhanced by treatments that increase plasma choline (for example, consumption of certain foods).

Cooper, Bloom, and Roth. "Acetylcholine." Chap. 7 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 194-225.

------. "Treating Neurological and Psychiatric Diseases." Chap. 13 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 500-501.

Nitsch, R. M., J. K. Blusztajn, A. G. Pittas, B. E. Slack, J. H. Growdon, and R. J. Wurtman. "Evidence for a Membrane Defect in Alzheimer Disease." Brain Proc. Natl. Acad. Sci. USA 89 (1992): 1671-1675.

PubMed abstract:  To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P less than 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P less than 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine choline-phosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.

Ulus, I. H., R. J. Wurtman, C. Mauron, and J. K. Blusztajn. "Choline Increases Acetylcholine Release and Protects Against the Stimulation-Induced Decrease in Phosphatide Levels within Membranes of Rat Corpus Striatum." Brain Research 484 (1989): 217-227.

PubMed abstract:  This study examined the possibility that membrane phospholipids might be a source of choline used for acetylcholine (ACh) synthesis. Slices of rat striatum or cerebellum were superfused with a choline-free or choline-containing (10, 20 or 40 microM) physiological solution with eserine, for alternating 20 min periods of rest or electrical stimulation. Superfusion media were assayed for choline and ACh, and slice samples taken before and after stimulation were assayed for choline, ACh, various phospholipids, protein and DNA. The striatal slices were able to sustain the stimulation-induced release of ACh, releasing a total of about 3 times their initial ACh contents during the 8 periods of stimulation and rest. During these 8 cycles, 885 pmol/micrograms DNA free choline was released from the slices into the medium, an amount about 45-fold higher than the initial or final free choline levels in the slices. Although repeated stimulation of the striatal slices failed to affect tissue levels of free choline or of ACh, this treatment did cause significant, dose-related (i.e., number of stimulation periods) stoichiometric decreases in tissue levels of phosphatidylcholine (PC) and of the other major phospholipids; tissue protein levels also declined significantly. Addition of exogenous choline to the superfusion medium produced dose-related increases in resting and evoked ACh release. The choline also fully protected the striatal slices from phospholipid depletion for as many as 6 stimulation periods. Cerebellar slices liberated large amounts of free choline into the medium but did not release measurable quantities of ACh; their phospholipid and protein levels did not decline with electrical stimulation. These data show that membrane phospholipids constitute a reservoir of free choline that can be used for ACh synthesis. When free choline is in short supply, ACh synthesis and release are sustained at the expense of this reservoir. The consequent reduction in membrane PC apparently is associated with a depletion of cellular membrane. The use of free choline by cholinergic neurons for two purposes, the syntheses of both ACh and membrane phospholipids, may thus impart vulnerability to them in situations where the supply of free choline is less than that needed for acetylation.

Ulus, I. H., M. C. Scally, and R. J. Wurtman. "Enhancement by Choline of the Induction of Adrenal Tyrosine Hydroxylase by Phenoxybenzamine, 6-Hydroxydopamine, Insulin or Exposure to Cold." J. Pharmacol. Exp. Ther. 204, no. 3(1978): 676-682.

PubMed abstract:  Treatments that increase the release of acetylcholine from the splanchnic nerve have previously been shown to induce the enzyme tyrosine hydroxylase in adrenal chromaffin cells. Such treatments include the systemic administration of the drugs phenoxybenzamine and 6-hydroxydopamine, insulin-induced hypoglycemia, and prolonged exposure to cold. We have reported that the administration of choline also induces the adrenal enzyme and have suggested that the mechanism of this induction involves an increase in the amount of acetylcholine released each time the splanchnic nerve fires. In the present studies, rats received both choline and one of the above treatments. Choline caused an augmentation of the adrenomedullary response to each of the treatments, but it had no apparent effect on a presynaptic enzyme, choline acetyltransferase. These observations strongly support the view that choline availability determines both the amount of acetylcholine present in nerve terminals and the amount liberated when cholinergic neurons fire.

Norephinephrine and Epinephrine

Cooper, Bloom, and Roth. "Norepinephrine and Epinephrine." Chap. 8 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 226-292.

------. "Treating Neurological and Psychiatric Diseases." Chap. 13 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 487-493.

Insel, P. A. "Adrenergic Receptors-Evolving Concepts and Clinical Implications." N. Engl. J. Med. 334, no. 9 (1996): 580-585.

Wurtman R. J., and J. Axelrod. "Control of Enzymatic Synthesis of Adrenaline in the Adrenal Medulla by Adrenal Cortical Steroids." J. Biol. Chem. 241, no. 10 (1965): 2301-2305.

Wurtman, R. J., A. Casper, L. Pohorecky and F. C. Bartter. "Impaired Secretion of Epinephrine in Response to Insulin Among Hypophysectomized Dogs." Proc. N. A. S. 61 (1968): 522-528.

Wurtman, R. J. "Presynaptic Control of Release of Amine Neurotransmitters by Precursor Levels." NIPS 3 (1988): 158-163.

