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The demise of old certitudes and the birth of novel opportunities in neuropsychopharmacology
The demise of old certitudes and the birth of novel opportunities in neuropsychopharmacology Editorial overview Joseph T Coyle Current Opinion in Pharmacology 2004, 4:1–3 This overview comes from a themed issue on Neurosciences Edited by Joseph Coyle 1471-4892/$ – see front matter ß 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2003.12.001
Joseph T Coyle Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA e-mail: [email protected]
Joseph T Coyle is the Eben S Draper Professor of Psychiatry and Neuroscience at Harvard Medical School. His research has been directed at the understanding of the neurobiology of severe neuropsychiatric disorders, with a particular interest in the role of glutamatergic neurotransmission in their pathophysiology.
Abbreviations LTP long-term potentiation mGluR metabotropic glutamate receptor NMDA N-methyl-D-aspartate
It has been an honor and pleasure to be invited to organize this issue of Current Opinion in Pharmacology. This responsibility prompted some reflection on how the field has evolved over the 35 years in which I have been involved. When I commenced pharmacological research in 1968, CNS drug discovery was primarily based on serendipity, linked to attempts to tether behavioral effects of drugs to alterations in chemical neurotransmission. Neurons were believed to use only one neurotransmitter, and the mature nervous system was thought to be ‘hard-wired’, with neurogenesis ceasing soon after birth. Psychiatric disorders were thought to be ‘functional’ without any brain pathology, and treatments other than palliative ones for neurodegenerative disorders were viewed with considerable pessimism. Except for rare conditions, genetics was thought to be irrelevant to the etiology of most neuropsychiatric disorders. The serial destruction of these scientific certitudes over the past 35 years has brought the field to a molecular era of neuropsychotropic drug discovery where genetic risk factors are used to identify molecular targets for drug development. Ultimately, as the genetics of neuropsychiatric disorders and pharmacogenetics advance, one can envision a future with highly selective drug treatments tailored to an individual’s particular genetic subtype of disorder and the drug metabolism status. Thus, these reflections have dictated the selection of topics for this issue. I have tried to include, together with the more traditional neuropharmacological issues, research areas that stretch the concept of pharmacology to therapeutic interventions involving genes and even cells. Glutamate is the primary excitatory neurotransmitter in the brain and is utilized by over 40% of synapses. Although, initially, the focus of interest in glutamate was in excitotoxicity, the ubiquitous distribution of glutamatergic neurons in brain implies that glutamatergic dysfunction probably occurs in many CNS disorders. Glutamatergic neurotransmimssion has been implicated in learning and memory through the process of long-term potentiation (LTP). LTP is a use-dependent enhancement of excitatory neurotransmission and typically requires the activation of voltage-dependent N-methyl-Daspartate (NMDA) receptors as a result of robust stimulation of AMPA receptors. Lynch describes a new group of agents that are allosteric positive
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Current Opinion in Pharmacology 2004, 4:1–3
2 Neurosciences
modulators of the AMPA receptor. Known as ampakines, they have been shown to promote LTP, augment expression of hippocampal brain-derived neurotrophic factor and enhance memory in experimental animals and human subjects with a remarkably benign side effect profile. The NMDA receptor has the peculiar feature of requiring simultaneous binding of two ligands. Unless the glycine site on the NMDA receptor (glycine B receptor) is occupied, glutamate cannot open the channel. One of the first identified NMDA receptor antagonists was kynurenic acid, which blocks the glycine B receptor. Kynurenic acid is a metabolite of tryptophan; another metabolite is quinolinic acid, which is an agonist at the glutamate recognition site on the NMDA receptor. Schwarcz reviews how the levels of these two opposing ligands are altered in neuropsychiatric disorders in ways that probably contribute to their pathophysiology. Furthermore, he elucidates how the synthetic enzyme for kynurenic acid can be exploited to generate more potent antagonists for treating conditions involving increased NMDA receptor activity. One of the concerns about developing drugs to manipulate glutamatergic neurotransmission was that a number of targets appeared to be limited (i.e. the NMDA and AMPA receptors). The discovery of the metabotropic glutamate receptors (mGluRs), which modulate glutamatergic neurotransmission, markedly increased the array of therapeutic targets. mGluRs are class III G-proteincoupled receptors, and are unique among this family for their large extracellular domain containing the glutamate binding site. Marek focuses on mGluR2/3, which is expressed primarily in the cortico-limbic structures and striatum. Potent agonists and antagonists for mGluR2/3 have been developed. One agonist, LY354740, has been shown to have anxiolytic affects in animal models, as well as in a clinical trial of generalized anxiety disorder. Other