- Email: [email protected]
Drugs Acting on 5-Hydroxytryptamine Receptors
717
buspirone3 that act as agonists on the 5-HT lA receptor have already found a place in the treatment of anxiety.4 Other similarly acting drugs are now being evaluated clinically in the treatment of depression, and the selective 5-HT2 receptor antagonist, ritanserinis being studied in anxiety disorders. However, most research has lately been directed towards drugs that 4
either mimic the action of 5-HT on a "5-HTi-like" receptor subtype or block its action on the 5-HT3 receptor. The link between 5-HT and migraine came from several observations-platelet 5-HT falls rapidly at the onset of an attack; headaches are triggered in migraineurs by 5-HT releasing agents; intravenous 5-HT aborts a migraine headache;6 and agents that ameliorate migraine (eg, ergotamine, methysergide, pizotifen) interact with 5-HT receptors.7,8 However, some of the unwanted side-effects, particularly of the ergot derivatives, may be linked to actions on other
receptors.
Drugs Acting on 5-Hydroxytryptamine Receptors discovered a little over 40 years and colleagues1 and was so called ago by Rapport in serum and its ability to of its location because increase tone in blood vessels; it is also known as 5-hydroxytryptamine (5-HT). Today this substance continues to be the focus of much research, the fruits of which are leading to new therapeutic approaches for disorders as diverse as emesis, migraine, and anxiety. Such investigations may also lead to treatments for depression, schizophrenia, drug abuse states, and memory impairment. Although the extent of these potential clinical applications may initially appear surprising, the breadth of 5-HT’s role in medicine has been suspected for many years. 5-HT has long been known to influence the cardiovascular, gastrointestinal, and central nervous systems, and in many tissues it has opposing effects. Like all neurotransmitters, 5-HT elicits cellular responses by acting on discrete receptors. To explain the many diverse and opposing actions, the existence of receptor subtypes for 5-HT had been proposed. Only lately, however, have selective agonists and antagonists for the receptor subtypes been produced; the result of these endeavours has been an explosion of research barely anticipated 5 years ago. There is now strong evidence that 5-HT receptors can be divided into three types—5-HT, 5-HT2, and 5-HT3-with further subdivisions of the 5-HT type, and possibly of the other types as well.Drugs such as SEROTONIN
was
1
Rapport MM, Green AA, Page IH. Serum vasoconstrictor (serotonin): IV. Isolation and characterisation. J Biol Chem 1948; 176: 1243-51. 2.Bradley PB, Engel G, Feniuk W, et al. Proposals for the classification and nomenclature of functional for receptors 5-hydroxytryptamine.
Neuropharmacology 1986; 25: 563-76.
The factors that initiate migraine attacks vary, but involvement of the craniovasculature in the disease has long been suspected.9 Heyckl° suggested that the normal circulation to the head via the carotid arteries passes through a capillary bed that can be bypassed by the opening of arteriovenous anastomoses (shunts). According to this theory the pain of migraine occurs when the shunt vessels open, leading to ischaemia and excessive distension of the arterioles supplying the shunts. These observations lately prompted Humphrey and colleagues at Glaxo to propose the existence of a specific 5-HT receptor subtype in the affected cranial blood vessels, and so they focused their attention on identifying the subtype concerned. It now seems that a specific 5-HT1-like receptor occurs predominantly in certain cranial blood vessels supplied by the carotid arteries. Stimulation of these receptors causes constriction of the arteriovenous shunt vessels to redirect the blood flow to the capillary bedY 5-HT itself and ergotamine appear to relieve migraine by such actions, but they also have generalised vasoconstrictor effects throughout the body, which are a recognised hazard for ergotamine. By contrast, the vasoconstrictor actions of sumatriptan, a drug developed to be highly selective for the 5-HTl-like 3. Hamon M,
Cossery J-M, Spaminato U, Gozlan
H. Are there selective
ligands for
5-HT1A and 5-HT1B receptor binding sites in brain? Trends in Pharmacol Sci 1986; 7: 336-38. 4.
