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Volume transmission in the brain—Novel mechanisms for neural transmission
1428
BOOK REVIEWS
breadth of observation, this volume, as the editors note in their preface “. is the first to consider the question of stereotyped behaviour from a broad biological and clinical perspective”. Why has there been such a long wait? The answer is not hard to find once one has read a few chapters of this varied and stimulating book. Stereotypies have remained largely at a descriptive level: there is no agreement as to their aetiology, function, treatment or even definition. What are stereotypies? Most authors agree that they are movements that are repetitive, invariant and purposeless, without an observable goal, and also that thoughts, cognitions and speech can become stereotyped too. The repetitiveness and invariance of stereotypies are fairly obvious elements of a definition: the lack of purpose is also important. Teitelbaum and his colleagues, and Frith and Done, both point to actions which could be classed as stereotyped but clearly do not fall into the same categories as pathological stereotypies. For instance, Frith and Done report cases of stereotyped responding on a rule governed task: once the rule has been worked out normal human subjects respond stereotypically to obtain further reinforcement. Do these stereotypies have the same status as the stereotyped actions shown by amphetamine addicts or amphetamine-treated rats? Frith and Done side-step this by adding further criteria: stereotypies should be compulsive and not under conscious control. This still leaves open the possibility that tics and tremors could be considered stereotypies, a point discussed by Stoessl as well. The resting tremors of a patient with Parkinson’s disease, or the batswing tremor of Wilson’s disease, would not generally be thought of as stereotypies, despite their repetitious, involuntary, invariable and purposeless nature. On the other hand the tics and coprolalia of Tourette’s syndrome might be. Some of these awkward problems of definition are avoided by Philip Teitelbaum’s approach. He regards stereotypies as fragments of actions, disintegrated elements of more complex sequences of behaviour. This notion is in part compatible with that of Trevor Robbins and his colleagues, but leads to interesting differences. The Lyon and Robbins hypothesis-briefly and crudely, that amphetamine in rats produces stereotypies by enhancing the rate of behavioural output, leading to the emission of only those simple actions that can be produced at a high rate-associates stereotypies with overactivity of central dopamine systems. But Teitelbaum and his colleagues show that stereotypical, fragmentary actions are produced also by loss of dopamine. Electrolytic lesions made in the anterolateral hypothalamus of the rat impairs motor skills. Teitelbaum shows that the remaining motor functions in these rats are fragments, stereotypical remnants of more complex sequences of actions. While the neurology of this must be complex-electrolytic lesions made anywhere in the lateral hypothalamus transect a bewildering variety of fibre systems-it nevertheless does highlight the fact that stereotypies as fragmentary actions are not simply the product of overactivity in CNS monoamine systems. Psychologically stereotypies also seem to have a bipolar nature. Amphetamine, the archetypal psychomotor stimulant, increases arousal and produces stereotypies: but the stereotypies shown by caged animals (in zoos or on farms, as well as in laboratories) are thought to be a reaction to under-arousal, to impoverished environments. Environmental enrichment-which increases arousal-invariably eliminates these “cage stereotypies”. But, Hutt and Hutt always argued that the stereotypies shown by autistic children were not the product of hypoarousal but were a response to chronic hyperarousal, the stereotypies functioning to control and reduce this. Oh dear: increases and decreases in dopamine activity, increased and decreased arousal, problems of definition. One begins to understand why the editors “. after some deliberation . . decided not to seek a highly integrated, comprehensive account of all aspects of stereotyped behaviour”. The chapters here discuss psychological, pharmacological, neuological, psychiatric and behavioural issues and quite clearly there is no concensus. Does this matter? The term stereotyped remains a useful shorthand for describing a variety of actions and thoughts, and the chapters here demonstrate the continuing interest in stereotypies. It is a pleasure to read an academic book that does not prosecute some laboured party line, but instead presents complementary and antagonistic ideas, observations and theories. It is a splendid starting point for a novitiate who wishes to begin studying stereotyped behaviour. This book is full of interesting insights, particularly in the chapters dealing with psychiatric issues. Frith and Done report an observation made by John Ferrier in 1795: “When lunatics attempt to write, there is perpetual recurrence of one or two favourite ideas, intermixed with phrases which convey scarcely any meaning either separately, or in connection with the other parts.” Now that’s interesting: can you name any academic to which it might apply? PHILIP WINN
Volume Transmission in the Brain-Novel Mechanisms F. AGNATI. Raven Press, New York, 1991. THIS BOOK presents “Volume Transmission
as a collection
for Neural Transmission.