Dopamine

Acworth, I. N., M. J. During, and R. J. Wurtman. "Tyrosine: Effects on Catecholamine Release." Brain Res. Bull. 21, no. 3 (1988): 473-477.

PubMed abstract:  Tyrosine administration elevates striatal levels of dopamine metabolites in animals given treatments that accelerate nigrostriatal firing, but not in untreated rats. We examined the possibility that the amino acid might actually enhance dopamine release in untreated animals, but that the technique of measuring striatal dopamine metabolism was too insensitive to demonstrate such an effect. Dopamine release was assessed directly, using brain microdialysis of striatal extracellular fluid. Tyrosine administration (50-200 mg/kg IP) did indeed cause a dose related increase in extracellular fluid dopamine levels with minor elevations in levels of DOPAC and HVA, its major metabolites, which were not dose-related. The rise in dopamine was short-lived, suggesting that receptor-mediated feedback mechanisms responded to the increased dopamine release by diminishing neuronal firing or sensitivity to tyrosine. These observations indicate that measurement of changes in striatal DOPAC and HVA, if negative, need not rule out increases in nigrostriatal dopamine release.

Anden, N. E., M. Grabowska-Anden, and B. Liljenberg. "On the Presence of Autoreceptors on Dopamine Neurons in Different Brain Regions."  J. Neural Transmission 57 (1983): 129-137.

PubMed abstract:  The alpha-methyltyrosine-induced disappearance of dopamine was inhibited by the selective dopamine autoreceptor agonist B-HT 920 in the corpus striatum, the nucleus accumbens, the olfactory tubercle, the limbic cortex, and the rostral part of the cerebral cortex of the rat. These inhibitory actions of B-HT 920 were almost completely reversed by the dopamine receptor antagonist haloperidol, indicating that they were caused by a stimulation of dopamine autoreceptors. In the caudal cortex and the cerebellum, the effects of B-HT 920 and haloperidol were less clear, perhaps due to a low concentration of dopamine and to the occurrence of this dopamine in both dopamine and noradrenaline neurons. In the hypothalamus, B-HT 920 and haloperidol did not change the alpha-methyltyrosine-induced disappearance of dopamine in agreement with previous findings that the tubero-infundibular dopamine neurons are not regulated via dopamine receptors.

Bjorklund, A., and O. Lindvall. "Parkinson Disease Gene Therapy Moves Toward the Clinic." Nature Medicine 6 (2000): 1207-1208.

Burns, R. S., P. A. LeWitt, M. H. Ebert, H. Pakkenberg, and I. J Kopin. "The Clinical Syndrome of Striatal Dopamine Deficiency." N. Engl. J. Med. 312, no. 22 (1985): 1418-1421.

PubMed abstract:  Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a syndrome that resembles Parkinson's disease. To compare the biochemical abnormalities produced by this compound in human beings with those occurring in Parkinson's disease, we examined biogenic amine metabolites in cerebrospinal fluid and urine from six patients with MPTP-induced parkinsonism and eight patients with Parkinson's disease. In both forms of parkinsonism, the cerebrospinal fluid levels of homovanillic acid, the major metabolite of dopamine, were reduced, whereas the levels of the serotonin metabolite 5-hydroxyindoleacetic acid were normal. The cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the major metabolite of norepinephrine in the brain, after adjustment for plasma MHPG, were elevated (greater than 6.0 ng per milliliter) in MPTP-induced parkinsonism, whereas MHPG levels were reduced (less than 6.0) in Parkinson's disease. Neurons containing norepinephrine in the brain are involved in the degenerative process of Parkinson's disease, whereas they are spared in MPTP-induced parkinsonism. The selective destruction by MPTP of nigrostriatal dopamine neurons that is responsible for the movement disorder also appears to result in an increase in central noradrenergic activity, which is not possible in Parkinson's disease. Thus, differences in central noradrenergic activity, reflected in cerebrospinal fluid levels of MHPG, distinguish these two forms of parkinsonism.

Cooper, Bloom, and Roth. " Dopamine." Chap. 9 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 293-351.

------. "Treating Neurological and Psychiatric Diseases." Chap. 13 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 493-499, 501-506.

Guillin, O., J. Diaz, P. Carroll, N. Griffon, J. C. Schwartz, and P. Sokoloff. "BDNF Controls Dopamine D3 Receptor Expression and Triggers Behavioural Sensitization."  Nature 411 (2001): 86-89.

PubMed abstract:  Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.

Schultz, W., P. Dayan, and P. R. Montague. "A Neural Substrate of Prediction and Reward." Science 275 (1997): 1593-1599.

PubMed abstract:  The capacity to predict future events permits a creature to detect, model, and manipulate the causal structure of its interactions with its environment. Behavioral experiments suggest that learning is driven by changes in the expectations about future salient events such as rewards and punishments. Physiological work has recently complemented these studies by identifying dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events. Taken together, these findings can be understood through quantitative theories of adaptive optimizing control.

Seeman, P. "Dopamine Receptors and Psychosis." Scientific American: Science & Medicine 2, no. 5 (1995): 28-37.

Strange, P. G. "Dopamine Receptors." Tocris Reviews 15 (2000). Bristol, UK: Tocris Cookson Ltd.