Taylor DP. Buspirone, a new approach to the treatment of anxiety. FASEB J 1988; 2:
2445-52. 5. Awouters F,
Niemegeers CJE, Megens AAHP, Meert TF, Janssen PAJ. Pharmacological profile of ritanserin: a very specific S2-antagonist. Drug Dev Res
1988; 15: 61-73. JW, Lambert GA, Goudsky PJ, Zagami AS. 5-hydroxytryptamine and its putative aetiological involvement in migraine. Cephalagia 1989; 9 (suppl Q): 7-13. 7. Lance JW. Fifty years of migraine research. Aust NZ J Med 1988; 18: 1-7. 8. Muller-Schweinitzer E, Weidmann H. Ergot alkaloids and related compounds. In: Berde B, Schild HO, eds. New York: Springer-Verlag, 1978: 233-319 9 Tunis MM, Wolff HG. Studies on headache: long-term observations of the reactivity of the cranial arteries in subjects with vascular headache of the migraine type. Arch Neurol Neurosurg Psychiatry 1953; 70: 551-57. 10. Heyck H. Pathogenesis of migraine. Res Clin Stud Headache 1969; 2: 1-28. 11. Saxena PR. The arteriovenous anastomoses and veins in migraine research. In: Blau, JN, ed. Migraine—therapeutic, conceptual and research aspects. Amsterdam, Elsevier, 1987: 581-96. 6. Lance
718
receptor type, are specific for carotid shunt vessels and have no significant effects on blood flow to the peripheral circulation.12,13 Precise pharmacological characterisation of the 5-HT1-like receptor mediating these effects is underway. Meanwhile, results of clinical trials are very encouraging,14,15 and clinical evaluation of the mechanism of action of sumatriptan in migraine may lead to a better understanding of the disease. A 5-HT receptor mediating excitation of neuronal tissue in the gastrointestinal system was first characterised by Gaddum and Picarelli in 1957 ;16 inhibition of the response by morphine led to its designation as an "M" receptor, although it is now known that morphine has no direct action on this receptor. Interest in the receptor was revived in 1979 by Fozard, 17 and research teams at Merrel Dow, Sandoz, and Glaxo subsequently detected novel agonist and antagonist drugs with high selectivity and specificity of action. 18-20 The M receptor has now been redesignated the 5-HT 3 receptor. Compounds acting on this receptor were detected without knowledge as to the functional role of 5-HT3 receptors, although early hypotheses were directed towards the treatment of migraine 21 Tyers et al at Glaxo reasoned that if the receptors were present on peripheral nerves they should also be present and have a functional role in the brain. Joint studies undertaken with Costall and colleagues at the University of Bradford22-24 established that 5-HT3 receptors are present in the brain in limbic and cortical areas known to be involved in controlling mood, emotion, reward, and memory. The location of these receptors complements earlier behavioural findings in animals which showed that 5-HT3 receptor antagonists reduce the increased psychomotor drive associated with a mesolimbic dopamine excess; this effect is consistent with the requirements of an Humphrey PPA, Perrin MJ, Feniuk W, Oxford AW. The pharmacology of the novel 5-HT1-like receptor agonist GR 43175. Cephalalgia 1989; 9: 23-33. 13. Feniuk W, Humphrey PPA, Perrin MJ. GR43175 does not share the complex pharmacology of the ergots. Cephalalgia 1989; 9: 35-39. 14. Doenicke A, Brand J, Perrin VL. Possible benefit of GR43175, a novel 5-HT,-like receptor agonist, for the acute treatment of migraine. Lancet 1988; i: 1309-11. 15. Perrin VL, Farkkilla M, Goasguen J, Doenicke A, Brand J, Ifelt-Hansen P. Overview 12.
