Summary
The aim of this review is to summarize the effects of acute and chronic treatment with barbiturates, ethanol and benzodiazepines on cholinergic mechanisms in the brains of experimental animals. A single dose of each of these substances reduces the turnover of ACh in the brain. Long-term treatment has the opposite effect; complicated interactions including decreased content of ACh are induced. Barbiturates have been shown to bind stereospecifically to muscarinic and nicotinic receptors in the brain, but this has not been observed for ethanol or the benzodiazepines. The effects on the cholinergic system are affected by the length of treatment and choice of treatment regimen. No effect on cholinergic parameters, such as muscarinic receptors, in the brain is observed on withdrawal of ethanol or barbiturate treatment when the animals are still tolerant towards the substances. The increase in the number of muscarinic receptors observed in several brain regions on withdrawal is seen as a sign of cholinergic supersensitivity. The number of receptors returns to normal when abstinence convulsions have occurred. The assumption of a cholinergic influence is supported by the finding that atropine, given as a single dose on the day of withdrawal of barbital, can prevent the muscarinic receptor changes. Furthermore, long-term barbital or ethanol treatment can induce permanent persistent changes in the cholinergic system in the brain. Cognitive defects and a significant permanent reduction in the content of ACh can be measured in rats which have had long-term barbital treatment. Similarly, a reduced number of muscarinic receptors has been measured in different brain regions of chronic alcoholics. Accumulating data support the role of the cholinergic system in expressing symptoms of physical dependence on barbiturates, ethanol and benzodiazepines as well as in the permanent long-term effects observed after end of treatment.
Similar content being viewed by others
References
Airaksinen MM, Peura P (1987) Mechanisms of alcohol withdrawal syndrome. Med Biol 65: 105–112
Arendt T, Marchbank R, Gray JA (1987) Effect of prolonged ethanol consumption on cholinergic function in the basal forebrain and memory. Biochem Soc Trans 15: 499–500
Arendt T, Hennig D, Gray JA, Marchbanks R (1988) Loss of neurons in the rat basal forebrain cholinergic projection system after prolonged intake of ethanol. Brain Res Bull 21: 563–570
Arendt T, Allen Y, Marchbank RM, Schugens MM, Sinden J, Lantos PL, Gray JA (1989) Cholinergic system and memory in the rat: effects of chronic ethanol, embryonic basal forebrain transplants and excitotoxic lesions of cholinergic basal forebrain projection system. Neuroscience 33: 435–462
Atweh S, Simon JR, Kuhar MJ (1975) Utilization of sodium-dependent high affinity choline uptake in vitro as a measure of the activity of cholinergic neurons in vivo. Life Sci 17: 1535–1544
Balduini W, Costa LG (1989) Effects of ethanol on muscarinic receptor-stimulated phosphoinositide metabolism during brain development. J Pharmacol Exp Ther 250: 541–547
Bianchi C, Beani L, Bertelli A (1975) Effects of some anti-epileptic drugs on brain acetylcholine. Neuropsychopharmacology 14: 327–332
Bolander HC, Wahlström G (1984) The interaction between atropine and some lipid-soluble barbiturates in rats. Acta Pharmacol Toxicol 54: 81–85
Cappell HD, Sellers EM, Busto U (1986) Benzodiazepines as drugs of abuse and dependence. Res Adv Alcohol Drug Probl 9: 53–126
Carmichael FJ, Israel YJ (1975) Effects of ethanol on neurotransmitter release by rat brain cortical slices. J Pharmacol Exp Ther 193: 824–834