White, F. J. "Dopamine Receptors Get a Boost." Nature 411 (2001): 35-37.

Williams G. V., and P. S. Goldman-Rakic. "Modulation of Memory Fields by Dopamine D1 Receptors in Prefrontal Cortex." Nature 376 (1995): 572-575.

PubMed abstract:  Dopamine has been implicated in the cognitive process of working memory but the cellular basis of its action has yet to be revealed. By combining iontophoretic analysis of dopamine receptors with single-cell recording during behaviour, we found that D1 antagonists can selectively potentiate the 'memory fields' of prefrontal neurons which subserve working memory. The precision shown for D1 receptor modulation of mnemonic processing indicates a direct gating of selective excitatory synaptic inputs to prefrontal neurons during cognition.

Serotonin

Cooper, Bloom, and Roth. "Serotonin and Histamine." Chap. 10 in The Biochemical Basis of Neuropharmacology. 7th ed.
New York: Oxford University Press, 1996, 352-391.

------. "Treating Neurological and Psychiatric Diseases." Chap. 13 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 487-493.

Fernstrom, J. D., and R. J. Wurtman. "Brain Serotonin Content: Increase Following Ingestion of Carbohydrate Diet." Science 174 (1971): 1023-1025.

------. "Brain Serotonin Content: Physiological Dependence on Plasma Tryptophan Levels." Science 173 (1971): 149-152.

------. "Brain Serotonin Content: Physiological Regulation by Plasma Neutral Amino Acids." Science 178 (1972): 414-416.

Martin, G. M. "Advances in Serotonin Receptor Research: Molecular Biology, Signal Transduction and Therapeutics." CNS Drug Reviews 3, no. 3 (1997): 294-299.

Nishizawa, S., C. Benkelfat, S. N. Young, M. Leyton, S. Mzengeza, C. de Montigny, P. Blier, and  M. Diksic.  "Differences between Males and Females in Rates of Serotonin Synthesis in Human Brain." Proc. Natl. Acad. Sci. USA 94 (1997): 5308-5313.

PubMed abstract:  Rates of serotonin synthesis were measured in the human brain using positron emission tomography. The sensitivity of the method is indicated by the fact that measurements are possible even after a substantial lowering of synthesis induced by acute tryptophan depletion. Unlike serotonin levels in human brain, which vary greatly in different brain areas, rates of synthesis of the indolamine are rather uniform throughout the brain. The mean rate of synthesis in normal males was found to be 52% higher than in normal females; this marked difference may be a factor relevant to the lower incidence of major unipolar depression in males.

O'Rourke, D., J. J. Wurtman, R. J. Wurtman, R. Chebli, and R. Gleason. "Treatment of Seasonal Depression With d-Fenfluramine." J. Clin. Psychiatry 50, no. 9 (1989): 343-347.

PubMed abstract:  Eighteen patients with seasonal affective disorder (SAD) participated in a double-blind, placebo-controlled crossover study in 1986-1987. Each received, in random order, d-fenfluramine (15 mg p.o. twice daily)-a serotonin-releasing drug previously shown to suppress carbohydrate craving-or a placebo; these were given for 4 weeks separated by a 2-week washout period. Symptoms were assessed by means of clinical interviews and the Hamilton Rating Scale for Depression (HAM-D) with a special SAD addendum (AAD). Patients were also weighed. Depression scores (mean +/- SE) were identical before treatment with drug (20.9 +/- 1.3, HAM-D; 13.3 +/- 0.8, AAD) or placebo (21.4 +/- 1.2, HAM-D: 13.2 +/- 0.6, AAD). During placebo treatment, mean HAM-D scores declined by 22% (p less than .02) and AAD scores by 9% (p greater than .2). During d-fenfluramine treatment, HAM-D scores fell by 71% (p less than .001) and AAD scores by 73% (p less than .001). Thirteen (72%) of the patients demonstrated complete reversal of their abnormal test scores while taking d-fenfluramine. The group as a whole lost weight (mean = 1.2 kg) while receiving d-fenfluramine (p less than .033) but not when taking placebo. A second study, conducted in 1987-1988 with nine subjects who had previously responded to d-fenfluramine, showed that the drug remains effective for the full 3-month annual period of symptoms. These results indicate that d-fenfluramine may be useful in treating SAD and suggest that serotonin is involved in both SAD's affective and appetitive symptoms.

Schaechter, J. D., and R. J. Wurtman. "Tryptophan Availability Modulates Serotonin Release from Rat Hypothalamic Slices." J. Neurochem. 53, no. 6 (1989): 1925-1933.