of initial clinical studies with intravenous and oral GR43175 in acute migraine. Cephalagia 1989; 9 (suppl): 63-72. 16. Gaddum JH, Picarelli ZP. Two kinds of tryptamine receptor. Br J Pharmacol 1957; 12: 323-28. 17. Fozard JR, Mobarok Ali ATM, Newgrosh G. Blockade of serotonin receptors on autonomic neurons by (-)cocaine and some related compounds. Eur J Pharmacol 1979; 59: 195-210. 18. Fozard JR. A potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 1984; 326: 36-44. 19. Richardson BP, Engel G, Donatsch P, Stadler PA. Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 1985; 316: 126-31. 20. Butler A, Hill JM, Ireland SJ, Jordan CC, Tyers MB. Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors Br J Pharmacol 1988; 94: 397-412. 21. Fozard JR. The development and early clinical evaluation of selective 5-HT3 receptor antagonists. In: Fozard JR, ed. The penpheral actions of 5-hydroxytryptamine. Oxford: Oxford University Press, 1989: 354-76. 22. Kilpatrick GJ, Jones BJ, Tyers MB Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature 1987; 33: 746-48. 23. Barnes NM, Costall B, Ironside JW, Naylor RJ. Identification of 5-HT3 recognition sites in human brain using 3H zacopride. J Pharm Pharmacol 1988; 40: 668. 24. Barnes NM, Costall B, Naylor RJ. 3H zacopride identifies 5-HT3 binding sites in rat etorhinal cortex. Br J Pharmacol 1988; 94: 391P
antipsychotic agent. 25 Such antagonists improve impaired cognitive performance26 and "disinhibit" the suppressed behaviour displayed by animals placed in a novel and hostile environment.27 An important feature of the action of the 5-HT3receptor antagonists is that they do not influence normal behaviour, and have no apparent side-effects either during treatment or after cessation of long-term treatment. The early behavioural studies were carried out with the highly selective 5-HT33 receptor antagonist ondansetron, which is now being investigated in patients with schizophrenia or anxiety disorders. In addition, animal work indicates an action of 5-HT33 receptor antagonists on the reward system of the brain28,29 that may be useful in treating dependency, including withdrawal from benzodiazepines such as diazepam. More recently, cholinergic function in the limbic-cortical circuitry has been shown to be enhanced by 5-HT3receptor antagonists;this action may explain why these compounds improve cognitive performance in animals and may have implications for the treatment of age-associated memory impairments, possibly even those associated with early Alzheimer’s disease. The antiemetic effects of 5-HT3 receptor antagonists have also been studied, with the focus on emesis induced by cancer chemotherapy and radiotherapy. Anti-emetic activity has generally been associated with dopamine antagonist drugs such as metoclopramide, but several research groups showed independently in animals that selective 5-HT3 receptor antagonists can prevent cisplatin-induced emesis.31,32 These findings held out the possibility of new therapies lacking the dopamine blocking action of metoclopramide and hence the extrapyramidal sideeffects. Clinical trials have now established the effectiveness of 5-HT3 receptor antagonists such as ICS 205-930, ondansetron, and granisetron in the of emesis associated with cancer treatment chemotherapy33-35 and radiotherapy. 36 Such activity is Domeney AM, Naylor RJ, Tyers MB. Effects of the 5-HT3 receptor antagonist GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br J Pharmacol 1987; 92: 881-94. 26. Barnes JM, Costall B, Kelly ME, Naylor RJ, Onaivi ES, Tomkins DM, Tyers MB. GR38032F improves performance m a mouse habituation task, and inhibits cholinergic-linked deficits. Br J Pharmacol (in press). 27. Jones BJ, Costall B, Domeney AM, et al. The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist. Br J Pharmacol 1988; 93: 985-93. 28. Hagan RM, Butler A, Hill JM, Jordan CC, Ireland SJ, Tyers MB. Effect of the 5-HT3 receptor antagonist, GR38032F, on responses to injection of a neurokinin agonist into the ventral tegmental area of the rat brain. Eur J Pharmacol 1987; 138: 303-05. 29. Carboni E, Acquas E, Leone P, Perezzani L, Di Chiara G. 5-HT3 receptor antagonists block morphine- and nicotine-induced place-preference conditioning. Eur J Pharmacol 1988; 151: 159-60. 30. Barnes JM, Bames NM, Costall B, Naylor RJ, Tyers MB. 5-HT3 receptors mediate inhibition of acetylochine release in cortical tissue. Nature 1989; 338: 762-63. 31. Miner WD, Sanger GJ. Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism Br Pharmacol J 1986; 88: 497-99. 32. Stables R, Andrews PLR, Bailey HE, et al. Antiemetic properties of the 5-HT3 receptor antagonist, GR38032F. Cancer Treat Rev 1987; 14: 333-36. 33. Leibundgut U, Lancranjan I. First results with ICS 205-930 (5-HT3 receptor antagonist) in prevention of chemotherapy-induced emesis. Lancet 1987; i; 1198 34. Cunningham D, Hawthorn J, Pople A, et al. Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5-HT3 receptor antagonist Lancet 1987; 25. Costall B,
i: 1461-63 35. Carmichael J, Cantwell BMJ, Edwards CM, et al. A pharmacokinetic study of granisetron (BRL43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response. Cancer Chemother Pharmacol 1989; 24: 45-49.
719
consistent with the finding that 5-HT3 receptors are present in high densities on afferent vagus nerves, and in the
postrema and dorsal vagal complex of animals37-areas that are important in the emetic area
reflex.
Pharmacological advances arising from the use of compounds with highly selective actions on 5-HT receptor subtypes show the clear potential for therapeutic benefit. Moreover, such compounds provide tools with which scientists can better understand the role of 5-HT in disease. This area of research will speed along in the next few years, and is undoubtedly worth watching.