potential therapeutic targets include schizophrenia, chronic pain and seizure disorders. Although dopamine plays a central role in reinforcing the effects of drugs of abuse, recent research reviewed by Kalivas demonstrates that cortical and amygdalar glutamatergic dysregulation are critical for the persistent plastic changes that account for addiction and the prolonged propensity for relapse. A surprising aspect of these plastic changes is that the cystine ante-porter on glia plays a critical role in regulating the extracellular levels of glutamate in animal models of addiction. Neurotransmitter transporters were one of the first identified molecular targets for psychotropic drug action (e.g. tricyclic antidepressants and cocaine). As reviewed by Gonza´ lez and Robinson, molecular strategies have disclosed a complex array of processes that regulate the trafficking, localization and activity of transporters. Current Opinion in Pharmacology 2004, 4:1–3
Thus, transporters are not merely passive scavengers of neurotransmitters but dynamic participants in signal transduction. Classic neurotransmitters continue to attract attention as therapeutic targets. Newhouse, Potter and Singh review the cognitive enhancing effects of nicotinic receptor agonists, especially nicotine, and address therapeutic potential in Alzheimer’s disease, schizophrenia and Parkinson’s disease. Burnstock discusses the role of ATP as a universal cotransmitter in nerves and how its role varies during pathological processes such as inflammation. Driving a stake in the heart of Dale’s law, he wisely recommends giving up the practice of identifying neurons by their neurotransmitter (e.g. glutamatergic neurons) because cotransmission is ubiquitous, and instead referring to their process (e.g. glutamatergic neurotransmission). The past decade has seen the introduction of a second generation of antipsychotic medications that have greatly reduced the risk of extrapyramidal side effects associated with first generation antipsychotics such as chlorpromazine and haloperidol. Meltzer critically reviews the concept of ‘atypical’, a label that has been attached to these newer antipsychotics, and considers whether their differences extend beyond side effect profiles to possibly enhanced therapeutic effects. The delayed onset of the therapeutic effects of antidepressants indicates that mere inhibition of biogenic amine transport, which is immediate, cannot explain the mechanism of therapeutic action. Castren reviews an emerging area of research which suggests that antidepressants may exert their therapeutic effects through stimulation of the production of brain-derived neurotrophic factor and other factors that promote synaptic plasticity and neurogenesis. An under-appreciated consequence of substance abuse is the negative impact on fetal brain development resulting from substance abuse during pregnancy. For example, ethanol abuse during pregnancy appears to be the most frequent preventable cause of mental subnormality. Stanwood and Levitt review the developmental impact of fetal cocaine exposure and elucidate the consequent persistent neuronal dysregulation that might account for cognitive and behavioral impairments later in life. Pharmacogenetics is a rapidly advancing field that attempts to identify polymorphisms of drug metabolizing enzymes and drug targets to optimize treatment. Bondy and Zill critically review the current status of pharmacogenetics as it impacts neuropsychopharmacology. Pathological aggregation of proteins is emerging as a common mechanism for neurodegenerative disorders www.sciencedirect.com
Editorial overview Coyle 3
including Jacob-Creutzfeld disease and Alzheimer’s disease. Le and Appel summarize the current knowledge of the genetics of Parkinsons’s disease and show that the different mutations share a common mechanistic theme — alteration in the ubiquitin proteosome system. Lipinski and Yuan discuss mechanisms of neurotoxicity in hereditary neurodegenerative disorders caused by mutations that result in expanded polyglutamine repeats in the affected genes. These disorders include Huntington’s disease, spinocerebellar ataxia and spinobulbar muscular atrophy. Because of shared pathways for neurodegeneration in these disorders, the authors propose treatments that inhibit intra-neuronal aggregation of polyglutamine repeats to prevent selective neuronal vulnerability. The use of novel biological systems to deliver treatments in brain disorders is attracting considerable attention.
www.sciencedirect.com
Lowenstein and Castro review the rapidly moving area of viral vector-mediated gene transfer in the brain and show that progress is being made with regard to cell specificity, methods of delivery and efficiency of transfection. Tai and Svendsen discuss the use of stem cells to treat damaged cells in neuropsychiatric disorders. They emphasize that trophic effects, as opposed to replacement, could be the primary therapeutic effect of stem cells and that they could prove to be the source of ‘therapeutic agents’ when modified before transplantation. I hope that you, the reader, find this series of reviews as stimulating and informative as I have. As old shibboleths of neuroscience fall, the boundaries of neuropsychopharmacology have expanded to include genetics, molecular biology and cell biology, and to bring realistic hope for more effective treatments of devastating diseases that were inconceivable a decade ago.
