Abstract
Acetyl-L-carnitine (ALCAR) is the acetyl ester of carnitine that has been reported to be beneficial in depressive disorders and Alzheimer's disease. A 7-day administration of ALCAR in rats increased dopamine and serotonin output in the nucleus accumbens shell and it prevented the development of escape deficit produced by acute exposure to unavoidable stress. No tolerance developed to this protective effect, which appeared to be mediated by (1) the activation of 5-HT1A receptors, as it was antagonized by the administration of WAY100635 30 min before stress exposure; and (2) a process of neuronal plasticity dependent on NMDA receptor activity, as subcutaneous dizocilpine infusion during ALCAR treatment prevented the development of the protective effect on stress. Chronic stress exposure maintains an escape deficit condition that is reverted by a long-term treatment with antidepressants, but the same condition was not modified by long-term ALCAR administration. Thus, ALCAR cannot be defined as an antidepressant.
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
Angelucci L, Ramacci MT . (1989): Hypothalamo-pituitaryadrenocortical function in aging: effects of acetyl-L-carnitine. In De Simone C, Arrigoni-Martelli E (eds), Stress, immunity and ageing: a role for acetyl-L-carnitine. Amsterdam, Elsevier, pp 109–118
Arduini A, Gorbunov N, Arrigoni-Martelli E, Dottori S, Molajoni F, Russo F, Federici G . (1993): Effects of L-carnitine and its acetate and propionate esters on the molecular dynamics of human erythrocyte membrane. Biochim Biophys Acta 1146: 229–235
Aureli T, Miccheli A, Ricciolini R, Di Cocco ME, Ramacci MT, Angelucci L, Ghirardi O, Conti F . (1990): Aging brain: Effect of acetyl-L-carnitine treatment on rat brain energy and phospholipid metabolism. A study by 31P and 1H NMR spectroscopy. Brain Res 526: 108–112
Bell JG, Sargent JR, Tocher DR, Dick JR . (2000): Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders? Prostaglandins Leukot Essent Fatty Acids 63: 21–25
Bella R, Bondi R, Raffaele R, Pennisi G . (1990): Effect of acetyl-L-carnitine on geriatric patients suffering from dysthymic disorders. Int J Clin Pharmacol Res 10: 355–360
Bidzinska B, Petraglia F, Angioni S, Genazzani AD, Criscuolo M, Ficarra G, Gallinelli A, Trentini GP, Genazzani AR . (1993): Acetyl-L-carnitine effect on pituitary and plasma β-endorphin responsiveness to different chronic intermittent stressors. J Neuroendocrinol 5: 151–155
Bieber LL . (1988): Carnitine. Annu Rev Biochem 57: 261–283
Bliss EL, Ailion J, Zwanzinger J . (1968): Metabolism of norepinephrine, serotonin and dopamine in the rat brain with stress. J Pharmacol Exp Ther 164: 122–134
Blokland A, Bothmer J, Honig W, Jolles J . (1993): Behavioral and biochemical effects of acute central metabolic inhibition: effects of acetyl-L-carnitine. Eur J Pharmacol 235: 275–281
Bresolin N, Freddo L, Vergani L, Angelini C . (1982): Carnitine, carnitine acyltransferases, and rat brain function. Exp Neurol 78: 285–292
Butterfield DA, Rangachari A . (1993): Acetylcarnitine increases membrane cytoskeletal protein-protein interactions. Life Sci 52: 297–303
Chaouloff F . (2000): Serotonin, stress and corticoids. J Psychopharmacol 14: 139–151
Courzon G . (1971): Effects of adrenal hormones and stress on brain serotonin. Am J Clin Nutr 24: 830–834
D'Amour FE, Smith DL . (1941): A method for determining loss of pain sensation. J Pharmacol Exp Ther 72: 74–79
De Montis MG, Gambarana C, Ghiglieri O, Tagliamonte A . (1995): Reversal of stable behavioural modifications through NMDA receptor inhibition in rats. Behav Pharmacol 6: 562–567
Di Chiara G, Imperato A . (1988): Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85: 5274–5278
Di Chiara G, Tanda G . (1997): Blunting of reactivity of dopamine transmission to palatable food: a biochemical marker of anhedonia in the CMS model? Psychopharmacology (Berl) 112: 398–402