Dyslexia SOME children unexpectedly encounter difficulties in learning to read, although most sail through the process of acquiring the complex set of rules and exceptions with apparently little effort-that much has been known since formal reading instruction became widely available at the end of the last century. Research into dyslexia between then and now has largely concentrated on two issues: who may be
appropriately labelled a dyslexic, and what causes the condition? Important new developments on both fronts have been greeted by psychological and educational
communities with uncharacteristic unanimity. It has always been difficult to classify children with reading problems as dyslexic. To give an extreme example, it is clearly inappropriate to use this term in children who are severely subnormal because their reading disability is neither selective nor unexpected and most likely reflects global intellectual limitations. Driven by considerations such as these, typical solutions have been to apply the dyslexia label only to those children of normal intelligence who have a reading impairment, and to define such children as those whose reading skills are in the bottom 5-10 % for their age. Brain and Reading, the proceedings of the Seventh International Rodin Remediation Conference held in Stockholm last year, marks the new degree of agreement between scientists concerned with identifying the basis of dyslexia by providing an up-to-date commentary on the latest developments in dyslexia research. The overall conclusion that emerges from the many approaches to research described by the contributors is that the definition of dyslexia as a rarefied impairment of reading is inappropriate. Dyslexic children are impaired in many language skills, to varying extents. They are 36.Priestman TJ, Priestman SG. Studies with ondansetron in the management of radiation-induced emesis. EurJCancer(m press). 37.Kilpatrick GJ, Jones BJ, Tyers MB.binding of the 5-HT3 ligand, [3H]GR65630, to rat area postrema, vagus nerve and the brains of several species. Eur JPharmacol 1989; 159: 157-64. 1.von Euler C, Lundberg I, Lennerstrand G, eds.Brain and reading. Southampton: MacMillan, 1989.
have been late in starting to talk, to show subtle deficits in spoken as well as written language, and to have limited immediate memory for verbal material. So, for most children classed as dyslexic, the reading disorder appears to be the most severe manifestation of a generalised language impairment. What is the nature of the language deficit underlying dyslexia? The dominant view among the psychological community is that the central deficit resides at some point in the processes of representing speech sounds, and in maintaining and manipulating these phonological representations in memory. Poor readers have trouble in making explicit judgments about the sound structure of spoken words. Dyslexic children typically have difficulty in identifying the number of sounds in the spoken word "cat", or in synthesising the sounds "duh", "oh", and "guh" into a single recognisable word. The view of leading speech theorists A. and I. Liberman2 is that this deficit in what is termed "phonological awareness" reflects difficulties in making explicit the highly automatic and specialised processes involved in speech perception and speech production. They argue that learning to read similarly involves the conscious decomposition of complex sounds into single sounds that can then be matched to letters, and that problems in this classification of sound segments will lead to failure in learning to read phonically. Powerful support for this view is provided by the range of training studies in phonological awareness that show reliable benefits in reading achievement. Dyslexic children also have short-term memory impairments. Poor readers, compared with children of ordinary skills, have difficulty even with the simple task of repeating back an unfamiliar spoken item. Gathercole and Baddeley3 have shown that such repetition deficits also characterise children with more general language disorders, suggesting that reading and language impairments have a common aetiology. The difficulty in retaining novel speech sounds may impair the learning of letter-sound correspondence rules in the early stages of reading, and may also explain why both poor readers and language disordered children tend to be slower in learning new words than do children with normal reading and
likely
to
language development. Further evidence for a deficit in language analytical dyslexic children is provided by Olson and colleagues in Colorado.4 These workers studied the genetic contributions of different cognitive skills involved in reading, by obtaining behavioural measurements from dyslexic children who had either
skills in
2. Liberman IY. Phonology and beginning reading revisited. In. von Euler C, Lundberg I, Lennerstrand G, eds. Brain and reading. Southampton: MacMillan, 1989: 207-20. 3. Gathercole SE, Baddeley AD. The role of phonological memory in normal and disordered language development. In: von Euler C, Lundberg I, Lennerstrand G, eds. Brain and reading. Southampton: MacMillan, 1989: 245-55. 4. Olson R, Wise B, Conners F, Rack J. Deficits in disabled readers’ phonological and orthographic coding: etiology and remediation. In: von Euler C, Lundberg I, Lennerstrand G, eds. Brain and reading. Southampton: MacMillan, 1989: 233-42.