PubMed abstract:  Application of a novel in vitro experimental system has allowed us to describe the relationship between tryptophan availability and serotonin release from rat hypothalamic slices. Superfusing hypothalamic slices with a physiologic medium containing l-tryptophan (1, 2, 5, or 10 microM) caused dose-dependent elevations in tissue tryptophan levels; the magnitude of the elevations produced by supplementing the medium with less than 5 microM tryptophan was within the physiologic range for rat brain tryptophan levels. Slice serotonin levels rose biphasically as the tryptophan concentration in the medium was increased. Superfusing the slices with medium supplemented with a low tryptophan concentration (1 or 2 microM) caused proportionally greater incremental changes in serotonin levels than the increases caused by further elevating the tryptophan concentration (5 or 10 microM). The spontaneous release of serotonin from the slices exhibited a dose-dependent relationship with the tryptophan concentration of the superfusion medium. Electrically evoked serotonin release, which was calcium-dependent and tetrodotoxin-sensitive, also increased in proportion to the medium tryptophan concentration. These data suggest that the rate at which serotonin is released from hypothalamic nerve terminals is coupled to brain tryptophan levels. Accelerations in hypothalamic serotonin synthesis, caused by elevating brain tryptophan levels, result in proportionate increases in the rates of serotonin release during rest and with membrane depolarization.

Wurtman, R. J., and J. J. Wurtman. "Carbohydrates and Depression." Scientific American 1 (1989): 68-75.

Wurtman, J. J., and R. J. Wurtman. "D-Fenfluramine Selectively Decreases Carbohydrate But Not Protein Intake in Obese Subjects." Intl. J. Obesity 8, no. 1 (1984): 79-84.

PubMed abstract:  Studies on normal rats and on obese human subjects exhibiting 'carbohydrate-craving' suggest that brain mechanisms exist allowing appetites for carbohydrates and proteins to be regulated independent of those for calories and for tastes of the carbohydrates. We observe that virtually all of the excess in daily energy intake among these obese people can be accounted for by carbohydrate snacks, and that a serotonin-releasing drug, d-fenfluramine, selectively diminishes the tendency to consume these snacks.

Melatonin and Sleep

Lynch, H. J., R. J. Wurtman, M. A. Moskowitz, M. C. Archer, and M. H. Ho. "Daily Rhythm in the Human Urinary Melatonin." Science 187 (1975), 169-171.

PubMed abstract:  The melatonin in urine samples from six healthy adult volunteers was concentrated on Amberlite XAD-2 resin, eluted with organic solvents, and quantitated by use of a bioassay technique (the dermal melanaphore response of larval anurans to melatonin in their bathing medium). The melatonin content of samples collected between 11 p.m. and 7 a.m. was, in each case, several times higher than that of samples collected between 7 a.m. and 3 p.m. or between 3 p.m. and 11 p.m.

Wurtman, R. J., J. Axelrod, and E. W. Chu. "Melatonin, a Pineal Substance: Effect on the Rat Ovary." Science 141 (1963): 277-278.

Zhdanova, I. V., R. J. Wurtman, M. M. Regan, J. A. Taylor, J. P. Shi, and  O. U. Leclair. "Melatonin Treatment for Age-Related Insomnia." J. Clin. Endocrin. Metab. 86, no. 10 (2001): 4727-4730.

PubMed abstract:  Older people typically exhibit poor sleep efficiency and reduced nocturnal plasma melatonin levels. The daytime administration of oral melatonin to younger people, in doses that raise their plasma melatonin levels to the nocturnal range, can accelerate sleep onset. We examined the ability of similar, physiological doses to restore nighttime melatonin levels and sleep efficiency in insomniac subjects over 50 yr old. In a double-blind, placebo-controlled study, subjects who slept normally (n = 15) or exhibited actigraphically confirmed decreases in sleep efficiency (n = 15) received, in randomized order, a placebo and three melatonin doses (0.1, 0.3, and 3.0 mg) orally 30 min before bedtime for a week. Treatments were separated by 1-wk washout periods. Sleep data were obtained by polysomnography on the last three nights of each treatment period. The physiologic melatonin dose (0.3 mg) restored sleep efficiency (P < 0.0001), acting principally in the midthird of the night; it also elevated plasma melatonin levels (P < 0.0008) to normal. The pharmacologic dose (3.0 mg), like the lowest dose (0.1 mg), also improved sleep; however, it induced hypothermia and caused plasma melatonin to remain elevated into the daylight hours. Although control subjects, like insomniacs, had low melatonin levels, their sleep was unaffected by any melatonin dose.

Zhdanova, I. V., et al. "Sleep-Inducing Effects of Low Doses of Melatonin Ingested in the Evening." Clin. Pharmacol. Ther. 57 (1995): 552-558.

PubMed abstract:  We previously observed tht low oral doses of melatonin given at noon increase blood melatonin concentrations to those normally occurring nocturnally and facilitate sleep onset, as assessed using and involuntary muscle relaxation test. In this study we examined the induction of polysomnographically recorded sleep by similar doses given later in the evening, close to the times of endogenous melatonin release and habitual sleep onset. Volunteers received the hormone (oral doses of 0.3 or 1.0 mg) or placebo at 6, 8, or 9 PM. Latencies to sleep onset, to stage 2 sleep, and to rapid eye movement (REM) sleep were measured polysomnographically. Either dose given at any of the three time points decreased sleep onset latency and latency to stage 2 sleep. Melatonin did not suppress REM sleep or delay its onset. Most volunteers could clearly distinguish between the effects of melatonin and those of placebo when the hormone was tested at 6 or 8 PM. Neither melatonin dose induced "hangover" effects, as assessed with mood and performance tests administered on the morning after treatment. These data provide new evidence that nocturnal melatonin secretion may be involved in physiologic sleep onset and that exogenous melatonin may be useful in treating insomnia.

