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Nicotine-improved aspects of psychomotor performance and cognitive ability: Fact or fiction
NICOTINIC ACETYLCHOLINE RECEPTORS (nAChR) AND NEUROTRANSMITTER RELEASE
S T R U C T U R E AND D I S T R I B U T I O N O F N I C O T I N I C RECEPTORS IN HUMAN BRAIN F. Clementi, F. Rubboli, C. Gotti, B. Balestra, E. Perry* CNR Center Cytopharmacology, Dept. Medical Pharmacology, Univ. of Milan, via Vanvitelli 32, 20129 Milan, Italy; *MRC Dept. Neuropathology, Newcastle upon Tyne, NE4 6BE, UK
S. Wonnacott School of Biology & Biochemistry, University of Bath, Bath BA27AY, UK It has been known since the experiments of Armitaget that nicotine can evoke the release of neurotransmitters in the brain. More recent in vitro and in vivo studies have confirmed that nicotine-evoked transmitter release is mediated by nAChR in the rat brain2. nAChR are located on cell bodies, nerve terminals and possibly also on "preterminar' regions of axons. Best characterised is dopamine (DA) release from striatum. Using pertosed synaptosomes preloaded with [~H]DA, nicotine evokes, [3H]DA release ~th an ECs0 of ~0.5~M. This action is blocked by mecamylamine and reproduced by nicotinic agonists. Using the potent agonist anatoxin-a (ECs00.lpM) we have found that [IH]DA release is (i) Ca2÷ and Na+ dependent; (ii) partially blocked by TTX; (iii) prevented by Cd2+; (iv) partially blocked by eagatoxin IVA. These results indicate that pres~(naptic dAChR elicit transmitter release by opening voltage gated Caz÷ channels, notably P-type channels. This presumably occurs by depoladsation adsing from the influx of Na+ via the nAChR channel but v~th some contribution from TTX-sensitive Na+ channels. An effect of nicotine could not be detected in the presence of sub-maximal' depoladsation by KCI. Chronic nicot[ne treatment upregulates the number of [~H]nicotine binding sites in rodent and human brain 3. Upregulation of nAChR number in the frontal cortex was paralleled by a downregulation of [3H]DA release, whereas no significaQt change in receptor binding or functional response was observed in stdatum. To investigate the physiological relevance of presynaptic nAChR we have used in vivo microdialysis in freely moving rats to measure DA release in the stdatum. Locally administered nicotine (via the dialysis probe) evokes a dose-dependent release of DA: At lower concentrations of nicotine, this response is abolished by mecamylamine and is totally prevented by TTX. This difference in TTX sensitivity from in vitro assays suggests the involvement of "preterminal" nAChRM tArmitage et aL, (1969)Br. J. Pharmacol.35: 152-160. ~Wonnacott et al., (1990) "Biology of Nicotine Dependence"pp87-101. ~Nonnacott (1990)Trends in Pharmacol. ScL 11: 216-219.
Neuronal nicotinic receptors are expressed in the central nervous system (CNS), autonomic ganglia and andrenal medulla. Different subunits (a2-c~8; 138-1~4)have been identified that, appropriately assembled, can generate several different receptor isoforms, with distinct localization and pharmacological profile. These subunits are co-expressed, and probably assembled, in the same receptor molecule or can be independently expressed in the different areas. The expression of a3, a7 and 132 mRNA in the human brain was studied by in situ hybridization and compared to 3H-nicotine, 3H-cytisine and ]25I-c~bungarotoxin binding in contiguous sections. The 132 probe showed a strong hybridization signal in the dentate gyms and in the CA2/CA3 region Of the hippocampus; the t~3 probe showed strong hybridization in the dorsomedial, lateral posterior, ventroposteromedial and reticular nuclei of the thalamus. The a7 mRNA was high in dentate granular layer and the CA2/CA3 region of the hippocampus, in the caudate nucleus and in some nuclei of the thalamus. 3H-Nicotine binding was high in the thalamic nuclei, the putamen and in the hippocampal formation in the subicular complex and the stratum lacunosum moleculare. The level of 125I-abungarotoxin binding was particularly high in the hippocampus and in the pyramidal cells of the CA1 region, but was relatively low in the subicular cofnplex. Our data indicate that in the human brain nicotinic receptor subtypes have discrete distributions and probably have a different subunit composition. To better understand the functions of the different receptors, we have analyzed the biophysical and pharmacological properties of nicotinic receptors present in human neuroblastoma cell lines and compared them with those of purified and reconstituted receptors.
Supported by grantsfromBBSRC,WellcorneTrust and EC.
FUNCTIONS OF NICOTINIC RECEPTORS IN HUMAN BRAIN A. Nordber, Department of Clinical Neuroscience and Family Medicine, Division of Nicotine Research, Karolinska institutet, Huddinge University Hospital, Sweden.