Chan AW, Abel EL (1982) Absence of long-lasting effects on brain receptors for neurotransmitters in rats prenatally exposed to ethanol. Res Commun Subst Abuse 3: 219–224
Collins AC, Burch JB, de Fiebre CM, Marks MJ (1988) Tolerance to and cross-tolerance between ethanol and nicotine. Pharmacol Biochem Behav 29: 365–373
Consolo S, Ladinsky H, Peri G, Garattini S (1974) Effect of diazepam on mouse whole brain area acetylcholine and choline levels. Eur J Pharmacol 27: 266–268
Costa E (1979) The role of gamma-aminobutyric acid in the action of 1,4-benzodiazepines. Trends Pharmacol Sci 1: 41–44
Deitrich RA, Dunwiddie TV, Harris RA, Erwin VG (1989) Mechanisms of action of ethanol: initial central nervous system actions. Pharmacol Rev 41: 489–537
Drachman DA, Leavitt JL (1974) Human memory and the cholinergic system. A relationsship to aging? Arch Neurol 30: 113–121
Dodson BA, Barswell LM, Miller KW (1987) Barbiturates bind to an allosteric regulatory site on nicotinic acetylcholine receptor-rich membranes. Mol Pharmacol 32: 119–126
Dodson BA, Urh RR, Miller KW (1990) Relative potencies for barbiturate binding to the Torpedo acetylcholine receptor. Br J Pharmacol 101: 710–714
Ebel A, Vigran R, Mack G, Durkin T, Mandel P (1979) Cholinergic involvement in ethanol in toxication and withdrawal-induced seizure susceptibility. Psychopharmacology 61: 251–254
Engel J, Liljequist S (1983) The involvement of different central neurotransmitters in mediating stimulatory and sedative effects of ethanol. In: Pohorecky LA, Brick J (eds) Stress and alcohol use. Elsevier Science, Amsterdam, pp 153–169
Erickson CK, Graham DT (1973) Alteration of cortical and reticular acetylcholine release by ethanol in vivo. J Pharmacol Exp Ther 185: 583–593
Freund G, Ballinger W (1988) Loss of cholinergic muscarinic receptors in the frontal cortex of alcohol abusers. Alcohol Clin Exp Res 12: 630–638
Freund G, Ballinger W (1989 a) Loss of muscarinic and benzodiazepine neuroreceptors from hippocampus of alcohol abusers. Alcohol 6: 23–31
Freund G, Ballinger W (1989 b) Neuroreceptor changes in the putamen of alcohol abusers. Alcohol Clin Exp Res 13: 213–218
George FR (1987) Genetic and environmental factors in ethanol self-administration. Pharmacol Biochem Behav 27: 379–384
Haefely WE (1983) Tranquillizers. In: Graham-Smith DG, Cowen PJ (eds) Tranquillizers in psychopharmacology, part 1. Preclinical psychopharmacology. Exerpta Medica, Amsterdam, pp 107–151
Haefely W (1986) Biological basis of drug-induced tolerance, rebound, and dependence. Contribution of recent research on benzodiazepines. Pharmacopsychiatry 19: 353–361
Hellström-Lindahl E, Winblad B, Nordberg A (1992) Muscarinic and nicotinic receptors in the cortex and thalamus of brains of chronic alcoholics. Alcohol and Alcoholism (submitted)
Himmelsbach CK (1943) IV. With reference to physical dependence. Fed Proc 2: 201–203
Ho IK, Harris RA (1981) Mechanism of action of barbiturates. Annu Rev Pharmacol Toxicol 21: 83–111
Hoffman PL, Tabakoff B (1985) Ethanol's action on brain biochemistry. In: Tarter R, Van-Tiel DH (eds) Alcohol and the brain, chronic effects. Plenum Medical Book Company, New York, pp 19–68
Hoffman PL, Moses F, Luthin GR, Tabakoff B (1986) Acute and chronic effects of ethanol on receptor-mediated phosphatidylinositol 4,5-biphosphate breakdown in mouse brain. Mol Pharmacol 31: 13–18
Hoffman PL, Rabe CS, Moses F, Tabakoff B (1989) N-methyl-D-aspartate receptors and ethanol: inhibition of calcium flux and cyclic GMP production. J Neurochem 52: 1937–1940