Glutamate and Aspartate

Cooper, Bloom, and Roth. "Amino Acid Transmitters." Chap. 6 in The Biochemical Basis of Neuropharmacology. 7th ed.
New York: Oxford University Press, 1996, 171-193.

Krystal, J. H., et al. "NMDA Agonists and Antagonists as Probes of Glutamatergic Dysfunction and Pharmacotherapies in Neuropsychiatric Disorders." Harvard Rev. Psychiatry 7 (1999): 125-143.

PubMed abstract:  Antagonists of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors and agonists of the glycine-B coagonist site of these receptors have been important tools for characterizing the contributions of NMDA receptor pathophysiology to a large number of neuropsychiatric conditions and for treating these conditions. Among these disorders are Alzheimer's disease, chronic pain syndromes, epilepsy, schizophrenia, Parkinson's disease, Huntington's disease, addiction disorders, major depression, and anxiety disorders. This review will examine pathophysiological and therapeutic hypotheses generated or supported by clinical studies employing NMDA antagonists and glycine-B agonists and partial agonists. It will also consider ethical issues related to human psychopharmacological studies employing glutamatergic probes.

Malenka, R. C., and R.A. Nicoll. "Long-Term Potentiation-A Decade of Progress?" Science 285 (1999): 1870-1874.

PubMed abstract:  Long-term potentiation of synaptic transmission in the hippocampus is the leading experimental model for the synaptic changes that may underlie learning and memory. This review presents a current understanding of the molecular mechanisms of this long-lasting increase in synaptic strength and describes a simple model that unifies much of the data that previously were viewed as contradictory.

Schoepp, D. D., J. A. Monn, G. J.  Marek, G. Aghajanian, and B. Moghaddam. "LY354740: A Systematically Active mGlu2/mGlu3 Receptor Agonist." CNS Drug Reviews 5, no. 1 (1999): 1-12.

Schoepp, D. D. "Novel Functions for Subtypes of Metabotropic Glutamate Receptors." Neurochem. Int. 24, no. 5 (1994): 439-449.

PubMed abstract:  Metabotropic or "G-protein coupled" glutamate receptors (mGluRs) were discovered and established as a new type of excitatory amino acid receptor by their unique coupling mechanism (phosphoinositide hydrolysis) and pharmacological characteristics. Recently, the cloning of mGluRs and the availability of selective pharmacological agents has greatly increased knowledge of these receptors. It is now recognized that mGluRs are a highly heterogenous family of glutamate receptors with novel molecular structure that are linked to multiple second messenger pathways. Members of this family have unique pharmacological properties and function to modulate the presynaptic release of glutamate and the post-synaptic sensitivity of the cell to glutamate excitation. New information on mGluRs is elucidating the functions of mGluR subtypes in normal and pathological aspects of neuronal transmission. Basic knowledge of the role of specific mGluRs in CNS function and pathologies will further expand in the near future. This knowledge is providing the framework for the discovery of novel pharmacological approaches to modulate excitatory amino acid neuronal transmission.

GABA and Glycine

Anagnostaras, S. G., M. G. Craske, and M. S. Fanselow. "Anxiety: At the Intersection of Genes and Experience." Nature Neurosci. 2, no. 9 (1999): 780-782.

PubMed abstract:  Human anxiety disorders arise from a combination of genetic vulnerability and traumatic experience. Mice with a GABAA receptor mutation may provide a model for these disorders.

Betz, H., and C. M. Becker. "The Mammalian Glycine Receptor: Biology and Structure of a Neuronal Chloride Channel." Protein. Neurochem. Int. 13, no. 2 (1988): 137-146.

Cooper, Bloom, and Roth. "Amino Acid Transmitters." Chap. 6 in The Biochemical Basis of Neuropharmacology. 7th ed.
New York: Oxford University Press, 1996, 126-171.

Crestani, F., et al. "Decreased GABA-A Receptor Clustering results in Enhanced Anxiety and a Bias for Threat Cues." Nature Neurosci. 2, no. 9 (1999): 833-839.

PubMed abstract:  Patients with panic disorders show a deficit of GABAA receptors in the hippocampus, parahippocampus and orbitofrontal cortex. Synaptic clustering of GABAA receptors in mice heterozygous for the gamma2 subunit was reduced, mainly in hippocampus and cerebral cortex. The gamma2 +/- mice showed enhanced behavioral inhibition toward natural aversive stimuli and heightened responsiveness in trace fear conditioning and ambiguous cue discrimination learning. Implicit and spatial memory as well as long-term potentiation in hippocampus were unchanged. Thus gamma2 +/- mice represent a model of anxiety characterized by harm avoidance behavior and an explicit memory bias for threat cues, resulting in heightened sensitivity to negative associations. This model implicates GABAA-receptor dysfunction in patients as a causal predisposition to anxiety disorders.