Edited by KJELL FUXE and LUIGI
of chapters the material discussed at the held in Stockholm late in 1989. It is a broad are arranged in 10 sections and almost all aspects of volume transmission substantial statement as to where research on volume transmission has advanced. series, Adtiances in Neuroscience. If the succeeding volumes are as topical and collection will be invaluable. What is volume transmission? It is known by other names: Niewenhuys in the Brain”
Wenner-Gren symposium on and detailed book: 46 chapters are discussed. It represents a This book is also the first in a thorough as this one then the described
it as “paracrine”
BGOK REVIEWS
1429
Leslie Iversen talked about “chemically addressed” systems in transmission, Herkenham as “parasynaptic”, which information was exclsively coded by the receptor-ligand interactions, and not by anatomical connections. All of these authors were describing the same thing: the release by neurones in the central nervous system of transmitter other than at morphologically specialized synaptic junctions. Volume transmission is analogous to the release of hormones by glands in the body, where the chemical message is secreted into the bloodstream and circulates until it is either destroyed or finds a target receptor. In the CNS, neurotransmitters are released from neurones into the extracellular spaces, in which they can diffuse until an appropriate receptor is found, or they are degraded. The various sections of the book cover different aspects of volume transmission: Fuxe and Agnati concisely review its history while others-Laurent Descarries, Miles Herkenham and Sylvester Vizi, for instance-describe the basic research conducted in their laboratories that has taken volume transmission from a position as an unusual phenomenon to an almost universally accepted principle. The many other excellent chapters deal with such issues as steroid actions on the CNS, the role of glial cells (principally astrocytes) in volume transmission and mechanisms of activation and deactivation in volume transmission systems. The role of volume transmission in normal and pathological conditions, and in transplanted tissue are also discussed. One chapter however has a section all to itself, and deservedly so. Andrez Pellionisz discusses the importance of volume transmission to theoretical models of brain functioning. As he points out “a ‘wireless’ general influence on a whole circuit would effectively destroy the logical structure of any meticulously laid-out network that implements logical algebra, just like a rainstorm would short circuit and thus incapacitate a computer or telephone network”. But, he argues, logical algebraic formulations of brain theory have already been rejected by many, and in fact the presence of volume transmission argues strongly in favour of “massively parallel neural interconnectedness”. Nevertheless, despite the strength of his arguments and his skilful marshalling of data, Pellionisz’s conclusion is rather baleful. He believes that quantification will take a very long time and that in the meanwhile “. volume transmission will probably mean to most workers hardly more than an intriguing exception to the rule of regular wired communication among brain cells” a conclusion that is surely too gloomy. This book is testament to the fact that a great many eminent neuroscientists have accepted the principle of volume transmission and are establishing how it affects their specialist fields, fields that are themselves very varied: hypothalamic function, neural regeneration, cortical mechanisms, neurone-glia interactions and others are all represented here. Indeed, there are still other issues not covered here that add even more to the practical impact consideration of volume transmission might have. Salomon Langer some years ago showed that postsynaptic alpha-l and alpha-2 noradrenaline receptors on skeletal muscle received their ligand from different sources. He argued that the former were intrasynaptic receptors, the latter extrasynaptic, and that their natural ligands could come from different sources. Most importantly, he recognised that the presence of reuptake mechanisms at synaptic receptor sites would form an effective barrier between intra- and extrasynaptic receptors and therefore separate different transduction mechanisms for classical synaptic transmission and volume transmission. Evidence has been presented recently that a similar situation may exist in the CNS (CLARKE, A. J. M. et al. Psychopharmacology 103, 366-374, 1991) raising the possibility that different drugs administered for experimental or therapeutic purposes may affect synaptic or volume systems differentially, and that reuptake blockers in particular could encourage cross-talk between volume and synaptic transmission systems, an hypothesis that psychopharmacologists are going to have to wrestle with. Maybe Andrez Pellionisz is right to be pessimistic about the immediate future of volume transmission, but I doubt it. Volume transmission, first ignored, then disputed, now accepted, has arrived and has important practical and theoretical implications. Like it or not, the principles by which neurones communicate cannot be ignored when thinking about general neural theory or about how one might affect normal or abnormal brain function. This volume is an excellent introduction to the history, current status and likely future of volume transmission and will, I suspect, be seen as a seminal edition in years to come. PHILIP WINN
The Right Cerebral Hemisphere 1990.
