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S.12.03 Physiological regulation of α7 nicotinic receptor activity by endogenous levels of the brain metabolite kynurenic acid: Clinical implications
S128
S.12.
pathways. Since there may be early indicators clinical features, select therapeutic targets.
Nicotinic
receptor
are iudicatious that declines in uAChRs of pathology aud associated with distinct uAChR subtypes may represent poteutial
References
[l] [2]
[3]
[4]
[5]
Court, J.A., Martin-Ruiz C., Graham, A., Perry E. 2000. Nicotinic receptors in human brain: topography and pathology. J. Chem. Neuroanat. 20, 281&298. Graham, A.J., Martin-Ruiz, CM., Teaktong, T., Ray, M.A., Court, J.A. 2002 Human brain nicotinic receptors, their distribution and participation in ueuropsychiatric disorders. Cum Drug Targets - CNS & Neural. Disord. 1, 3877397. Martin-Ruiz, CM., Haroutunian, VH., Long, I?, Young, A.H., Davis, K.L., Perry, E.K., Court, J.A. Dementia rating and nicotinic receptor expression in the pre-frontal cortex in schizophrenia. Biol. Psych& In press. Martin-Ruiz, C., Lawrence, S., Piggott, M., Kuryatov, A., Lindstrom, J., Gotti, C., Cookson, M.R., Perry, R,H., Perry, E.K., Court, J.A. Nicotinic receptors in the putamen of patients with dementia with Leuy bodies and Parkinson’ s disease: relation to changes in alpha-synuclein expression. Neurosci. L&t. 335, 134-138. (2002) Teaktong, T., Graham A.J., Court, J.A., Perry, R.H., Jams, E., Johnson, M., Hall, R., Perry, E. 2002. Alzheimer’ s disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor imnunoreactivity in astrocytes. Glia 41, 2077211.
IS 12 03
Physiological regulation of cr7 nicotinic receptor activity by endogenous levels of the brain metabolite kynurenic acid: Clinical implications
R. Schwartz’, E.F.R. Pereira2, M. Alkoudou2, L.E.F. Ahneida2, W.P. Fawcett2, W.R. Raudal12, P Guidetti’, M.T. Sapko’, P. Yu3, D.A. Tagle3, E.X. Albuquerque4. ‘Maryland Psychiatric Research Centel; Maryland, L!S.A.; 2 University of Maryland, School of Medicine, Baltimore, L!S.A.; 3National Institutes of Health, Bethesda, L!S.A.; 4University of Maryland and, ICB, CCS, UFRJJ Rio de Janeiro, Brazil Previous studies from our laboratories have demo&rated that the tryptophau metabolite kyuureuic acid (KYNA), which is produced aud released by astrocytes in the brain, modulates uicotiuic choliuergic activity in the rat hippocampus. At physiologically relevant couceutratious, KYNA inhibits non-competitively the activity of a7 uAChRs [.I Neurosci 21:7463, 2001]. To test the hypothesis that eudogeuous levels of KYNA control a7 uAChR activity aud ueuroual excitability in the central nervous system, mice were geuerated with a uull mutation in the geue that eucodes the major enzyme that catalyzes KYNA synthesis in the brain, kyuureuiue amiuotrausferase II @ATII@). Ligaud-gated chamlnel activity was measured by the application of the patch-clamp technique to CA1 stratum radiatum aud stratum lacuuosum moleculare iuterueurous of 21- or 22-day-old male wild type (WT) aud KATII? mice. All mice used were positively ideutified by PCR as WT or KATII?. At all ages studied, KYNA levels in braiu tissue were significantly lower in KATII? thau in WT mice. a7 uAChR activity, measured as peak amplitude or uet charge of whole-cell currents that were evoked by choline aud sensitive to blockade by 10 uM methyllycacouitiue, was 60% higher in ueurous of KATII? mice thau in ueurous of WT mice. The iucreased a7 uAChR activity was uot due to chauges in receptor expression, because the munber of a-buugarotoxiu sites in the hippocampi of both groups of animals were uot significantly differeut. In contrast, a3fi4 uAChR activity, measured as uet charge of AChtriggered NMDA postsyuaptic currents, as well as GABA aud
subtypes:
Focus
on u-7
NMDA receptor activities (measured as peak amplitude or uet charge of agonist-evoked whole-cell currents) were the same in both groups of animals. Electrophysiological experiments carried out in hippocampal slices also revealed that the frequency of spoutaueous action poteutials recorded from CA1 pyramidal ueurous was higher in KATII? thau in WT mice. The fiudiugs that eudogeuous levels of KYNA control a7 uAChR activity aud ueuroual excitability in the braiu is relevant for uuderstaudiug the pathophysiology of diseases such as schizophrenia in which braiu levels of KYNA are iucreased aud a7 uAChR activity is decreased. Support: USPHS gram NS25296.