During, M. J., M. K. Ryder, and D. D. Spencer. "Hippocampal GABA transporter function in temporal-lobe epilepsy." Nature 376 (1995): 174-177.

PubMed abstract:  Electrophysiological studies of human temporal-lobe epilepsy suggest that a loss of hippocampal GABA-mediated inhibition may underlie the neuronal hyperexcitability. However, GABA (gamma-aminobutyric acid)-containing cells are preserved and GABA receptors are maintained in the surviving hippocampal neurons. Diminished GABA release may therefore mediate the loss of inhibition. Here we show that, in the human brain, potassium-stimulated release of GABA was increased, and glutamate-induced, calcium-independent release of GABA was markedly decreased, in epileptogenic hippocampi, in contrast with contralateral, non-epileptogenic hippocampi. The glutamate-induced GABA release in vivo was transporter-mediated in rats. Furthermore, in amygdala-kindled rats, a model for human epilepsy, a decrease in glutamate-induced GABA release was associated with a 48% decrease in the number of GABA transporters. These data suggest that temporal-lobe epilepsy is characterized in part by a loss of glutamate-stimulated GABA release that is secondary to a reduction in the number of GABA transporters.

Gale, K., and M. J. Iadarola. "Seizure Protection and Increased Nerve-Terminal GABA: Delayed Effects of GABA Transmission Inhibition." Science 208 (1980): 288-291.

PubMed abstract:  Changes in gamma-aminobutyric acid (GABA) occurring in the presence and in the absence of GABA-containing nerve terminals were estimated in rats in which the dense GABA projection to the substantia nigra was surgically destroyed on one side of the brain. The net increase in GABA of the denervated nigra was compared with that of the intact nigra at various times after a single injection of gama-vinyl-GABA, which irreversibly inhibits GABA transaminase. Total GABA reached a maximum within 12 hours, but the GABA pool associated with nerve terminals did not increase until 36 hours and peaked at 60 hours. The onset and peak of anticonvulsant activity against maximal electroshock seizures directly paralleled the time course for the increase in GABA in nerve terminals, but was not positively correlated with that independent of the terminals. This result supports the concept that elevating GABA in nerve terminals facilitates GABA-mediated synaptic transmission and predicts anticonvulsant activity.

Martin, D. L., and K. Rimvall. "Regulation of GABA Synthesis in the Brain." J. Neurochem. 60, no. 2 (1993): 395-407.

PubMed abstract:  Gamma-Aminobutyric acid (GABA) is synthesized in brain in at least two compartments, commonly called the transmitter and metabolic compartments, and because regulatory processes must serve the physiologic function of each compartment, the regulation of GABA synthesis presents a complex problem. Brain contains at least two molecular forms of glutamate decarboxylase (GAD), the principal synthetic enzyme for GABA. Two forms, termed GAD65 and GAD67, are the products of two genes and differ in sequence, molecular weight, interaction with the cofactor, pyridoxal 5'-phosphate (pyridoxal-P), and level of expression among brain regions. GAD65 appears to be localized in nerve terminals to a greater degree than GAD67, which appears to be more uniformly distributed throughout the cell. The interaction of GAD with pyridoxal-P is a major factor in the short-term regulation of GAD activity. At least 50% of GAD is present in brain as apoenzyme (GAD without bound cofactor; apoGAD), which serves as a reservoir of inactive GAD that can be drawn on when additional GABA synthesis is needed. A substantial majority of apoGAD in brain is accounted for by GAD65, but GAD67 also contributes to the pool of apoGAD. The apparent localization of GAD65 in nerve terminals and the large reserve of apoGAD65 suggest that GAD65 is specialized to respond to short-term changes in demand for transmitter GABA.

Adenosine and Coffee; Histamine and Itch

Braas, K. M., A. C. Newby, V. S. Wilson, and S. H. Snyder. "Adenosine-Containing Neurons in the Brain Localized by Immunocytochemistry." J. Neurosci. 6, no. 7 (1986), 1952-1961.

PubMed abstract:  Specific sensitive rabbit antisera directed against the adenosine derivative laevulinic acid (O2',3'-adenosine acetal), which are capable of detecting as little as 1 pmol of adenosine by radioimmunoassay and which require more than 1000- to 40,000-fold greater concentrations of adenine nucleotides to displace adenosine binding to antisera, have been developed. These antisera were employed to localize adenosine immunoreactivity throughout the rat CNS using the peroxidase-antiperoxidase (PAP) complex and avidin-biotin-peroxidase complex (ABC) immunocytochemical techniques. Intense staining for adenosine immunoreactivity was localized to the cytoplasm of perikarya and fibers in neuronal cell groups of discrete rat brain regions. Areas containing highest levels of immunoreactivity included the pyramidal cells of the hippocampus, the granule cells of the dentate gyrus, subnuclei of the thalamus, amygdala, and hypothalamus, the primary olfactory cortex, and many motor and sensory nuclei of the brain stem and spinal cord. High levels also occurred in certain layers of the cerebral cortex, the caudate-putamen, the septal nuclei, and the Purkinje cell layer of the cerebellum. Varying the extent of tissue hypoxia altered only the levels of endogenous immunoreactive adenosine without changing the pattern of distribution of the immunoreactivity. Staining was abolished by immunoabsorption and by pretreatment of tissue sections with adenosine deaminase. The localization of adenosine to discrete neuronal groups in the brain supports the possibility of a neurotransmitter or neuromodulatory role for adenosine.