Hoffman PL, Rabe CS, Grant KA, Valverius P, Hudspith M, Tabakoff B (1990) Ethanol and the NMDA receptor. Alcohol 7: 229–231
Hunt WA (ed) (1985) Alcohol and biological membranes. The Guildford Press, New York
Hunt WA, Dalton TK (1976) Regional brain acetylcholine levels in rats acutely treated with ethanol or rendered ethanol dependent. Brain Res 109: 628–631
Hunt WA, Majchrowicz E, Dalton TK (1979) Alterations in high-affinity choline uptake in brain after acute and chronic ethanol treatment. J Pharmacol Exp Ther 210: 259–263
Jope RJ, Jenden DJ (1981) Effects of acute ethanol treatment on cholinergic functions in rats. Substances Alcohol Actions/Misuses 2: 15–23
Kalant H (1985) Tolerance, learning and neurochemical adaptation. Can J Physiol Pharmacol 63: 1483–1494
Kelly SJ, Black AC, West JR (1989) Changes in the muscarinic cholinergic receptors in the hippocampus of rats exposed to ethyl alcohol during the brain growth spurt. J Pharmacol Exp Ther 249: 798–804
Koob G, Bloom F (1988) Cellular and molecular mechanisms of drug dependence. Science 242: 715–723
Kuriyama K, Ohkuma S (1990) Alteration in the function of cerebral neurotransmitter receptors during the establishment of alcohol dependence: neurochemical aspects. Alcohol and Alcoholism 25: 239–249
Lader MH (1987) Benzodiazepine dependence. ISI Atlas Science: Pharmacology 1: 299–302
Lader M (1988) The psychopharmacology of addiction — benzodiazepine tolerance and dependence. In: Lader M (ed) The psychopharmacology of addiction. Oxford University Press, Oxford New York Yokyo, pp 1–14
Lerer B, Stanley M, McIntyre I, Altman H (1984) Electroconvulsive shock and brain muscarinic receptors: relationship to anterograde amnesia. Life Sci 35: 2659–2664
Light K, Serbus DC, Santiago M (1989) Exposure of rats of ethanol from postnatal day 4 to 8: alteration of cholinergic neurochemistry in the cerebral cortex and corpus striatum at day 20. Alcohol Clin Exp Res 13: 29–35
Lovinger DM, White G, Weight FF (1989) Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243: 1721–1724
Marks J (ed) (1978) The benzodiazepines. Use, overuse, misuse, abuse. MTP Ltd, Lancaster
McBridge A, Turnbull MJ (1970) The brain acetylcholine system in barbitone-dependent and withdrawn rats. Br J Pharmacol 39: 210
McNamara JO (1978) Muscarinic cholinergic receptors participate in the kindling model of epilepsy. Brain Res 154: 415–420
Mohammed AK, Wahlström G, Tiger G, Björklund PE, Stenström A, Magnusson O, Archer T, Fowler CJ, Nordberg A (1987) Impaired performance of rat in the Morris swim-maze test late in abstinence following long-term sodium barbital treatment. Drug Alcohol Depend 20: 203–213
Mohammed AK, Wahlström G, Archer T, Nordberg A (1990) Learning deficits in aged rats pretreated chronically with barbital and tested late in abstinence: alleviation by tetrahydroaminoacridine. J Neural Transm (P-D Sect) 2: 285–294
Muller P, Britton R, Seeman P (1980) The effects of long-term ethanol on brain receptors for dopamine, acetylcholine, serotonin and noradrenaline. Eur J Pharmacol 65: 31–37
Murphy SM, Tyrer P (1988) The essence of benzodiazepine dependence in the psychopharmacology of addiction. In: Lader L (ed) The pharmacology of addiction. Oxford University Press, Oxford New York Tokyo, pp 157–167
Nabeshima T, Tohyama K, Ichiara K, Kameyama T (1990) Effect of benzodiazepines on passive avoidance response and latent learning in mice: relationship to benzodiazepine receptors and the cholinergic neuronal system. J Pharmacol Exp Ther 255: 789–794
Nilvebrant L, Sparf B (1986) Dicyclamine, benzenol and oxybutynine distinguish between subclasses of muscarinic binding sites. Eur J Pharmacol 123: 133–143
