Abstract
Previous studies have suggested that an abnormality in neuronal nicotinic acetylcholine receptor expression or function may be involved in the neuropathophysiology of schizophrenia. [3H]-nicotine and [3H]-epibatidine binding were compared in postmortem brain from control and schizophrenic subjects with varying smoking histories. In control subjects, increased receptor binding was seen in hippocampus, cortex, and caudate with increasing tobacco use. In contrast, schizophrenic smokers had reduced nicotinic receptor levels in these brain regions compared to control smokers. Chronic haloperidol and nicotine treatment, in the rat, was used to assess neuroleptic effects on receptor up-regulation by nicotine. A significant increase in cortical nicotinic receptors was seen in both nicotine treated as well as haloperidol and nicotine co-treated animals, suggesting that the abnormal regulation of high affinity neuronal nicotinic receptors in schizophrenics following nicotine use was not related to chronic neuroleptic treatment.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Adler LE, Hoffer LD, Griffith J, Waldo MC, Freedman R . (1992): Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biol Psychiatry 32: 607–616
Adler LE, Hoffer LD, Wiser A, Freedman R . (1993): Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 150: 1856–1861
Adler LE, Olincy A, Waldo M, Harris JG, Griffith J, Stevens K, Flach K, Nagamoto H, Bickford P, Leonard S, Freedman R . (1998): Schizophrenia, sensory gating, and nicotinic receptors. Schizophr Bull 24: 189–202
Albuquerque EX, Pereira EFR, Braga MFM . (1998): A basal α4β2 nicotinic receptor (nAChR) activity controls the release of GABA from hippocampal neurons. Soc Neurosci Abstr 24: 1581
Alkondon M, Pereira EFR, Barbosa CT, Albuquerque EX . (1997): Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices. J Pharm Exp Ther 283: 1396–1411
Araujo DM, Lapchak PA, Collier B, Quirion R . (1988): Characterization of N-[3H]methylcarbamylcholine binding sites and effect of N-methylcarbamylcholine on acetylcholine release in rat brain. J Neurochem 51: 292–299
Baenziger JE, Chew JP . (1997): Desensitization of the nicotinic acetylcholine receptor mainly involves a structural change in solvent-accessible regions of the polypeptide backbone. Biochemistry 36: 3617–3624
Benwell ME, Balfour DJ, Anderson JM . (1988): Evidence that tobacco smoking increases the density of (−)-[3H]nicotine binding sites in human brain. J Neurochem 50: 1243–1247
Bertolino M, Kellar KJ, Vicini S, Gillis RA . (1997): Nicotinic receptor mediates spontaneous GABA release in the rat dorsal motor nucleus of the vagus. Neuroscience 79: 671–681
Blaha CD, Allen LF, Das S, Inglis WL, Latimer MP, Vincent SR, Winn P . (1996): Modulation of dopamine efflux in the nucleus accumbens after cholinergic stimulation of the ventral tegmental area in intact, pedunculopontine tegmental nucleusles-lesioned, and laterodorsal tegmental nucleus-lesioned rats. J Neurosci 16: 714–722
Bowman WC, Marshall IG, Gibb AJ, Harborne AJ . (1988): Feedback control of transmitter release at the neuromuscular junction. Trends Pharmacol Sci 9: 16–20
Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, Collins AC, Leonard S . (1997a): Effect of smoking history on [3H]nicotine binding in human postmortem brain. J Pharmacol Exp Ther 282: 7–13
Breese CR, Adams C, Logel J, Drebing C, Rollins Y, Barnhart M, Sullivan B, Demasters BK, Freedman R, Leonard S . (1997b): Comparison of the regional expression of nicotinic acetylcholine receptor alpha7 mRNA and [1251]-alpha-bungarotoxin binding in human postmortem brain. J Comp Neurol 387: 385–398
Court JA, Lloyd S, Thomas N, Piggott MA, Marshall EF, Morris CM, Lamb H, Perry RH, Johnson M, Perry EK . (1998): Dopamine and nicotinic receptor binding and the levels of dopamine and homovanillic acid in human brain related to tobacco use. Neuroscience 87: 63–78
Dalack GW, Healy DJ, Meador-Woodruff JH . (1998): Nicotine dependence in schizophrenia: Clinical phenomena and laboratory findings. Am J Psychiatry 155: 1490–1501