buspirone3 that act as agonists on the 5-HT lA receptor have already found a place in the treatment of anxiety.4 Other similarly acting drugs are now being evaluated clinically in the treatment of depression, and the selective 5-HT2 receptor antagonist, ritanserinis being studied in anxiety disorders. However, most research has lately been directed towards drugs that 4
either mimic the action of 5-HT on a "5-HTi-like" receptor subtype or block its action on the 5-HT3 receptor. The link between 5-HT and migraine came from several observations-platelet 5-HT falls rapidly at the onset of an attack; headaches are triggered in migraineurs by 5-HT releasing agents; intravenous 5-HT aborts a migraine headache;6 and agents that ameliorate migraine (eg, ergotamine, methysergide, pizotifen) interact with 5-HT receptors.7,8 However, some of the unwanted side-effects, particularly of the ergot derivatives, may be linked to actions on other
receptors.
Drugs Acting on 5-Hydroxytryptamine Receptors discovered a little over 40 years and colleagues1 and was so called ago by Rapport in serum and its ability to of its location because increase tone in blood vessels; it is also known as 5-hydroxytryptamine (5-HT). Today this substance continues to be the focus of much research, the fruits of which are leading to new therapeutic approaches for disorders as diverse as emesis, migraine, and anxiety. Such investigations may also lead to treatments for depression, schizophrenia, drug abuse states, and memory impairment. Although the extent of these potential clinical applications may initially appear surprising, the breadth of 5-HT’s role in medicine has been suspected for many years. 5-HT has long been known to influence the cardiovascular, gastrointestinal, and central nervous systems, and in many tissues it has opposing effects. Like all neurotransmitters, 5-HT elicits cellular responses by acting on discrete receptors. To explain the many diverse and opposing actions, the existence of receptor subtypes for 5-HT had been proposed. Only lately, however, have selective agonists and antagonists for the receptor subtypes been produced; the result of these endeavours has been an explosion of research barely anticipated 5 years ago. There is now strong evidence that 5-HT receptors can be divided into three types—5-HT, 5-HT2, and 5-HT3-with further subdivisions of the 5-HT type, and possibly of the other types as well.Drugs such as SEROTONIN
was
1
Rapport MM, Green AA, Page IH. Serum vasoconstrictor (serotonin): IV. Isolation and characterisation. J Biol Chem 1948; 176: 1243-51. 2.Bradley PB, Engel G, Feniuk W, et al. Proposals for the classification and nomenclature of functional for receptors 5-hydroxytryptamine.
Neuropharmacology 1986; 25: 563-76.
The factors that initiate migraine attacks vary, but involvement of the craniovasculature in the disease has long been suspected.9 Heyckl° suggested that the normal circulation to the head via the carotid arteries passes through a capillary bed that can be bypassed by the opening of arteriovenous anastomoses (shunts). According to this theory the pain of migraine occurs when the shunt vessels open, leading to ischaemia and excessive distension of the arterioles supplying the shunts. These observations lately prompted Humphrey and colleagues at Glaxo to propose the existence of a specific 5-HT receptor subtype in the affected cranial blood vessels, and so they focused their attention on identifying the subtype concerned. It now seems that a specific 5-HT1-like receptor occurs predominantly in certain cranial blood vessels supplied by the carotid arteries. Stimulation of these receptors causes constriction of the arteriovenous shunt vessels to redirect the blood flow to the capillary bedY 5-HT itself and ergotamine appear to relieve migraine by such actions, but they also have generalised vasoconstrictor effects throughout the body, which are a recognised hazard for ergotamine. By contrast, the vasoconstrictor actions of sumatriptan, a drug developed to be highly selective for the 5-HTl-like 3. Hamon M,
Cossery J-M, Spaminato U, Gozlan
H. Are there selective
ligands for
5-HT1A and 5-HT1B receptor binding sites in brain? Trends in Pharmacol Sci 1986; 7: 336-38. 4.