and Psychiatric
Disorder.
By J. CUTTING. Oxford
Medical
Publication,
Oxford,
JOHN CUTTING has written a provocatively bold book that will endear him more to psychologists and neurologists than to his fellow psychiatrists. The overarching thesis of “The Right Cerebral Hemisphere and Psychiatric Disorder” is Cutting’s conviction that “the only way schizophrenia and other psychiatric disorders may be understood is to regard them as complex neuropsychological problems”. This is by no means an original argument but rarely has it been advocated with such cogent fervour. Cutting’s book, comprising 22 chapters, is arranged in three parts. In the first he gives a comprehensive account of the history of ideas concerning the asymmetric roles of the cerebral hemispheres. Here he traces the nineteenth century influence of Gall, Esquirol, Wigan, Broca, Jackson, Wernicke and Dejerine upon contemporary views concerning the functioning of the cortical hemisphere. His scholarship is less impressive
BOOK REVIEWS
breadth of observation, this volume, as the editors note in their preface “. is the first to consider the question of stereotyped behaviour from a broad biological and clinical perspective”. Why has there been such a long wait? The answer is not hard to find once one has read a few chapters of this varied and stimulating book. Stereotypies have remained largely at a descriptive level: there is no agreement as to their aetiology, function, treatment or even definition. What are stereotypies? Most authors agree that they are movements that are repetitive, invariant and purposeless, without an observable goal, and also that thoughts, cognitions and speech can become stereotyped too. The repetitiveness and invariance of stereotypies are fairly obvious elements of a definition: the lack of purpose is also important. Teitelbaum and his colleagues, and Frith and Done, both point to actions which could be classed as stereotyped but clearly do not fall into the same categories as pathological stereotypies. For instance, Frith and Done report cases of stereotyped responding on a rule governed task: once the rule has been worked out normal human subjects respond stereotypically to obtain further reinforcement. Do these stereotypies have the same status as the stereotyped actions shown by amphetamine addicts or amphetamine-treated rats? Frith and Done side-step this by adding further criteria: stereotypies should be compulsive and not under conscious control. This still leaves open the possibility that tics and tremors could be considered stereotypies, a point discussed by Stoessl as well. The resting tremors of a patient with Parkinson’s disease, or the batswing tremor of Wilson’s disease, would not generally be thought of as stereotypies, despite their repetitious, involuntary, invariable and purposeless nature. On the other hand the tics and coprolalia of Tourette’s syndrome might be. Some of these awkward problems of definition are avoided by Philip Teitelbaum’s approach. He regards stereotypies as fragments of actions, disintegrated elements of more complex sequences of behaviour. This notion is in part compatible with that of Trevor Robbins and his colleagues, but leads to interesting differences. The Lyon and Robbins hypothesis-briefly and crudely, that amphetamine in rats produces stereotypies by enhancing the rate of behavioural output, leading to the emission of only those simple actions that can be produced at a high rate-associates stereotypies with overactivity of central dopamine systems. But Teitelbaum and his colleagues show that stereotypical, fragmentary actions are produced also by loss of dopamine. Electrolytic lesions made in the anterolateral hypothalamus of the rat impairs motor skills. Teitelbaum shows that the remaining motor functions in these rats are fragments, stereotypical remnants of more complex sequences of actions. While the neurology of this must be complex-electrolytic lesions made anywhere in the lateral hypothalamus transect a bewildering variety of fibre systems-it nevertheless does highlight the fact that stereotypies as fragmentary actions are not simply the product of overactivity in CNS monoamine systems. Psychologically stereotypies also seem to have a bipolar nature. Amphetamine, the archetypal psychomotor stimulant, increases