Nio E, Kogure K, Yae T, Onodera H (1991) The effects of maternal ethanol exposure on neurotransmission and second messenger system: a quantitative autoradiographic study in the rat brain. Dev Brain Res 62: 51–60
Norberg L, Wahlström G (1986) Interactions between hexobarbital and thiopental in male rats evaluated with anaesthesia threshold. Acta Pharmacol Toxicol 58: 96–104
Nordberg A, Sundwall A (1975) Effect of pentobarbital on endogenous acetylcholine and biotransformation of radioactive choline in different brain regions. In: Waser PG (ed) Cholinergic mechanisms. Raven Press, New York, pp 229–239
Nordberg A, Sundwall A (1977) Effect of sodium pentobarbital on the apparent turnover of acetylcholine in different brain regions. Acta Physiol Scand 99: 336–344
Nordberg A, Wahlström G (1977) Effect of long-term forced oral barbital administration on endogenous acetylcholine in different regions of rat brain. Eur J Pharmacol 43: 237–242
Nordberg A, Wahlström G (1979) Regional biosynthesis of acetylcholine in brain following oral chronic barbitone treatment of rat. J Neurochem 32: 371–378
Nordberg A, Wahlström G (1980) Changes in cholinergic function in brain late in the abstinence after chronic barbital treatment to rat. Drug Alcohol Depend 7: 51–61
Nordberg A, Wahlström G (1982 a) Atropine modulates changes in striatal muscarinic receptor binding sites in barbital abstinence in the rat. Acta Physiol Scand 115: 369–371
Nordberg A, Wahlström G (1982 b) Changes in populations of cholinergic binding sites in brain after exposure to barbital in rats. Brain Res 246: 105–112
Nordberg A, Wahlström G (1982 c) Tolerance, physical dependence and changes in muscarinic receptor binding sites after chronic ethanol treatment in the rat. Life Sci 31: 277–287
Nordberg A, Wahlström G (1984) Different interactions of steric isomers of hexobarbital to muscarinic agonist and antagonist binding sites in brain. Brain Res 310: 189–192
Nordberg A, Adolfsson R, Aquilonius S-M, Marklund S, Oreland L, Winblad B (1980) Brain enzymes and acetylcholine receptors in senile dementia of Alzheimer type and chronic alcohol abuse. In: Amaducci L, Davison AN, Antuono P (eds) Aging of the brain and dementia, vol 13. Raven Press, New York, pp 169–171
Nordberg A, Wahlström G, Larsson C (1980) Increased number of muscarinic binding sites in brain following chronic barbital treatment. Life Sci 26: 231–237
Nordberg A, Larsson C, Perdahl E, Winblad B (1982) Cholinergic activity in hippocampus in chronic alcoholism. Drug Alcohol Depend 10: 333–344
Nordberg A, Wahlström G, Eriksson B (1985) Relation between muscimol, quinuclidinyl benzilate and nicotine binding sites in brain after very long treatment with ethanol in rats. Eur J Pharmacol 115: 301–304
Nordberg A, Wahlström C, Eriksson B (1986)3H-muscimol and3H-quinuclidinyl benzilate binding in rat cortex in the abstinence after long-term treatment. Acta Physiol Scand 126: 153–156
Nordberg A, Fuxe K, Holmstedt B, Sundwall A (eds) (1989 a) Nicotinic receptors in the CNS-their role in synaptic transmission. Prog Brain Res 79: 3–366
Nordberg A, Zhang X, Fredriksson A, Eriksson P (1991) Neonatal nicotine exposure induces permanent changes in brain nicotinic receptors and behaviour in adult mice. Dev Brain Res 63: 201–207
Nordgren I, Lundgren G, Karlén B (1987) Effects of diazepam on muscarinic acetylcholine receptor binding in vivo and on oxotremorine-induced tremor and hypothermia in mice. Pharmacol Toxicol 60: 258–261