I S 12 04
a7 Nicotinic acetylcholine Neuropsychopharmacological
receptors: significance
T.H. Svensson. Karolinska Institutet, Department and Pharmacology, Stockholm, Sweden
of Physiology
Clinical studies show a dramatically iucreased prevalence of cigarette smoking among schizophrenic patients (around 90 % in several studies) aud uicotiue may improve cognitive functioning, such as working memory, as well as relieve negative, but uot positive symptoms. Several sets of data, both precliuical aud clinical, suggest a dysregulatiou of the mesocorticolimbic dopamiue (DA) system in schizophrenia, with au euhauced striatal dopaminergic activity, considered importaut for positive symptoms, coucomitant with au impaired prefroutal dopamiue fuuctiouiug, which is thought to contribute to negative aud cognitive symptoms. Significantly, whereas couveutioual autipsychotic drugs, such as haloperidol, essentially seem to act through blockage of mesolimbit D2 receptors, atypical autipsychotics, such as clozapiue, in addition to displayiug a lower D2 occupancy in striatal braiu regions, actually facilitates DA release in the prefroutal cortex. Experimental studies show that systemic nicotine, especially wheu administered chronically, also causes a preferential activation of prefroutal DA release, aud wheu schizophrenic patients are switched from typical autipsychotics to clozapiue, they spoutaueously reduce their cigarrette smoking. Nicotine may temporarily alleviate the typical sensory gatiug deficits in schizophrenia, au effect that may be executed at least in part via hippocampal a7 uAChR, judging from experimental studies. In addition, postmortem studies report a reduced expression of a7 uAChR in several forebraiu regions in schizophrenia. Our work show that a7 uAChR are involved in the stimulatory effect of uicotiue ou the mesocorticolimbic DA system, which geuerally plays a pivotal role in the pharmacological modulation of schizophrenia, as well as for the emotional state in general. The DA ueurous that origiuate in the ventral tegmeutal area @‘TA) geuerally display two major modes of fuuctiou, i.e. single spike firing aud burst firing, aud our previous evidence shows that burst firing is specifically drivel1 by glutamatergic affereuts, which to a significant extent origiuate in the medial prefroutal cortex (mPFC), acting at somatodeudritic NMDA receptors ou the VTA DA ueurous. Thus, midbrain DA ueurous in the deaffereuted slice preparatiou ouly display single spike firing. In contrast, DA ueurous in uiuo respond with rapid activation responses to euviromneutal stimuli of rewardiug or atteutioual siguificauce, seudiug a “teaching signal to the brain” which facilitates learuiug aud reward predictive capacity. In other studies we have showu that burst activation of midbrain DA ueurous uot ouly represents their most effective meaus of transmitter release, but also potently induces activation
S.12.
pathways. Since there may be early indicators clinical features, select therapeutic targets.
Nicotinic
receptor
are iudicatious that declines in uAChRs of pathology aud associated with distinct uAChR subtypes may represent poteutial
References
[l] [2]
[3]
[4]
[5]
Court, J.A., Martin-Ruiz C., Graham, A., Perry E. 2000. Nicotinic receptors in human brain: topography and pathology. J. Chem. Neuroanat. 20, 281&298. Graham, A.J., Martin-Ruiz, CM., Teaktong, T., Ray, M.A., Court, J.A. 2002 Human brain nicotinic receptors, their distribution and participation in ueuropsychiatric disorders. Cum Drug Targets - CNS & Neural. Disord. 1, 3877397. Martin-Ruiz, CM., Haroutunian, VH., Long, I?, Young, A.H., Davis, K.L., Perry, E.K., Court, J.A. Dementia rating and nicotinic receptor expression in the pre-frontal cortex in schizophrenia. Biol. Psych& In press. Martin-Ruiz, C., Lawrence, S., Piggott, M., Kuryatov, A., Lindstrom, J., Gotti, C., Cookson, M.R., Perry, R,H., Perry, E.K., Court, J.A. Nicotinic receptors in the putamen of patients with dementia with Leuy bodies and Parkinson’ s disease: relation to changes in alpha-synuclein expression. Neurosci. L&t. 335, 134-138. (2002) Teaktong, T., Graham A.J., Court, J.A., Perry, R.H., Jams, E., Johnson, M., Hall, R., Perry, E. 2002. Alzheimer’ s disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor imnunoreactivity in astrocytes. Glia 41, 2077211.
