Involvement of the Basal Cholinergic Forebrain in the Mediation of General (Propofol) Anesthesia

Background:Recent studies have pointed out the involvement of the basal forebrain &ggr;-aminobutyric acid–mediated system in mediating the effects of general anesthesia. In this study, the authors asked whether the basal forebrain cholinergic system is also involved in mediating the effects of general anesthetics such as propofol. Methods:Cholinergic lesions were produced by administration of the selective immunotoxin 192 immunoglobulin G–saporin into the lateral ventricles, the medial septum, or the nucleus basalis magnocellularis. The anesthetic potency of propofol was determined using an anesthetic score with a crossover counterbalanced design. Animals were given intraperitoneal propofol (25 or 50 mg/kg) repeatedly every 15 min to set up a subanesthetic (low-dose) or anesthetic (high-dose) state. The anesthetic score was assessed for each cumulative dose. Control of the cholinergic depletion was performed using histochemical acetylcholinesterase staining on brain slices. Results:A shift from a subanesthetic state to an anesthetic state was observed mainly in the rats with the immunotoxin injected into the lateral ventricles or the medial septum and vertical diagonal band of Broca, compared with controls. In those rats, the density of acetylcholinesterase reaction products was normal in the striatum and the thalamus, but reduced in the cortex and the hippocampus. Conclusion:The anesthetic potency of propofol was increased in all rats with hippocampal lesions, whatever the injection sites, compared with controls. These results demonstrate that a cholinergic dysfunction in the basal forebrain potentiates the anesthetic effects of propofol.

[1]  M. Gallagher,et al.  Aging causes partial loss of basal forebrain but no loss of pontine reticular cholinergic neurons , 2006, Neuroreport.

[2]  A. Artru,et al.  Physostigmine reversal of general anesthesia for intraoperative neurological testing: associated EEG changes. , 1986, Anesthesia and analgesia.

[3]  T. Kikuchi,et al.  Age‐related modifications of effects of ketamine and propofol on rat hippocampal acetylcholine release studied by in vivo brain microdialysis , 2000, Acta anaesthesiologica Scandinavica.

[4]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[5]  R. Wiley,et al.  The behavioral functions of the cholinergic basalforebrain : lessons from 192 IgG-SAPORIN , 1998, International Journal of Developmental Neuroscience.

[6]  R. Galani,et al.  Combined Damage to Entorhinal Cortex and Cholinergic Basal Forebrain Neurons, Two Early Neurodegenerative Features Accompanying Alzheimer's Disease: Effects on Locomotor Activity and Memory Functions in Rats , 2007, Neuropsychopharmacology.

[7]  L. Thal,et al.  Time course of cholinergic and monoaminergic changes in rat brain after immunolesioning with 192 IgG-saporin , 1994, Neuroscience Letters.

[8]  H. C. Dringenberg.  Serotonergic receptor antagonists alter responses to general anaesthetics in rats. , 2000, British journal of anaesthesia.

[9]  M. Durieux,et al.  Volatile anaesthetics have differential effects on recombinant m1 and m3 muscarinic acetylcholine receptor function. , 1998, British Journal of Anaesthesia.

[10]  B. Jones,et al.  The organization of central cholinergic systems and their functional importance in sleep-waking states. , 1993, Progress in brain research.

[11]  F. J. van der Staay,et al.  Long‐term effects of immunotoxic cholinergic lesions in the septum on acquisition of the cone‐field task and noncognitive measures in rats , 2006, Hippocampus.

[12]  G. Buzsáki,et al.  Nucleus basalis and thalamic control of neocortical activity in the freely moving rat , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  A. Fassoulaki,et al.  Physostigmine increases the dose of propofol required to induce anaesthesia , 1997, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[14]  Jingyi Ma,et al.  The Septohippocampal System Participates in General Anesthesia , 2002, The Journal of Neuroscience.

[15]  M. Durieux.  Inhibition by Ketamine of Muscarinic Acetylcholine Receptor Function , 1995, Anesthesia and analgesia.

[16]  J. Gross,et al.  Physostigmine reversal of midazolam-induced sedation. , 1982, Anesthesiology.