Davies AR, Hardick DJ, Blagbrough IS, Potter BV, Wolstenholme AJ, Wonnacott S . (1999): Characterization of the binding of [3H]methyllycaconitine: A new radioligand for labelling alpha 7-type neuronal nicotinic acetylcholine receptors. Neuropharmacology 38: 679–690
de Leon J, Dadvand M, Canuso C, White AO, Stanilia JK, Simpson GM . (1995): Schizophrenia and smoking: An epidemiological survey in a state hospital. Am J Psychiatry 152: 453–455
Decina P, Caracci G, Sandik R, Berman W, Mukherjee S, Scapicchio P . (1990): Cigarette smoking and neuroleptic-induced parkinsonism. Biol Psychiatry 28: 502–508
Eilers H, Schaeffer E, Bickler PE, Forsayeth JR . (1997): Functional deactivation of the major neuronal nicotinic receptor caused by nicotine and a protein kinase C-dependent mechanism. Mol Pharmacol 52: 1105–1112
Fenster CP, Whitworth TL, Sheffield EB, Quick MW, Lester RA . (1999): Upregulation of surface alpha4beta2 nicotinic receptors is initiated by receptor desensitization after chronic exposure to nicotine. J Neurosci 19: 4804–4814
Flores CM, Davila-Garcia MI, Ulrich YM, Kellar KJ . (1997): Differential regulation of neuronal nicotinic receptor binding sites following chronic nicotine administration. J Neurochem 69: 2216–2219
Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA, Breese CR, Adams C, Patterson D, Adler LE, Kruglyak L, Leonard S, Byerley W . (1997): Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA 94: 587–592
Freedman R, Hall M, Adler LE, Leonard S . (1995): Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38: 22–33
George TP, Sernyak MJ, Ziedonis DM, Woods SW . (1995): Effects of clozapine on smoking in chronic schizophrenic outpatients. J Clin Psychiatry 56: 344–346
Goff DC, Henderson DC, Amico E . (1992): Cigarette smoking in schizophrenia: Relationship to psychopathology and medication side effects. Am J Psychiatry 149: 1189–1194
Goldstein G, Allen DN, van Kammen DP . (1998): Individual differences in cognitive decline in schizophrenia. Am J Psychiatry 155: 1117–1118
Grady SR, Marks MJ, Collins AC . (1994): Desensitization of nicotine-stimulated [3H]dopamine release from mouse striatal synaptosomes. J Neurochem 62: 1390–1398
Grenhoff J, Svensson TH . (1988): Selective stimulation of limbic dopamine activity by nicotine. Acta Physiol Scand 133: 595–596
Heinrichs RW, Zakzanis KK . (1998): Neurocognitive deficit in schizophrenia: A quantitative review of the evidence. Neuropsychology 12: 426–445
Houghtling RA, Davila-Garcia ML, Kellar KJ . (1995): Characterization of (+/−) (−)[3H]epibatidine binding to nicotinic cholinergic receptors in rat and human brain. Mol Pharmacol 48: 280–287
Hsu YN, Edwards SC, Wecker L . (1997): Nicotine enhances the cyclic AMP-dependent protein kinase-mediated phosphorylation of α4 subunits of neuronal nicotinic receptors. J Neurochem 69: 2427–2431
Hyde TM, Nawroz S, Goldberg TE, Bigelow LB, Strong D, Ostrem JL, Weinberger DR, Kleinman JE . (1994): Is there cognitive decline in schizophrenia? A cross-sectional study. Br J Psychiatry 164: 494–500
Jann MW, Saklad SR, Ereshefsky L, Richards AL, Harrington CA, Davis CM . (1986): Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance. Psychopharmacology 90: 468–470
Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD, Meyer J, Zambuto CT, Schmitt K, Matise TC, Harkavy FJ, Hampe C, Lee H, Shore D, Wynne D, Faraone SV, Tsuang MT, Cloninger CR . (1998): NIMH Genetics Initiative Millenium Schizophrenia Consortium: Linkage analysis of African-American pedigrees. Am J Med Genet 81: 282–289
Keppel G . (1991): Design and Analysis: A Researcher's Handbook, 3rd ed. Englewood Cliffs, NJ, Prentice-Hall, Inc
Lee MJ, Breese CR, Leonard S . (1998): The effect of nicotine and haloperidol on high affinity nicotinic receptors and dopamine D2 receptors in the rat brain. J Neurosci 24: 833
Leonard S, Adams C, Breese CR, Adler LE, Bickford P, Byerley W, Coon H, Griffith JM, Miller C, Myles-Worsley M, Nagamoto HT, Rollins Y, Stevens KE, Waldo M, Freedman R . (1996): Nicotinic receptor function in schizophrenia. Schizophr Bull 22: 431–445