Taylor DP. Buspirone, a new approach to the treatment of anxiety. FASEB J 1988; 2:
2445-52. 5. Awouters F,
Niemegeers CJE, Megens AAHP, Meert TF, Janssen PAJ. Pharmacological profile of ritanserin: a very specific S2-antagonist. Drug Dev Res
1988; 15: 61-73. JW, Lambert GA, Goudsky PJ, Zagami AS. 5-hydroxytryptamine and its putative aetiological involvement in migraine. Cephalagia 1989; 9 (suppl Q): 7-13. 7. Lance JW. Fifty years of migraine research. Aust NZ J Med 1988; 18: 1-7. 8. Muller-Schweinitzer E, Weidmann H. Ergot alkaloids and related compounds. In: Berde B, Schild HO, eds. New York: Springer-Verlag, 1978: 233-319 9 Tunis MM, Wolff HG. Studies on headache: long-term observations of the reactivity of the cranial arteries in subjects with vascular headache of the migraine type. Arch Neurol Neurosurg Psychiatry 1953; 70: 551-57. 10. Heyck H. Pathogenesis of migraine. Res Clin Stud Headache 1969; 2: 1-28. 11. Saxena PR. The arteriovenous anastomoses and veins in migraine research. In: Blau, JN, ed. Migraine—therapeutic, conceptual and research aspects. Amsterdam, Elsevier, 1987: 581-96. 6. Lance
718
receptor type, are specific for carotid shunt vessels and have no significant effects on blood flow to the peripheral circulation.12,13 Precise pharmacological characterisation of the 5-HT1-like receptor mediating these effects is underway. Meanwhile, results of clinical trials are very encouraging,14,15 and clinical evaluation of the mechanism of action of sumatriptan in migraine may lead to a better understanding of the disease. A 5-HT receptor mediating excitation of neuronal tissue in the gastrointestinal system was first characterised by Gaddum and Picarelli in 1957 ;16 inhibition of the response by morphine led to its designation as an "M" receptor, although it is now known that morphine has no direct action on this receptor. Interest in the receptor was revived in 1979 by Fozard, 17 and research teams at Merrel Dow, Sandoz, and Glaxo subsequently detected novel agonist and antagonist drugs with high selectivity and specificity of action. 18-20 The M receptor has now been redesignated the 5-HT 3 receptor. Compounds acting on this receptor were detected without knowledge as to the functional role of 5-HT3 receptors, although early hypotheses were directed towards the treatment of migraine 21 Tyers et al at Glaxo reasoned that if the receptors were present on peripheral nerves they should also be present and have a functional role in the brain. Joint studies undertaken with Costall and colleagues at the University of Bradford22-24 established that 5-HT3 receptors are present in the brain in limbic and cortical areas known to be involved in controlling mood, emotion, reward, and memory. The location of these receptors complements earlier behavioural findings in animals which showed that 5-HT3 receptor antagonists reduce the increased psychomotor drive associated with a mesolimbic dopamine excess; this effect is consistent with the requirements of an Humphrey PPA, Perrin MJ, Feniuk W, Oxford AW. The pharmacology of the novel 5-HT1-like receptor agonist GR 43175. Cephalalgia 1989; 9: 23-33. 13. Feniuk W, Humphrey PPA, Perrin MJ. GR43175 does not share the complex pharmacology of the ergots. Cephalalgia 1989; 9: 35-39. 14. Doenicke A, Brand J, Perrin VL. Possible benefit of GR43175, a novel 5-HT,-like receptor agonist, for the acute treatment of migraine. Lancet 1988; i: 1309-11. 15. Perrin VL, Farkkilla M, Goasguen J, Doenicke A, Brand J, Ifelt-Hansen P. Overview 12.