[17]  Nancy J. Woolf,et al.  Cholinergic systems in mammalian brain and spinal cord , 1991, Progress in Neurobiology.

[18]  M. Steriade,et al.  Network modulation of a slow intrinsic oscillation of cat thalamocortical neurons implicated in sleep delta waves: cortically induced synchronization and brainstem cholinergic suppression , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  C. Lazarus,et al.  5,7‐DHT‐induced hippocampal 5‐HT depletion attenuates behavioural deficits produced by 192 IgG‐saporin lesions of septal cholinergic neurons in the rat , 2002, The European journal of neuroscience.

[20]  A. Toro-Matos,et al.  Physostigmine Antagonizes Ketamine , 1980, Anesthesia and analgesia.

[21]  M. Gallagher,et al.  Selective immunotoxic lesions of basal forebrain cholinergic cells: effects on learning and memory in rats. , 1995, Behavioral neuroscience.

[22]  T. Seppänen,et al.  Propofol anesthesia induces phase synchronization changes in EEG , 2001, Clinical Neurophysiology.

[23]  J. Dilger,et al.  Evidence for Direct Actions of General Anesthetics on an Ion Channel Protein: A New Look at a Unified Mechanism of Action , 1994, Anesthesiology.

[24]  Y. Liu,et al.  Interactions of general anaesthetics with single acetylcholine receptor channels. , 1995, European journal of anaesthesiology.

[25]  A. Björklund,et al.  Selective Lesioning of the Basal Forebrain Cholinergic System by Intraventricular 192 IgG–saporin: Behavioural, Biochemical and Stereological Studies in the Rat , 1995, The European journal of neuroscience.

[26]  G. Higgins,et al.  A double dissociation between serial reaction time and radial maze performance in rats subjected to 192 IgG‐saporin lesions of the nucleus basalis and/or the septal region , 2003, The European journal of neuroscience.

[27]  B. Jones.  Activity, modulation and role of basal forebrain cholinergic neurons innervating the cerebral cortex. , 2004, Progress in brain research.

[28]  P Fiset,et al.  Physostigmine reverses propofol-induced unconsciousness and attenuation of the auditory steady state response and bispectral index in human volunteers. , 2000, Anesthesiology.

[29]  T. Kikuchi,et al.  In vivo effects of propofol on acetylcholine release from the frontal cortex, hippocampus and striatum studied by intracerebral microdialysis in freely moving rats. , 1998, British journal of anaesthesia.

[30]  Z. Gu,et al.  Long term changes in brain cholinergic markers and nerve growth factor levels after partial immunolesion , 1998, Brain Research.

[31]  Jingyi Ma,et al.  Limbic System Participates in Mediating the Effects of General Anesthetics , 2006, Neuropsychopharmacology.

[32]  C. Lazarus,et al.  Central cholinergic depletion induced by 192 IgG-saporin alleviates the sedative effects of propofol in rats. , 2000, British journal of anaesthesia.

[33]  P. Cariani.  Anesthesia, Neural Information Processing, and Conscious Awareness , 2000, Consciousness and Cognition.

[34]  R. Galani,et al.  Selective immunolesions of CH4 cholinergic neurons do not disrupt spatial memory in rats , 2002, Physiology & Behavior.

[35]  Tatiana Witjas,et al.  Differential Dynamic of Action on Cortical and Subcortical Structures of Anesthetic Agents during Induction of Anesthesia , 2007, Anesthesiology.

[36]  C. H. Vanderwolf,et al.  Involvement of Direct and Indirect Pathways in Electrocorticographic Activation , 1998, Neuroscience & Biobehavioral Reviews.

[37]  B. H. Bland,et al.  Theta band oscillation and synchrony in the hippocampal formation and associated structures: the case for its role in sensorimotor integration , 2001, Behavioural Brain Research.

[38]  J. Edeline,et al.  Auditory thalamus bursts in anesthetized and non-anesthetized states: contribution to functional properties. , 2004, Journal of neurophysiology.

[39]  C. Lazarus,et al.  Combined lesions of cholinergic and serotonergic neurons in the rat brain using 192 IgG‐saporin and 5,7‐dihydroxytryptamine: neurochemical and behavioural characterization , 2000, The European journal of neuroscience.