N~COTXNE-IMPRQVEDASPECT$OF PSYCHOMOTOR PERFOllANCE AND COGNITIVEABILITY: FACT OR FICTION Professor Ian Hindmarfh,, HPRU, University of Surrey Milford Hospital, Godalming, Surrey, GU7 1UF, U.K. There are three phases in the psychopharmaco]ogical investigation of the effects of smoking tobacco. The f i r s t phase tnvolved sets of uncontrolled experiments using insensitive measures and poor design. As techniques advanced in the 1970s, so the standard of experimentation on the psychological impact of nicotine became more r e f i n e d . However, the f l a w i n the research o f t h i s period is that the effects observed cou]d be exp|alned s~mp|y by claiming that a smoker had been deprived of nicotine and the experimenta] condition was simply restoring the subject's previous dose. The t h i r d phase, duringthe past 5 years, used valid design and r e l i a b l e techniques for assessing the effects of nicotine. Smokers were not run under deprived conditions; the effects of nicotine were investigated f o r l o n g e r than acute dosing scenarios and the range of tests examined reflected the sorts of activities l i k e l y t o be a]tered by people smoking tobacco on a r e g u l a r basis. Under these conditions, i t was possible to investigate the t r u e impact of nicotine on aspects of performance and mental function. The paper presented features a review of several hundred papers which have appeared in the ] i t e r a t u r e since 1900, but concentrates on the more enlightened studies of the last few years to show that overall there is evidence that the use of nicotine produces a small but noticeable and robust improvement in various aspects of memory and cognitive function.
The discovery of the existence of multiple nicotinic receptors in the •human brain and their importance for higher functions such as learning, memory as well as dependence processes are relative new phenomena. The application of neurochemical, molecular biology techniques, functional studies have enhanced our knowledge about the nicotinic receptor in human brain, but also given new insight into the complexity. An important goal of the research is to define the functional importance of the receptors and test their possibility as targets for new treatment strategies of various mental disorders. The nicotinic receptors in human brain are well characterized by receptor binding studies in autopsy brain tissue. New nicotinic agonists such as epibatidine and ABT-418 provide valuable tools to distinguish nicotinic receptor subtype specificity. Studies are ongoing to map the regional distribution of receptor subtypes on mRNA level. Positron emission tomography offers a unique possibility to visualize nicotinic receptors in vivo in man. A kinetic model is used to analyse binding of 11C_nicotine in brain. In vivo quantification of nicotinic receptors in brain will probable provide further understanding of nicotine dependence processes, their underlying mechanisms and abstinence phenomena. Deficits in nicotinic receptors of the brain have been revealed in neurodegenerative disorders as Alzheimer's disease and Parkinson's disease. Studies also suggest that nicotinic receptors might be involved in diseases like schizophrenia and Tourette's syndrome. New selective nicotinic agonists targeting the subtypes of nicotinic receptors are of great interest to develop.
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S T R U C T U R E AND D I S T R I B U T I O N O F N I C O T I N I C RECEPTORS IN HUMAN BRAIN F. Clementi, F. Rubboli, C. Gotti, B. Balestra, E. Perry* CNR Center Cytopharmacology, Dept. Medical Pharmacology, Univ. of Milan, via Vanvitelli 32, 20129 Milan, Italy; *MRC Dept. Neuropathology, Newcastle upon Tyne, NE4 6BE, UK
S. Wonnacott School of Biology & Biochemistry, University of Bath, Bath BA27AY, UK It has been known since the experiments of Armitaget that nicotine can evoke the release of neurotransmitters in the brain. More recent in vitro and in vivo studies have confirmed that nicotine-evoked transmitter release is mediated by nAChR in the rat brain2. nAChR are located on cell bodies, nerve terminals and possibly also on "preterminar' regions of axons. Best characterised is dopamine (DA) release from striatum. Using pertosed synaptosomes preloaded with [~H]DA, nicotine evokes, [3H]DA release ~th an ECs0 of ~0.5~M. This action is blocked by mecamylamine and reproduced by nicotinic agonists. Using the potent agonist anatoxin-a (ECs00.lpM) we have found that [IH]DA release is (i) Ca2÷ and Na+ dependent; (ii) partially blocked by TTX; (iii) prevented by Cd2+; (iv) partially blocked by eagatoxin IVA. These results indicate that pres~(naptic dAChR elicit transmitter release by opening voltage gated Caz÷ channels, notably P-type channels. This presumably occurs by depoladsation adsing from the influx of Na+ via the nAChR channel but v~th some contribution from TTX-sensitive Na+ channels. An effect of nicotine could not be detected in the presence of sub-maximal' depoladsation by KCI. Chronic nicot[ne treatment upregulates the number of [~H]nicotine binding sites in rodent and human brain 3. Upregulation of nAChR number in the frontal cortex was paralleled by a downregulation of [3H]DA release, whereas no significaQt change in receptor binding or functional response was observed in stdatum. To investigate the physiological relevance of presynaptic nAChR we have used in vivo microdialysis in freely moving rats to measure DA release in the stdatum. Locally administered nicotine (via the dialysis probe) evokes a dose-dependent release of DA: At lower concentrations of nicotine, this response is abolished by mecamylamine and is totally prevented by TTX. This difference in TTX sensitivity from in vitro assays suggests the involvement of "preterminal" nAChRM tArmitage et aL, (1969)Br. J. Pharmacol.35: 152-160. ~Wonnacott et al., (1990) "Biology of Nicotine Dependence"pp87-101. ~Nonnacott (1990)Trends in Pharmacol. ScL 11: 216-219.