Leonard S, Adler LE, Olincy A, Breese CR, Gault J, Ross RG, Lee M, Cawthra E, Nagamoto HT, Freedman R . (1998a): The role of nicotine and nicotinic receptors in psychopathology. In Arneric SP, Brioni JD (eds), Neuronal Nicotinic Receptor: Pharmacology and Therapeutic Opportunities. New York, Wiley-Liss, Inc., pp 307–321
Leonard S, Gault J, Moore T, Hopkins J, Robinson M, Olincy A, Adler LE, Cloninger CR, Kaufmann CA, Tsuang MT, Faraone SV, Malaspina D, Svrakic DM, Freedman R . (1998b): Further investigation of a chromosome 15 locus in schizophrenia: Analysis of affected sibpairs from the NIMH Genetics Initiative. Am J Med Genet 81: 308–312
Leonard S, Logel J, Luthman D, Casanova M, Kirch D, Freedman R . (1993): Biological stability of mRNA isolated from human postmortem brain collections. Biol Psychiatry 33: 456–466
Liang SD, Vizi ES . (1997): Positive feedback modulation of acetylcholine release from isolated rat superior cervical ganglion. J Pharmacol Exp Ther 280: 650–655
Lohr JB, Flynn K . (1992): Smoking and schizophrenia. Schizophr Res 8: 93–102
Luntz-Leybman V, Bickford PC, Freedman R . (1992): Cholinergic gating of response to auditory stimuli in rat hippocampus. Brain Res 587: 130–136
MacDermott AB, Role LW, Siegelbaum SA . (1999): Presynaptic ionotropic receptors and the control of transmitter release. Annu Rev Neurosci 22: 443–485
Marks MJ, Collins AC . (1982): Characterization of nicotine binding in mouse brain and comparison with the binding of α-bungarotoxin and quinuclidinyl benzilate. Mol Pharmacol 22: 554–564
Marks MJ, Stitzel JA, Collins AC . (1985): Time course study of the effects of chronic nicotine infusion on drug response and brain receptors. J Pharmacol Exp Ther 235: 619–628
Marks MJ, Pauly JR, Gross SD, Deneris ES, Hermans-Borgmeyer I, Heinemann SF, Collins AC . (1992): Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J Neurosci 12: 2765–2784
Marks MJ, Smith KW, Collins AC . (1998): Differential agonist inhibition identifies multiple epibatidine binding sites in mouse brain. J Pharmacol Exp Ther 285: 377–386
McEvoy JP, Freudenreich O, Levin ED, Rose JE . (1995): Haloperidol increases smoking in patients with schizophrenia. Psychopharmacology 119: 124–126
Miller DD, Kelly MW, Perry PJ, Coryell WH . (1990): The influence of cigarette smoking on haloperidol pharmacokinetics. Biol Psychiatry 28: 529–531
Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R . (1996): Gating of auditory P50 in schizophrenics: Unique effects of clozapine. Biol Psychiatry 40: 181–188
Nakajima M, Yamamoto T, Nunoya K, Yokoi T, Nagashima K, Inoue K, Funae Y, Shimada N, Kamataki T, Kuroiwa Y . (1996): Role of human cytochrome P4502A6 in C-oxidation of nicotine. Drug Metab Dispos 24: 1212–1217
Olincy A, Young DA, Freedman R . (1997): Increased levels of the nicotine metabolite cotinine in schizophrenic smokers compared to other smokers. Biol Psychiatry 42: 1–5
Olincy A, Ross RG, Young DA, Roath M . Freedman R . (1998): Improvement in smooth pursuit eye movements after cigarette smoking in schizophrenic patients. Neuropsychopharmacology 18: 175–185
Peng X, Gerzanich V, Anand R, Whiting PJ, Lindstrom J . (1994): Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover. Mol Pharmacol 46: 523–530
Pidoplichko VI, DeBiasi M, Williams JT, Dani JA . (1997): Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390: 401–404
Rapier C, Lunt GG, Wonnacott S . (1990): Nicotinic modulation of [3H] dopamine release from striatal synaptosomes: pharmacological characterization. J Neurochem 54: 937–945
Riley BP, Makoff AM, Mogudi-Carter M, Jenkins TJ, Williamson R, Collier DA, Murray RM . (2000): High marker-density analyses of the α7-nicotinic cholinergic receptor subunit (CHRNA7) gene region on chromosome 15q13–q14 and 5′ RACE cloning of fragments specific to CHRNA7 or its partial duplication. Schizophr Res 41: 93
Romm E, Lippiello PM, Marks MJ, Collins AC . (1990): Purification of L-[3H]nicotine eliminates low affinity binding. Life Sci 46: 935–943
Rowell PP . (1995): Nanomolar concentrations of nicotine increase the release of [3H]dopamine from rat striatal synaptosomes. Neurosci Lett 189: 171–175