Current Opinion in Pharmacology 2004, 4:1–3
Joseph T Coyle Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA e-mail: [email protected]
Joseph T Coyle is the Eben S Draper Professor of Psychiatry and Neuroscience at Harvard Medical School. His research has been directed at the understanding of the neurobiology of severe neuropsychiatric disorders, with a particular interest in the role of glutamatergic neurotransmission in their pathophysiology.
Abbreviations LTP long-term potentiation mGluR metabotropic glutamate receptor NMDA N-methyl-D-aspartate
It has been an honor and pleasure to be invited to organize this issue of Current Opinion in Pharmacology. This responsibility prompted some reflection on how the field has evolved over the 35 years in which I have been involved. When I commenced pharmacological research in 1968, CNS drug discovery was primarily based on serendipity, linked to attempts to tether behavioral effects of drugs to alterations in chemical neurotransmission. Neurons were believed to use only one neurotransmitter, and the mature nervous system was thought to be ‘hard-wired’, with neurogenesis ceasing soon after birth. Psychiatric disorders were thought to be ‘functional’ without any brain pathology, and treatments other than palliative ones for neurodegenerative disorders were viewed with considerable pessimism. Except for rare conditions, genetics was thought to be irrelevant to the etiology of most neuropsychiatric disorders. The serial destruction of these scientific certitudes over the past 35 years has brought the field to a molecular era of neuropsychotropic drug discovery where genetic risk factors are used to identify molecular targets for drug development. Ultimately, as the genetics of neuropsychiatric disorders and pharmacogenetics advance, one can envision a future with highly selective drug treatments tailored to an individual’s particular genetic subtype of disorder and the drug metabolism status. Thus, these reflections have dictated the selection of topics for this issue. I have tried to include, together with the more traditional neuropharmacological issues, research areas that stretch the concept of pharmacology to therapeutic interventions involving genes and even cells. Glutamate is the primary excitatory neurotransmitter in the brain and is utilized by over 40% of synapses. Although, initially, the focus of interest in glutamate was in excitotoxicity, the ubiquitous distribution of glutamatergic neurons in brain implies that glutamatergic dysfunction probably occurs in many CNS disorders. Glutamatergic neurotransmimssion has been implicated in learning and memory through the process of long-term potentiation (LTP). LTP is a use-dependent enhancement of excitatory neurotransmission and typically requires the activation of voltage-dependent N-methyl-Daspartate (NMDA) receptors as a result of robust stimulation of AMPA receptors. Lynch describes a new group of agents that are allosteric positive
www.sciencedirect.com
Current Opinion in Pharmacology 2004, 4:1–3
2 Neurosciences
modulators of the AMPA receptor. Known as ampakines, they have been shown to promote LTP, augment expression of hippocampal brain-derived neurotrophic factor and enhance memory in experimental animals and human subjects with a remarkably benign side effect profile. The NMDA receptor has the peculiar feature of requiring simultaneous binding of two ligands. Unless the glycine site on the NMDA receptor (glycine B receptor) is occupied, glutamate cannot open the channel. One of the first identified NMDA receptor antagonists was kynurenic acid, which blocks the glycine B receptor. Kynurenic acid is a metabolite of tryptophan; another metabolite is quinolinic acid, which is an agonist at the glutamate recognition site on the NMDA receptor. Schwarcz reviews how the levels of these two opposing ligands are altered in neuropsychiatric disorders in ways that probably contribute to their pathophysiology. Furthermore, he elucidates how the synthetic enzyme for kynurenic acid can be exploited to generate more potent antagonists for treating conditions involving increased NMDA receptor activity. One of the concerns about developing drugs to manipulate glutamatergic neurotransmission was that a number of targets appeared to be limited (i.e. the NMDA and AMPA receptors). The discovery of the metabotropic glutamate receptors (mGluRs), which modulate glutamatergic neurotransmission, markedly increased the array of therapeutic targets. mGluRs are class III G-proteincoupled receptors, and are unique among this family for their large extracellular domain containing the glutamate binding site. Marek focuses on mGluR2/3, which is expressed primarily in the cortico-limbic structures and striatum. Potent agonists and antagonists for mGluR2/3 have been developed. One agonist, LY354740, has been shown to have anxiolytic affects in animal models, as well as in a clinical trial of generalized anxiety disorder. Other potential therapeutic targets include schizophrenia, chronic pain and seizure disorders. Although dopamine plays a central role in reinforcing the effects of drugs of abuse, recent research reviewed by Kalivas demonstrates that cortical and amygdalar glutamatergic dysregulation are critical for the persistent plastic changes that account for addiction and the prolonged propensity for relapse. A surprising aspect of these plastic changes is that the cystine ante-porter on glia plays a critical role in regulating the extracellular levels of glutamate in animal models of addiction. Neurotransmitter transporters were one of the first identified molecular targets for psychotropic drug action (e.g. tricyclic antidepressants and cocaine). As reviewed by Gonza´ lez and Robinson, molecular strategies have disclosed a complex array of processes that regulate the trafficking, localization and activity of transporters. Current Opinion in Pharmacology 2004, 4:1–3