Parker TH, Roberts RK, Henderson GI, Hoyumpa AM, Schmidt DE, Schenker S (1978) The effects of ethanol on cerebral regional acetylcholine concentration and utilization. Proc Soc Exp Biol Med 159: 270–275
Pelham RW, Marquis JK, Kugelman K, Munsat TL (1980) Prolonged ethanol consumption produces persistent alterations of cholinergic function in rat brain. Alcohol Clin Exp Res 4: 282–287
Phillis JW, Jhamandas K (1971) The effect of chlorpromazine and ethanol on in vivo release of acetylcholine from the cerebral cortex. Comp Gen Pharmacol 2: 306–310
Pietrzak ER, Wilce PA, Shanley BC (1988) The effect of chronic ethanol consumption on muscarinic receptors in rat brain. Neurochem Int 12: 447–452
Pietrzak ER, Wilce PA, Shanley BC (1990 a) Effects of chronic ethanol treatment and aging on brain phosphoinositide turnover and adenylate cyclase activity. Neurochem Int 17: 593–598
Pietrzak ER, Wilce PA, Shanley BC (1990 b) Interaction of chronic ethanol consumption and aging on brain muscarinic cholinergic receptors. J Pharmacol Exp Ther 252: 869–874
Popova JS, Petkov VV (1990) Effect of the combination of the benzodiazepine tranquilizer medazepam and the neotropic agent meclotenoxate on the activity of rat brain muscarinic receptors. Gen Pharmacol 21: 927–930
Popova J, Petkov VV, Tokuschieva L (1988) The effect of chronic diazepam and medazepam treatment on the number and affinity of muscarinic receptors in different rat brain structures. Gen Pharmacol 19: 227–231
Rabin RA, Wolfe BB, Dibner MD, Zahniser NR, Melchior C, Molinoff PB (1980) Effect of ethanol administration and withdrawal on neurotransmitter receptor systems in C57 mice. J Pharmacol Exp Ther 213: 491–496
Rawat AK (1974) Brain levels and turnover rates of presumptive neurotransmitters as influenced by administration and withdrawal of ethanol in mice. J Neurochem 22: 915–922
Rawat AK (1977) Developmental changes in the brain levels of neurotransmitters as influenced by maternal ethanol consumption in the rat. J Neurochem 28: 1175–1182
Serbus PC, Stull RE, Light KE (1986) Neonatal ethanol exposure to rat pups: result and alterations of cortical muscarinic and cerebellar H1histaminergic receptor binding dynamics. Neurotoxicology 7: 257–278
Skolnick P, Paul StM (1981) The mechanism(s) of action of the benzodiazepines. Med Res Rev 1: 3–22
Smith TL (1983) Influence of chronic ethanol consumption on muscarinic cholinergic receptors and their linkage to phospholipid metabolism in mouse synaptosomes. Neuropharmacology 22: 661–663
Smith TL (1987) Chronic ethanol consumption reduced3H-inositol (1,4,5) triphosphate specific binding in mouse cerebellar membrane fragments. Life Sci 41: 2863–2868
Smith TL, Yamamura HI, Lee I (1986) Effect of ethanol on receptor-stimulated phosphatidic acid and polyphosphoinositide metabolism in mouse brain. Life Sci 39: 1675–1684
Smyth RD, Beck H (1969) The effect of time and concentration of ethanol administration on brain acetylcholine metabolism. Arch Int Pharmacodyn Ther 182: 295–299
Syvälahti EKG, Hietala J, Röyttä M, Grönroos J (1988) Decrease in the number of rat brain dopamine and muscarinic receptors after chronic alcohol intake. Pharmacol Toxicol 62: 210–212
Tabakoff B, Hoffman PL (1987) Biochemical pharmacology of alcohol. In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, pp 1521–1526
Tabakoff B, Munoz-Marcus M, Fields JZ (1979) Chronic ethanol feeding produces an increase in muscarinic cholinergic receptors in mouse brain. Life Sci 25: 2173–2180
Wahlström G (1968) Hexobarbital (enhexymalum NFN) sleeping times and EEG threshold doses as measurements of tolerance to barbiturates in the rat. Acta Pharmacol Toxicol 26: 64–80