Rowell PP, Winkler DL . (1984): Nicotinic stimulation of [3H]acetylcholine release from mouse cerebral cortical synaptosomes. J Neurochem 43: 1593–1598
Sandyk R . (1993): Cigarette smoking: effects on cognitive functions and drug-induced parkinsonism in chronic schizophrenia. Int J Neurosci 70: 193–197
Sershen H, Toth E, Lajtha A, Vizi ES . (1995): Nicotine effects on presynaptic receptor interactions. Ann NY Acad Sci 757: 238–244
Stevens KE, Freedman R, Collins AC, Hall M, Leonard S, Marks MJ, Rose GM . (1996): Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains. Brain Res 15: 152–162
Stevens KE, Kem WR, Mahnir VM, Freedman R . (1998): Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharmacology 136: 320–327
Summers KL, Giacobini E . (1995): Effects of local and repeated systemic administration of (−)nicotine on extracellular levels of acetylcholine, norepinephrine, dopamine, and serotonin in rat cortex. Neurochem Res 20: 753–759
Summers KL, Kem WR, Giacobini E . (1997): Nicotinic agonist modulation of neurotransmitter levels in the rat frontoparietal cortex. Jap J Pharmacol 74: 139–146
Takahashi H, Takada Y, Nagai N, Urano T, Takada A . (1998): Nicotine increases stress-induced serotonin release by stimulating nicotinic acetylcholine receptor in rat striatum. Synapse 28: 212–219
Tian L, Prior C, Dempster J, Marshall IG . (1994): Nicotinic antagonist-produced frequency-dependent changes in acetylcholine release from rat motor nerve terminals. J Physiol 476: 517–529
Ulrich YM, Hargreaves KM, Flores CM . (1997): A comparison of multiple injections versus continuous infusion of nicotine for producing up-regulation of neuronal [3H]-epibatidine binding sites. Neuropharmacology 36: 1119–1125
Vibat CR, Lasalde JA, McNamee MG, Ochoa EL . (1995): Differential desensitization properties of rat neuronal nicotinic acetylcholine receptor subunit combinations expressed in Xenopus laevis oocytes. Cell Mol Neurobiol 15: 411–425
Ward JM, Cockcroft VB, Lunt GG, Smillie FS, Wonnacott S . (1990): Methyllycaconitine: A selective probe for neuronal alpha-bungarotoxin binding sites. FEBS Lett 270: 45–48
Wilkie GI, Hutson P, Sullivan JP, Wonnacoft S . (1996): Pharmacological characterization of a nicotinic autoreceptor in rat hippocampal synaptosomes. Neurochem Res 21: 1141–1148
Wonnacott S . (1997): Presynaptic nicotinic ACh receptors. Trends Neurosci 20: 92–98
Xiao Y, Meyer EL, Thompson JM, Surin A, Wroblewski J, Kellar KJ . (1998): Rat α3/β4 subtype of neuronal nicotinic acetylcholine receptor stably expressed in a transfected cell line: Pharmacology of ligand binding and function. Mol Pharmacol 54: 322–333
Yang X, Criswell HE, Breese GR . (1996): Nicotine-induced inhibition in medial septum involves activation of presynaptic nicotinic cholinergic receptors on gamma-aminobutyric acid-containing neurons. J Pharmacol Exp Ther 276: 482–489
Ziedonis DM, Kosten TR, Glazer WM, Frances RJ . (1994): Nicotine dependence and schizophrenia. Hosp Commun Psychiatry 45: 204–206
Acknowledgements
This work was supported by USPHS Grants AA11164 and a NARSAD Young Investigator Award to C.R.B., USPHS Grants DA09457 and DA12281 and the VA Medical Research Service to S.L., and USPHS Grants DA03194 and DA00197 to A.C.C.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Breese, C., Lee, M., Adams, C. et al. Abnormal Regulation of High Affinity Nicotinic Receptors in Subjects with Schizophrenia. Neuropsychopharmacol 23, 351–364 (2000). https://doi.org/10.1016/S0893-133X(00)00121-4
Received:
Revised:
Accepted:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(00)00121-4
Keywords
This article is cited by
-
Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment
Molecular Psychiatry (2023)
-
Lower cholinergic basal forebrain volumes link with cognitive difficulties in schizophrenia
Neuropsychopharmacology (2021)
-
Repeated Nicotine Strengthens Gamma Oscillations in the Prefrontal Cortex and Improves Visual Attention
Neuropsychopharmacology (2017)
-
Traits and Biomarkers for Addiction Risk in Schizophrenia
Current Addiction Reports (2017)
-
Achieving Smoking Cessation in Individuals with Schizophrenia: Special Considerations
CNS Drugs (2017)