arousal and produces stereotypies: but the stereotypies shown by caged animals (in zoos or on farms, as well as in laboratories) are thought to be a reaction to under-arousal, to impoverished environments. Environmental enrichment-which increases arousal-invariably eliminates these “cage stereotypies”. But, Hutt and Hutt always argued that the stereotypies shown by autistic children were not the product of hypoarousal but were a response to chronic hyperarousal, the stereotypies functioning to control and reduce this. Oh dear: increases and decreases in dopamine activity, increased and decreased arousal, problems of definition. One begins to understand why the editors “. after some deliberation . . decided not to seek a highly integrated, comprehensive account of all aspects of stereotyped behaviour”. The chapters here discuss psychological, pharmacological, neuological, psychiatric and behavioural issues and quite clearly there is no concensus. Does this matter? The term stereotyped remains a useful shorthand for describing a variety of actions and thoughts, and the chapters here demonstrate the continuing interest in stereotypies. It is a pleasure to read an academic book that does not prosecute some laboured party line, but instead presents complementary and antagonistic ideas, observations and theories. It is a splendid starting point for a novitiate who wishes to begin studying stereotyped behaviour. This book is full of interesting insights, particularly in the chapters dealing with psychiatric issues. Frith and Done report an observation made by John Ferrier in 1795: “When lunatics attempt to write, there is perpetual recurrence of one or two favourite ideas, intermixed with phrases which convey scarcely any meaning either separately, or in connection with the other parts.” Now that’s interesting: can you name any academic to which it might apply? PHILIP WINN
Volume Transmission in the Brain-Novel Mechanisms F. AGNATI. Raven Press, New York, 1991. THIS BOOK presents “Volume Transmission
as a collection
for Neural Transmission.
Edited by KJELL FUXE and LUIGI
of chapters the material discussed at the held in Stockholm late in 1989. It is a broad are arranged in 10 sections and almost all aspects of volume transmission substantial statement as to where research on volume transmission has advanced. series, Adtiances in Neuroscience. If the succeeding volumes are as topical and collection will be invaluable. What is volume transmission? It is known by other names: Niewenhuys in the Brain”
Wenner-Gren symposium on and detailed book: 46 chapters are discussed. It represents a This book is also the first in a thorough as this one then the described
it as “paracrine”
BGOK REVIEWS
1429
Leslie Iversen talked about “chemically addressed” systems in transmission, Herkenham as “parasynaptic”, which information was exclsively coded by the receptor-ligand interactions, and not by anatomical connections. All of these authors were describing the same thing: the release by neurones in the central nervous system of transmitter other than at morphologically specialized synaptic junctions. Volume transmission is analogous to the release of hormones by glands in the body, where the chemical message is secreted into the bloodstream and circulates until it is either destroyed or finds a target receptor. In the CNS, neurotransmitters are released from neurones into the extracellular spaces, in which they can diffuse until an appropriate receptor is found, or they are degraded. The various sections of the book cover different aspects of volume transmission: Fuxe and Agnati concisely review its history while others-Laurent Descarries, Miles Herkenham and Sylvester Vizi, for instance-describe the basic research conducted in their laboratories that has taken volume transmission from a position as an unusual phenomenon to an almost universally accepted principle. The many other excellent chapters deal with such issues as steroid actions on the CNS, the role of glial cells (principally astrocytes) in volume transmission and mechanisms of activation and deactivation in volume transmission systems. The role of volume transmission in normal and pathological conditions, and in transplanted tissue are also discussed. One chapter however has a section all to itself, and