Wahlström G (1974) Withdrawal in the rat after longterm forced oral barbital administration. Acta Pharmacol Toxicol 35: 131–144
Wahlström G (1976 a) The interaction between pilocarpine and hexobarbital in male rats. Psychopharmacology 49: 159–166
Wahlström G (1976 b) The interaction between hexobarbital and atropine or methylatropine in male rats. Acta Pharmacol Toxicol 38: 72–80
Wahlström G (1976 c) The interaction between spontaneous convulsions and tolerance to hexobarbital in the abstinence period after chronic barbital treatment in the rat. Life Sci 19: 1817–1826
Wahlström G (1977) The interaction between physostigmine and hexobarbital in male rats. Acta Pharmacol Toxicol 41: 289–297
Wahlström G (1978) The effects of atropine on the tolerance and the convulsions seen after withdrawal from forced barbital drinking in the rat. Psychopharmacology 59: 123–128
Wahlström G (1979) Some aspects of the changes induced by chronic barbital treatments in the male rats. Drug Alcohol Depend 4: 221–233
Wahlström G (1980) Atropine in the abstinence after chronic treatment in the rat. Pharmacol Biochem Behav 13 [Suppl 1]: 249–255
Wahlström G (1983) Interaction between spontaneous and electrically induced convulsions and their short- and long-term effects in the abstinence after chronic barbital treatment in the rat. Brain Res 266: 225–232
Wahlström G (1987) Ethanol exposure as inducer of stable voluntary ethanol drinking in the male rat. Alcohol Drug Depend 20: 105–114
Wahlström G, Ekwall T (1976) Tolerance to hexobarbital and supersensitivity to pilocarpine after chronic barbital treatment in the rat. Eur J Pharmacol 38: 123–129
Wahlström G, Nordberg A (1978) Decreased brain weights in rats after long-term barbital treatments. Life Sci 23: 1583–1590
Wahlström G, Norberg L (1984) A comparative investigation in the rat of the anesthetic effects of the isomers of two barbiturates. Brain Res 310: 261–267
Wahlström G, Nordberg A (1987) Studies of stable voluntary intake of ethanol induced by intermittent ethanol exposures. Alcohol and Alcoholism [Suppl 1]: 367–371
Wahlström G, Nordberg A (1988) Relation between voluntary ethanol intake in rats and changes in striatal muscarinic binding sites seen after induction of stable ethanol intake by an intermittent ethanol treatment. Brain Res 474: 189–191
Wigell AH, Overstreet DH (1984) Acquisition of behaviourally augmented tolerance to ethanol and its relationship to muscarinic receptors. Phsychopharmacology 83: 88–92
Wood JH, Katz JL, Winger G (1987) Abuse liability of benzodiazepines. Pharmacol Rev 39: 251–413
Yoshida K, Engel J, Liljequist S (1982) The effect of chronic ethanol administration on high affinity3H-nicotinic binding in rat brain. Naunyn-Schmiedbergs Arch Pharmacol 321: 74–76
Zhang X, Eriksson P, Fredriksson A, Nordberg A (1990) Influences of neonatal nicotine exposure on development of nicotinic receptor subtypes in brain and behaviour in adult mice. In: Adlkofer F, et al (eds) Effects of nicotine on biological systems. Advances of pharmacological sciences. Birkhäuser, Basel, pp 455–459
Zsilla G, Cheney PL, Costa E (1976) Regional change in the rate of turnover of acetylcholine in rat brain following diazepam or muscimol. Naunyn-Schmiedebergs Arch Pharmacol 294: 251–255
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nordberg, A., Wahlström, G. Cholinergic mechanisms in physical dependence on barbiturates, ethanol and benzodiazepines. J. Neural Transmission 88, 199–221 (1992). https://doi.org/10.1007/BF01244733
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01244733