of initial clinical studies with intravenous and oral GR43175 in acute migraine. Cephalagia 1989; 9 (suppl): 63-72. 16. Gaddum JH, Picarelli ZP. Two kinds of tryptamine receptor. Br J Pharmacol 1957; 12: 323-28. 17. Fozard JR, Mobarok Ali ATM, Newgrosh G. Blockade of serotonin receptors on autonomic neurons by (-)cocaine and some related compounds. Eur J Pharmacol 1979; 59: 195-210. 18. Fozard JR. A potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 1984; 326: 36-44. 19. Richardson BP, Engel G, Donatsch P, Stadler PA. Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 1985; 316: 126-31. 20. Butler A, Hill JM, Ireland SJ, Jordan CC, Tyers MB. Pharmacological properties of GR38032F, a novel antagonist at 5-HT3 receptors Br J Pharmacol 1988; 94: 397-412. 21. Fozard JR. The development and early clinical evaluation of selective 5-HT3 receptor antagonists. In: Fozard JR, ed. The penpheral actions of 5-hydroxytryptamine. Oxford: Oxford University Press, 1989: 354-76. 22. Kilpatrick GJ, Jones BJ, Tyers MB Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature 1987; 33: 746-48. 23. Barnes NM, Costall B, Ironside JW, Naylor RJ. Identification of 5-HT3 recognition sites in human brain using 3H zacopride. J Pharm Pharmacol 1988; 40: 668. 24. Barnes NM, Costall B, Naylor RJ. 3H zacopride identifies 5-HT3 binding sites in rat etorhinal cortex. Br J Pharmacol 1988; 94: 391P
antipsychotic agent. 25 Such antagonists improve impaired cognitive performance26 and "disinhibit" the suppressed behaviour displayed by animals placed in a novel and hostile environment.27 An important feature of the action of the 5-HT3receptor antagonists is that they do not influence normal behaviour, and have no apparent side-effects either during treatment or after cessation of long-term treatment. The early behavioural studies were carried out with the highly selective 5-HT33 receptor antagonist ondansetron, which is now being investigated in patients with schizophrenia or anxiety disorders. In addition, animal work indicates an action of 5-HT33 receptor antagonists on the reward system of the brain28,29 that may be useful in treating dependency, including withdrawal from benzodiazepines such as diazepam. More recently, cholinergic function in the limbic-cortical circuitry has been shown to be enhanced by 5-HT3receptor antagonists;this action may explain why these compounds improve cognitive performance in animals and may have implications for the treatment of age-associated memory impairments, possibly even those associated with early Alzheimer’s disease. The antiemetic effects of 5-HT3 receptor antagonists have also been studied, with the focus on emesis induced by cancer chemotherapy and radiotherapy. Anti-emetic activity has generally been associated with dopamine antagonist drugs such as metoclopramide, but several research groups showed independently in animals that selective 5-HT3 receptor antagonists can prevent cisplatin-induced emesis.31,32 These findings held out the possibility of new therapies lacking the dopamine blocking action of metoclopramide and hence the extrapyramidal sideeffects. Clinical trials have now established the effectiveness of 5-HT3 receptor antagonists such as ICS 205-930, ondansetron, and granisetron in the of emesis associated with cancer treatment chemotherapy33-35 and radiotherapy. 36 Such activity is Domeney AM, Naylor RJ, Tyers MB. Effects of the 5-HT3 receptor antagonist GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br J Pharmacol 1987; 92: 881-94. 26. Barnes JM, Costall B, Kelly ME, Naylor RJ, Onaivi ES, Tomkins DM, Tyers MB. GR38032F improves performance m a mouse habituation task, and inhibits cholinergic-linked deficits. Br J Pharmacol (in press). 27. Jones BJ, Costall B, Domeney AM, et al. The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist. Br J Pharmacol 1988; 93: 985-93. 28. Hagan RM, Butler A, Hill JM, Jordan CC, Ireland SJ, Tyers MB. Effect of the 5-HT3 receptor antagonist, GR38032F, on responses to injection of a neurokinin agonist into the ventral tegmental area of the rat brain. Eur J Pharmacol 1987; 138: 303-05. 29. Carboni E, Acquas E, Leone P, Perezzani L, Di Chiara G. 5-HT3 receptor antagonists block morphine- and nicotine-induced place-preference conditioning. Eur J Pharmacol 1988; 151: 159-60. 30. Barnes JM, Bames NM, Costall B, Naylor RJ, Tyers MB. 5-HT3 receptors mediate inhibition of acetylochine release in cortical tissue. Nature 1989; 338: 762-63. 31. Miner WD, Sanger GJ. Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism Br Pharmacol J 1986; 88: 497-99. 32. Stables R, Andrews PLR, Bailey HE, et al. Antiemetic properties of the 5-HT3 receptor antagonist, GR38032F. Cancer Treat Rev 1987; 14: 333-36. 33. Leibundgut U, Lancranjan I. First results with ICS 205-930 (5-HT3 receptor antagonist) in prevention of chemotherapy-induced emesis. Lancet 1987; i; 1198 34. Cunningham D, Hawthorn J, Pople A, et al. Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5-HT3 receptor antagonist Lancet 1987; 25. Costall B,
i: 1461-63 35. Carmichael J, Cantwell BMJ, Edwards CM, et al. A pharmacokinetic study of granisetron (BRL43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response. Cancer Chemother Pharmacol 1989; 24: 45-49.
719
consistent with the finding that 5-HT3 receptors are present in high densities on afferent vagus nerves, and in the
postrema and dorsal vagal complex of animals37-areas that are important in the emetic area
reflex.
Pharmacological advances arising from the use of compounds with highly selective actions on 5-HT receptor subtypes show the clear potential for therapeutic benefit. Moreover, such compounds provide tools with which scientists can better understand the role of 5-HT in disease. This area of research will speed along in the next few years, and is undoubtedly worth watching.