Brown, S. J., S. James, M. Reddington, and P. J. Richardson. "Both A1 and A2a Purine Receptors Regulate Striatal Acetylcholine Release." J. Neurochem. 55, no. 1 (1990), 31-38.

PubMed abstract:  The receptors responsible for the adenosine-mediated control of acetylcholine release from immunoaffinity-purified rat striatal cholinergic nerve terminals have been characterized. The relative affinities of three analogues for the inhibitory receptor were (R)-phenylisopropyladenosine greater than cyclohexyladenosine greater than N-ethylcarboxamidoadenosine (NECA), with binding being dependent of the presence of Mg2+ and inhibited by 5'-guanylylimidodiphosphate [Gpp(NH)p] and adenosine receptor antagonists. Adenosine A1 receptor agonists inhibited forskolin-stimulated cholinergic adenylate cyclase activity, with an IC50 of 0.5 nM for (R)-phenylisopropyladenosine and 500 nM for (S)-phenylisopropyladenosine. A1 agonists inhibited acetylcholine release at concentrations approximately 10% of those required to inhibit the cholinergic adenylate cyclase. High concentrations (1 microM) of adenosine A1 agonists were less effective in inhibiting both adenylate cyclase and acetylcholine release, due to the presence of a lower affinity stimulatory A2 receptor. Blockade of the A1 receptor with 8-cyclopentyl-1,3-dipropylxanthine revealed a half-maximal stimulation by NECA of the adenylate cyclase at 10 nM, and of acetylcholine release at approximately 100 nM. NECA-stimulated adenylate cyclase activity copurified with choline acetyltransferase in the preparation of the cholinergic nerve terminals, suggesting that the striatal A2 receptor is localized to cholinergic neurones. The possible role of feedback inhibitory and stimulatory receptors on cholinergic nerve terminals is discussed.

Clarke, B., E. Rowland, P. J. Barnes, J. Till, D. E. Ward, and E. A. Shinebourne. "Rapid and Safe Termination of Supraventricular Tachycardia in Children by Adenosine." The Lancet (1987): 299-301.

Cooper, Bloom, and Roth. "Serotonin and Histamine." Chap. 10 in The Biochemical Basis of Neuropharmacology. 7th ed.
New York: Oxford University Press, 1996, 391-409.

Fredholm, B. B. "Adenosine Receptors in the Central Nervous System." NIPS 10 (1995): 122-128.

Shankley, N. P., G. F. Watt, and J. W. Black. "Definition and Localization of Histamine H2 Receptors." Euro. J. Clin. Investig. 25, no. 1 (1995): 12-18.

Simons, F. E. R., and K. J. Simons. "The Pharmacology and Use of H1-Receptor-Antagonist Drugs." Drug Therapy 330, no. 23 (1994): 1663-1670.

PubMed abstract:  The second-generation H1-antagonist drugs are supplanting their predecessors in the treatment of allergic rhinoconjunctivitis and chronic urticaria. Their use can be justified mainly on the basis of a more favorable risk-benefit ratio, because they are less toxic to the central nervous system. Future research into H1 antagonists should include additional dose-response studies in patients with allergic disorders, especially children and the elderly; objective studies of adverse effects; studies of topical mucosal application of H1 antagonists; and studies of H1-antagonist enantiomers and active metabolites. With the cloning of the gene encoding the H1 receptor and increased understanding of the precise structural requirements for H1-receptor activity, H1 antagonists with an even more favorable therapeutic index may be developed.

Receptors

Anggard, E. "Nitric Oxide: Mediator, Murderer, and Medicine." The Lancet 343 (1994): 1199-1206.

PubMed abstract:  In the past ten years several research fields have converged to show that the tiny molecule nitric oxide (NO), a reactive gas, functions both as a signalling molecule in endothelial and nerve cells and as a killer molecule by activated immune cells--and it can be used as a new medicine by inhalation. This article reviews the biology of this remarkable molecule and discusses the implications for clinical medicine.

Cary, S. P. L., and M. A. Marletta. "The Case of CO Signaling: Why is the Jury Still Out." J. Clin. Investig. 107, no. 9 (2001): 1071-1073.

Cooper, Bloom, and Roth. "Cellular Mechanisms in Learning and Memory." Chap. 12 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 459-479. 

------. "Modulation of Synaptic Transmission." Chap. 5 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 103-125.

------. "Receptors." Chap. 4 in The Biochemical Basis of Neuropharmacology. 7th ed. New York: Oxford University Press, 1996, 82-102.

Fitzpatrick, F. A., and R. Soberman. "Regulated Formation of Eicosanoids." J. Clin. Investig. 107, no. 11 (2001): 1347-1351.

Sudhof, T. C. "The Synaptic Vesicle Cycle Revisited." Neuron 28, no. 2 (2000): 317-320.