Neuronal nicotinic receptors are expressed in the central nervous system (CNS), autonomic ganglia and andrenal medulla. Different subunits (a2-c~8; 138-1~4)have been identified that, appropriately assembled, can generate several different receptor isoforms, with distinct localization and pharmacological profile. These subunits are co-expressed, and probably assembled, in the same receptor molecule or can be independently expressed in the different areas. The expression of a3, a7 and 132 mRNA in the human brain was studied by in situ hybridization and compared to 3H-nicotine, 3H-cytisine and ]25I-c~bungarotoxin binding in contiguous sections. The 132 probe showed a strong hybridization signal in the dentate gyms and in the CA2/CA3 region Of the hippocampus; the t~3 probe showed strong hybridization in the dorsomedial, lateral posterior, ventroposteromedial and reticular nuclei of the thalamus. The a7 mRNA was high in dentate granular layer and the CA2/CA3 region of the hippocampus, in the caudate nucleus and in some nuclei of the thalamus. 3H-Nicotine binding was high in the thalamic nuclei, the putamen and in the hippocampal formation in the subicular complex and the stratum lacunosum moleculare. The level of 125I-abungarotoxin binding was particularly high in the hippocampus and in the pyramidal cells of the CA1 region, but was relatively low in the subicular cofnplex. Our data indicate that in the human brain nicotinic receptor subtypes have discrete distributions and probably have a different subunit composition. To better understand the functions of the different receptors, we have analyzed the biophysical and pharmacological properties of nicotinic receptors present in human neuroblastoma cell lines and compared them with those of purified and reconstituted receptors.
Supported by grantsfromBBSRC,WellcorneTrust and EC.
FUNCTIONS OF NICOTINIC RECEPTORS IN HUMAN BRAIN A. Nordber, Department of Clinical Neuroscience and Family Medicine, Division of Nicotine Research, Karolinska institutet, Huddinge University Hospital, Sweden.
N~COTXNE-IMPRQVEDASPECT$OF PSYCHOMOTOR PERFOllANCE AND COGNITIVEABILITY: FACT OR FICTION Professor Ian Hindmarfh,, HPRU, University of Surrey Milford Hospital, Godalming, Surrey, GU7 1UF, U.K. There are three phases in the psychopharmaco]ogical investigation of the effects of smoking tobacco. The f i r s t phase tnvolved sets of uncontrolled experiments using insensitive measures and poor design. As techniques advanced in the 1970s, so the standard of experimentation on the psychological impact of nicotine became more r e f i n e d . However, the f l a w i n the research o f t h i s period is that the effects observed cou]d be exp|alned s~mp|y by claiming that a smoker had been deprived of nicotine and the experimenta] condition was simply restoring the subject's previous dose. The t h i r d phase, duringthe past 5 years, used valid design and r e l i a b l e techniques for assessing the effects of nicotine. Smokers were not run under deprived conditions; the effects of nicotine were investigated f o r l o n g e r than acute dosing scenarios and the range of tests examined reflected the sorts of activities l i k e l y t o be a]tered by people smoking tobacco on a r e g u l a r basis. Under these conditions, i t was possible to investigate the t r u e impact of nicotine on aspects of performance and mental function. The paper presented features a review of several hundred papers which have appeared in the ] i t e r a t u r e since 1900, but concentrates on the more enlightened studies of the last few years to show that overall there is evidence that the use of nicotine produces a small but noticeable and robust improvement in various aspects of memory and cognitive function.
The discovery of the existence of multiple nicotinic receptors in the •human brain and their importance for higher functions such as learning, memory as well as dependence processes are relative new phenomena. The application of neurochemical, molecular biology techniques, functional studies have enhanced our knowledge about the nicotinic receptor in human brain, but also given new insight into the complexity. An important goal of the research is to define the functional importance of the receptors and test their possibility as targets for new treatment strategies of various mental disorders. The nicotinic receptors in human brain are well characterized by receptor binding studies in autopsy brain tissue. New nicotinic agonists such as epibatidine and ABT-418 provide valuable tools to distinguish nicotinic receptor subtype specificity. Studies are ongoing to map the regional distribution of receptor subtypes on mRNA level. Positron emission tomography offers a unique possibility to visualize nicotinic receptors in vivo in man. A kinetic model is used to analyse binding of 11C_nicotine in brain. In vivo quantification of nicotinic receptors in brain will probable provide further understanding of nicotine dependence processes, their underlying mechanisms and abstinence phenomena. Deficits in nicotinic receptors of the brain have been revealed in neurodegenerative disorders as Alzheimer's disease and Parkinson's disease. Studies also suggest that nicotinic receptors might be involved in diseases like schizophrenia and Tourette's syndrome. New selective nicotinic agonists targeting the subtypes of nicotinic receptors are of great interest to develop.
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20
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