Thus, transporters are not merely passive scavengers of neurotransmitters but dynamic participants in signal transduction. Classic neurotransmitters continue to attract attention as therapeutic targets. Newhouse, Potter and Singh review the cognitive enhancing effects of nicotinic receptor agonists, especially nicotine, and address therapeutic potential in Alzheimer’s disease, schizophrenia and Parkinson’s disease. Burnstock discusses the role of ATP as a universal cotransmitter in nerves and how its role varies during pathological processes such as inflammation. Driving a stake in the heart of Dale’s law, he wisely recommends giving up the practice of identifying neurons by their neurotransmitter (e.g. glutamatergic neurons) because cotransmission is ubiquitous, and instead referring to their process (e.g. glutamatergic neurotransmission). The past decade has seen the introduction of a second generation of antipsychotic medications that have greatly reduced the risk of extrapyramidal side effects associated with first generation antipsychotics such as chlorpromazine and haloperidol. Meltzer critically reviews the concept of ‘atypical’, a label that has been attached to these newer antipsychotics, and considers whether their differences extend beyond side effect profiles to possibly enhanced therapeutic effects. The delayed onset of the therapeutic effects of antidepressants indicates that mere inhibition of biogenic amine transport, which is immediate, cannot explain the mechanism of therapeutic action. Castren reviews an emerging area of research which suggests that antidepressants may exert their therapeutic effects through stimulation of the production of brain-derived neurotrophic factor and other factors that promote synaptic plasticity and neurogenesis. An under-appreciated consequence of substance abuse is the negative impact on fetal brain development resulting from substance abuse during pregnancy. For example, ethanol abuse during pregnancy appears to be the most frequent preventable cause of mental subnormality. Stanwood and Levitt review the developmental impact of fetal cocaine exposure and elucidate the consequent persistent neuronal dysregulation that might account for cognitive and behavioral impairments later in life. Pharmacogenetics is a rapidly advancing field that attempts to identify polymorphisms of drug metabolizing enzymes and drug targets to optimize treatment. Bondy and Zill critically review the current status of pharmacogenetics as it impacts neuropsychopharmacology. Pathological aggregation of proteins is emerging as a common mechanism for neurodegenerative disorders www.sciencedirect.com
Editorial overview Coyle 3
including Jacob-Creutzfeld disease and Alzheimer’s disease. Le and Appel summarize the current knowledge of the genetics of Parkinsons’s disease and show that the different mutations share a common mechanistic theme — alteration in the ubiquitin proteosome system. Lipinski and Yuan discuss mechanisms of neurotoxicity in hereditary neurodegenerative disorders caused by mutations that result in expanded polyglutamine repeats in the affected genes. These disorders include Huntington’s disease, spinocerebellar ataxia and spinobulbar muscular atrophy. Because of shared pathways for neurodegeneration in these disorders, the authors propose treatments that inhibit intra-neuronal aggregation of polyglutamine repeats to prevent selective neuronal vulnerability. The use of novel biological systems to deliver treatments in brain disorders is attracting considerable attention.
www.sciencedirect.com
Lowenstein and Castro review the rapidly moving area of viral vector-mediated gene transfer in the brain and show that progress is being made with regard to cell specificity, methods of delivery and efficiency of transfection. Tai and Svendsen discuss the use of stem cells to treat damaged cells in neuropsychiatric disorders. They emphasize that trophic effects, as opposed to replacement, could be the primary therapeutic effect of stem cells and that they could prove to be the source of ‘therapeutic agents’ when modified before transplantation. I hope that you, the reader, find this series of reviews as stimulating and informative as I have. As old shibboleths of neuroscience fall, the boundaries of neuropsychopharmacology have expanded to include genetics, molecular biology and cell biology, and to bring realistic hope for more effective treatments of devastating diseases that were inconceivable a decade ago.
Current Opinion in Pharmacology 2004, 4:1–3