Dyslexia SOME children unexpectedly encounter difficulties in learning to read, although most sail through the process of acquiring the complex set of rules and exceptions with apparently little effort-that much has been known since formal reading instruction became widely available at the end of the last century. Research into dyslexia between then and now has largely concentrated on two issues: who may be
appropriately labelled a dyslexic, and what causes the condition? Important new developments on both fronts have been greeted by psychological and educational
communities with uncharacteristic unanimity. It has always been difficult to classify children with reading problems as dyslexic. To give an extreme example, it is clearly inappropriate to use this term in children who are severely subnormal because their reading disability is neither selective nor unexpected and most likely reflects global intellectual limitations. Driven by considerations such as these, typical solutions have been to apply the dyslexia label only to those children of normal intelligence who have a reading impairment, and to define such children as those whose reading skills are in the bottom 5-10 % for their age. Brain and Reading, the proceedings of the Seventh International Rodin Remediation Conference held in Stockholm last year, marks the new degree of agreement between scientists concerned with identifying the basis of dyslexia by providing an up-to-date commentary on the latest developments in dyslexia research. The overall conclusion that emerges from the many approaches to research described by the contributors is that the definition of dyslexia as a rarefied impairment of reading is inappropriate. Dyslexic children are impaired in many language skills, to varying extents. They are 36.Priestman TJ, Priestman SG. Studies with ondansetron in the management of radiation-induced emesis. EurJCancer(m press). 37.Kilpatrick GJ, Jones BJ, Tyers MB.binding of the 5-HT3 ligand, [3H]GR65630, to rat area postrema, vagus nerve and the brains of several species. Eur JPharmacol 1989; 159: 157-64. 1.von Euler C, Lundberg I, Lennerstrand G, eds.Brain and reading. Southampton: MacMillan, 1989.
have been late in starting to talk, to show subtle deficits in spoken as well as written language, and to have limited immediate memory for verbal material. So, for most children classed as dyslexic, the reading disorder appears to be the most severe manifestation of a generalised language impairment. What is the nature of the language deficit underlying dyslexia? The dominant view among the psychological community is that the central deficit resides at some point in the processes of representing speech sounds, and in maintaining and manipulating these phonological representations in memory. Poor readers have trouble in making explicit judgments about the sound structure of spoken words. Dyslexic children typically have difficulty in identifying the number of sounds in the spoken word "cat", or in synthesising the sounds "duh", "oh", and "guh" into a single recognisable word. The view of leading speech theorists A. and I. Liberman2 is that this deficit in what is termed "phonological awareness" reflects difficulties in making explicit the highly automatic and specialised processes involved in speech perception and speech production. They argue that learning to read similarly involves the conscious decomposition of complex sounds into single sounds that can then be matched to letters, and that problems in this classification of sound segments will lead to failure in learning to read phonically. Powerful support for this view is provided by the range of training studies in phonological awareness that show reliable benefits in reading achievement. Dyslexic children also have short-term memory impairments. Poor readers, compared with children of ordinary skills, have difficulty even with the simple task of repeating back an unfamiliar spoken item. Gathercole and Baddeley3 have shown that such repetition deficits also characterise children with more general language disorders, suggesting that reading and language impairments have a common aetiology. The difficulty in retaining novel speech sounds may impair the learning of letter-sound correspondence rules in the early stages of reading, and may also explain why both poor readers and language disordered children tend to be slower in learning new words than do children with normal reading and
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to
language development. Further evidence for a deficit in language analytical dyslexic children is provided by Olson and colleagues in Colorado.4 These workers studied the genetic contributions of different cognitive skills involved in reading, by obtaining behavioural measurements from dyslexic children who had either
skills in
2. Liberman IY. Phonology and beginning reading revisited. In. von Euler C, Lundberg I, Lennerstrand G, eds. Brain and reading. Southampton: MacMillan, 1989: 207-20. 3. Gathercole SE, Baddeley AD. The role of phonological memory in normal and disordered language development. In: von Euler C, Lundberg I, Lennerstrand G, eds. Brain and reading. Southampton: MacMillan, 1989: 245-55. 4. Olson R, Wise B, Conners F, Rack J. Deficits in disabled readers’ phonological and orthographic coding: etiology and remediation. In: von Euler C, Lundberg I, Lennerstrand G, eds. Brain and reading. Southampton: MacMillan, 1989: 233-42.