IS 12 03
Physiological regulation of cr7 nicotinic receptor activity by endogenous levels of the brain metabolite kynurenic acid: Clinical implications
R. Schwartz’, E.F.R. Pereira2, M. Alkoudou2, L.E.F. Ahneida2, W.P. Fawcett2, W.R. Raudal12, P Guidetti’, M.T. Sapko’, P. Yu3, D.A. Tagle3, E.X. Albuquerque4. ‘Maryland Psychiatric Research Centel; Maryland, L!S.A.; 2 University of Maryland, School of Medicine, Baltimore, L!S.A.; 3National Institutes of Health, Bethesda, L!S.A.; 4University of Maryland and, ICB, CCS, UFRJJ Rio de Janeiro, Brazil Previous studies from our laboratories have demo&rated that the tryptophau metabolite kyuureuic acid (KYNA), which is produced aud released by astrocytes in the brain, modulates uicotiuic choliuergic activity in the rat hippocampus. At physiologically relevant couceutratious, KYNA inhibits non-competitively the activity of a7 uAChRs [.I Neurosci 21:7463, 2001]. To test the hypothesis that eudogeuous levels of KYNA control a7 uAChR activity aud ueuroual excitability in the central nervous system, mice were geuerated with a uull mutation in the geue that eucodes the major enzyme that catalyzes KYNA synthesis in the brain, kyuureuiue amiuotrausferase II @ATII@). Ligaud-gated chamlnel activity was measured by the application of the patch-clamp technique to CA1 stratum radiatum aud stratum lacuuosum moleculare iuterueurous of 21- or 22-day-old male wild type (WT) aud KATII? mice. All mice used were positively ideutified by PCR as WT or KATII?. At all ages studied, KYNA levels in braiu tissue were significantly lower in KATII? thau in WT mice. a7 uAChR activity, measured as peak amplitude or uet charge of whole-cell currents that were evoked by choline aud sensitive to blockade by 10 uM methyllycacouitiue, was 60% higher in ueurous of KATII? mice thau in ueurous of WT mice. The iucreased a7 uAChR activity was uot due to chauges in receptor expression, because the munber of a-buugarotoxiu sites in the hippocampi of both groups of animals were uot significantly differeut. In contrast, a3fi4 uAChR activity, measured as uet charge of AChtriggered NMDA postsyuaptic currents, as well as GABA aud
subtypes:
Focus
on u-7
NMDA receptor activities (measured as peak amplitude or uet charge of agonist-evoked whole-cell currents) were the same in both groups of animals. Electrophysiological experiments carried out in hippocampal slices also revealed that the frequency of spoutaueous action poteutials recorded from CA1 pyramidal ueurous was higher in KATII? thau in WT mice. The fiudiugs that eudogeuous levels of KYNA control a7 uAChR activity aud ueuroual excitability in the braiu is relevant for uuderstaudiug the pathophysiology of diseases such as schizophrenia in which braiu levels of KYNA are iucreased aud a7 uAChR activity is decreased. Support: USPHS gram NS25296.
I S 12 04
a7 Nicotinic acetylcholine Neuropsychopharmacological
receptors: significance
T.H. Svensson. Karolinska Institutet, Department and Pharmacology, Stockholm, Sweden
of Physiology
Clinical studies show a dramatically iucreased prevalence of cigarette smoking among schizophrenic patients (around 90 % in several studies) aud uicotiue may improve cognitive functioning, such as working memory, as well as relieve negative, but uot positive symptoms. Several sets of data, both precliuical aud clinical, suggest a dysregulatiou of the mesocorticolimbic dopamiue (DA) system in schizophrenia, with au euhauced striatal dopaminergic activity, considered importaut for positive symptoms, coucomitant with au impaired prefroutal dopamiue fuuctiouiug, which is thought to contribute to negative aud cognitive symptoms. Significantly, whereas couveutioual autipsychotic drugs, such as haloperidol, essentially seem to act through blockage of mesolimbit D2 receptors, atypical autipsychotics, such as clozapiue, in addition to displayiug a lower D2 occupancy in striatal braiu regions, actually facilitates DA release in the prefroutal cortex. Experimental studies show that systemic nicotine, especially wheu administered chronically, also causes a preferential activation of prefroutal DA release, aud wheu schizophrenic patients are switched from typical autipsychotics to clozapiue, they spoutaueously reduce their cigarrette smoking. Nicotine may temporarily alleviate the typical sensory gatiug deficits in schizophrenia, au effect that may be executed at least in part via hippocampal a7 uAChR, judging from experimental studies. In addition, postmortem studies report a reduced expression of a7 uAChR in several forebraiu regions in schizophrenia. Our work show that a7 uAChR are involved in the stimulatory effect of uicotiue ou the mesocorticolimbic DA system, which geuerally plays a pivotal role in the pharmacological modulation of schizophrenia, as well as for the emotional state in general. The DA ueurous that origiuate in the ventral tegmeutal area @‘TA) geuerally display two major modes of fuuctiou, i.e. single spike firing aud burst firing, aud our previous evidence shows that burst firing is specifically drivel1 by glutamatergic affereuts, which to a significant extent origiuate in the medial prefroutal cortex (mPFC), acting at somatodeudritic NMDA receptors ou the VTA DA ueurous. Thus, midbrain DA ueurous in the deaffereuted slice preparatiou ouly display single spike firing. In contrast, DA ueurous in uiuo respond with rapid activation responses to euviromneutal stimuli of rewardiug or atteutioual siguificauce, seudiug a “teaching signal to the brain” which facilitates learuiug aud reward predictive capacity. In other studies we have showu that burst activation of midbrain DA ueurous uot ouly represents their most effective meaus of transmitter release, but also potently induces activation