deservedly so. Andrez Pellionisz discusses the importance of volume transmission to theoretical models of brain functioning. As he points out “a ‘wireless’ general influence on a whole circuit would effectively destroy the logical structure of any meticulously laid-out network that implements logical algebra, just like a rainstorm would short circuit and thus incapacitate a computer or telephone network”. But, he argues, logical algebraic formulations of brain theory have already been rejected by many, and in fact the presence of volume transmission argues strongly in favour of “massively parallel neural interconnectedness”. Nevertheless, despite the strength of his arguments and his skilful marshalling of data, Pellionisz’s conclusion is rather baleful. He believes that quantification will take a very long time and that in the meanwhile “. volume transmission will probably mean to most workers hardly more than an intriguing exception to the rule of regular wired communication among brain cells” a conclusion that is surely too gloomy. This book is testament to the fact that a great many eminent neuroscientists have accepted the principle of volume transmission and are establishing how it affects their specialist fields, fields that are themselves very varied: hypothalamic function, neural regeneration, cortical mechanisms, neurone-glia interactions and others are all represented here. Indeed, there are still other issues not covered here that add even more to the practical impact consideration of volume transmission might have. Salomon Langer some years ago showed that postsynaptic alpha-l and alpha-2 noradrenaline receptors on skeletal muscle received their ligand from different sources. He argued that the former were intrasynaptic receptors, the latter extrasynaptic, and that their natural ligands could come from different sources. Most importantly, he recognised that the presence of reuptake mechanisms at synaptic receptor sites would form an effective barrier between intra- and extrasynaptic receptors and therefore separate different transduction mechanisms for classical synaptic transmission and volume transmission. Evidence has been presented recently that a similar situation may exist in the CNS (CLARKE, A. J. M. et al. Psychopharmacology 103, 366-374, 1991) raising the possibility that different drugs administered for experimental or therapeutic purposes may affect synaptic or volume systems differentially, and that reuptake blockers in particular could encourage cross-talk between volume and synaptic transmission systems, an hypothesis that psychopharmacologists are going to have to wrestle with. Maybe Andrez Pellionisz is right to be pessimistic about the immediate future of volume transmission, but I doubt it. Volume transmission, first ignored, then disputed, now accepted, has arrived and has important practical and theoretical implications. Like it or not, the principles by which neurones communicate cannot be ignored when thinking about general neural theory or about how one might affect normal or abnormal brain function. This volume is an excellent introduction to the history, current status and likely future of volume transmission and will, I suspect, be seen as a seminal edition in years to come. PHILIP WINN
The Right Cerebral Hemisphere 1990.
and Psychiatric
Disorder.
By J. CUTTING. Oxford
Medical
Publication,
Oxford,
JOHN CUTTING has written a provocatively bold book that will endear him more to psychologists and neurologists than to his fellow psychiatrists. The overarching thesis of “The Right Cerebral Hemisphere and Psychiatric Disorder” is Cutting’s conviction that “the only way schizophrenia and other psychiatric disorders may be understood is to regard them as complex neuropsychological problems”. This is by no means an original argument but rarely has it been advocated with such cogent fervour. Cutting’s book, comprising 22 chapters, is arranged in three parts. In the first he gives a comprehensive account of the history of ideas concerning the asymmetric roles of the cerebral hemispheres. Here he traces the nineteenth century influence of Gall, Esquirol, Wigan, Broca, Jackson, Wernicke and Dejerine upon contemporary views concerning the functioning of the cortical hemisphere. His scholarship is less impressive