Mongada, S., and A. Higgs. "The L-Arginine-Nitric Oxide Pathway." N. Engl. J. Med. 329, no. 27 (1993): 2002-2012.

Categories of Psychiatric Disease

Cattaneo, E., D. Rigamonti, D. Goffredo, C. Zuccato, F. Squitieri, and S. Sipione. "Loss of Normal Huntingtin Function: New Developments in Huntington's Disease Research." Trends Neurosci. 24, no. 3 (2001): 182-188.

PubMed abstract:  Huntington's disease is characterized by a loss of brain striatal neurons that occurs as a consequence of an expansion of a CAG repeat in the huntingtin protein. The resulting extended polyglutamine stretch confers a deleterious gain-of-function to the protein. Analysis of the mutant protein has attracted most of the research activity in the field, however re-examination of earlier data and new results on the beneficial functions of normal huntingtin indicate that loss of the normal protein function might actually equally contribute to the pathology. Thus, complete elucidation of the physiological role(s) of huntingtin and its mode of action are essential and could lead to new therapeutic approaches.

Cowan, W. M., and E. R. Kandel. "Prospects for Neurology and Psychiatry." JAMA 285, no. 5 (2001): 594-600.

PubMed abstract:  Neurological and psychiatric illnesses are among the most common and most serious health problems in developed societies. The most promising advances in neurological and psychiatric diseases will require advances in neuroscience for their elucidation, prevention, and treatment. Technical advances have improved methods for identifying brain regions involved during various types of cognitive activity, for tracing connections between parts of the brain, for visualizing individual neurons in living brain preparations, for recording the activities of neurons, and for studying the activity of single-ion channels and the receptors for various neurotransmitters. The most significant advances in the past 20 years have come from the application to the nervous system of molecular genetics and molecular cell biology. Discovery of the monogenic disorder responsible for Huntington disease and understanding its pathogenesis can serve as a paradigm for unraveling the much more complex, polygenic disorders responsible for such psychiatric diseases as schizophrenia, manic depressive illness, and borderline personality disorder. Thus, a new degree of cooperation between neurology and psychiatry is likely to result, especially for the treatment of patients with illnesses such as autism, mental retardation, cognitive disorders associated with Alzheimer and Parkinson disease that overlap between the 2 disciplines.

Fava M., and K. S. Kendler. "Major Depressive Disorder." Neuron 28, no. 2 (2000): 335-41.

Hyman, S. "Mental Illness: Genetically Complex Disorders of Neural Circuitry and Neural Communication." Neuron 28 (2000): 321-323.

Leckman, J. F., and M. A. Riddle. "Tourette's Syndrome: When Habit-Forming Systems Form Habits of Their Own?" Neuron 28 (2000): 349-354.

Peptide Neurotransmitters

Cooper, Bloom, and Roth. "Neuroactive Peptides." Chap. 11 in The Biochemical Basis of Neuropharmacology. 7th ed.
New York: Oxford University Press, 1996, 410-458.

Hokfelt, T., J. F. Rehfeld, L. Skirboll, B. Ivemark, M. Goldstein, and K. Markey. "Evidence for Coexistence of Dopamine and CCK in Meso-Limbic Neurones." Nature 285 (1980): 476-477.

PubMed abstract:  Vanderhaeghen et al. reported the occurrence of gastrin-like immunoreactivity in the mammalian brain. Subsequent studies have revealed that this immunoreactivity corresponded mainly to the COOH-terminal octapeptide of cholecystokinin (CCK-8), which has a COOH-terminal pentapeptide identical to gastrin. Also, two peptides resembling the NH- and the COOH-terminal tetrapeptide fragments of CCK-8 are present in the central nervous system (CNS). Using COOH-terminal-specific antisera raised to gastrin and/or CCK, the distribution of CCK neurones has been described with immunohistochemical techniques. Although high numbers of cells and nerve terminals are found in cortical areas, the CCK systems are also present in most other parts of the brain and spinal cord. In the CNS, true gastrin molecules, gastrin-17 and gastrin-34 have been located only in the neurohypophysis, hypothalamus and occasionally in the medulla oblongata (unpublished results). We describe here the occurrence of peptides in meso-limbic dopamine neurones in the rat brain. Evidence has also been obtained that mesencephalic dopamine neurones in the human brain contain similar peptides.

Nichols, M. L., et al. "Transmission of Chronic Nociception by Spinal Neurons Expressing the Substance P Receptor." Science 268 (1999): 1558-1561.

PubMed abstract:  Substance P receptor (SPR)-expressing spinal neurons were ablated with the selective cytotoxin substance P-saporin. Loss of these neurons resulted in a reduction of thermal hyperalgesia and mechanical allodynia associated with persistent neuropathic and inflammatory pain states. This loss appeared to be permanent. Responses to mildly painful stimuli and morphine analgesia were unaffected by this treatment. These results identify a target for treating persistent pain and suggest that the small population of SPR-expressing neurons in the dorsal horn of the spinal cord plays a pivotal role in the generation and maintenance of chronic neuropathic and inflammatory pain.