Di Chiara G, Loddo P, Tanda G . (1999): Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression. Biol Psychiatry 46: 1624–1633
Doherty MD, Gratton A . (1996): Medial prefrontal cortical D1 receptor modulation of the meso-accumbens dopamine response to stress: an electrochemical study in freely-behaving rats. Brain Res 715: 86–97
Dziedzicka-Wasylewska M, Willner P, Papp M . (1997): Changes in dopamine receptor mRNA expression following chronic mild stress and chronic antidepressant treatment. Behav Pharmacol 8: 607–618
Fariello RG, Ferraro TN, Golden GT, Demattei M . (1988): Systemic acetyl-carnitine elevates nigral levels of glutathione and GABA. Life Sci 43: 289–292
Farrel S, Vogel J, Bieber LL . (1986): Entry of acetyl-L-carnitine into biosynthetic pathways. Biochim Biophys Acta 876: 175–177
Finlay JM, Zigmond MJ, Abercrombie ED . (1995): Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam. Neuroscience 64: 619–928
Foreman PJ, Perez-Polo JR, Angelucci L, Ramacci MT, Taglialatela G . (1995): Effects of acetyl-L-carnitine treatment and stress exposure on the nerve growth factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats. Prog Neuropsychopharmacol Biol 19: 117–133
Forster EA, Cliffe IA, Bill DJ, Dover GM, Jones D, Reilly J, Fletcher A . (1995): A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY100635. Eur J Pharmacol 281: 81–88
Fritz IB . (1963): Carnitine and its role in fatty acid metabolism. Adv Lip Res 1: 285–333
Galli G, Fratelli M . (1993): Activation of apoptosis by serum deprivation in a teratocarcinoma cell line: inhibition by L-acetylcarnitine. Exp Cell Res 204: 54–60
Gambarana C, Ghiglieri O, Taddei I, Tagliamonte A, De Montis MG . (1995a): Imipramine and fluoxetine prevent the stress-induced escape deficits in rats through a distinct mechanism of action. Behav Pharmacol 6: 66–73
Gambarana C, Ghiglieri O, Tagliamonte A, D'Alessandro N, De Montis MG . (1995b): Crucial role of D1 dopamine receptors in mediating the antidepressant effect of imipramine. Pharmacol Biochem Behav 50: 147–151
Gambarana C, Masi F, Tagliamonte A, Scheggi S, Ghiglieri O, De Montis MG . (1999a): A chronic stress which impairs reactivity in rats also decreases dopaminergic transmission in the nucleus accumbens: a microdialysis study. J Neurochem 72: 2039–2046
Gambarana C, Ghiglieri O, Masi F, Scheggi S, Tagliamonte A, De Montis MG . (1999b): The effects of long-term administration of rubidium or lithium on reactivity to stress and on dopamine output in the nucleus accumbens in rats. Brain Res 826: 200–209
Gambarana C, Ghiglieri O, Tolu P, De Montis MG, Giachetti D, Bombardelli E, Tagliamonte A . (1999c): Efficacy of an Hypericum perforatum (St. John's wort) extract in preventing and reverting a condition of escape deficit in rats. Neuropsychopharmacol 21: 247–257
Gambarana C, Scheggi S, Tagliamonte A, Tolu P, De Montis MG . (2001): Animal models for the study of antidepressant activity. Brain Res Prot 7: 11–20
Garzya G, Corallo D, Fiore A, Lecciso G, Petrelli G, Zotti C . (1990): Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Exp Clin Res 16: 101–106
Ghiglieri O, Gambarana C, Scheggi S, Tagliamonte A, Willner P, De Montis MG . (1997): Palatable food induces an appetitive behaviour in satiated rats which can be inhibited by chronic stress. Behav Pharmacol 8: 619–628
Ghirardi O, Milano S, Ramacci MT, Angelucci R . (1988): Effect of acetyl-L-carnitine chronic treatment on discrimination models in aged rats. Physiol Behav 44: 769–773
Harsing LG, Sershen H, Toth E, Hashim A, Ramacci MT, Lajtha A . (1992): Acetyl-L-carnitine releases dopamine in rats corpus striatum: an in vivo microdialysis study. Eur J Pharmacol 218: 117–121
Hurd Y, Ungerstedt U . (1989): Cocaine: an in vivo microdialysis evaluation of its acute action on dopamine transmission in rat striatum. Synapse 3: 48–54
Kalivas PW, Duffy P . (1995): Selective activation of dopamine transmission in the shell of the nucleus accumbens by stress. Brain Res 675: 325–328
Kaneyuki H, Yokoo H, Tsuda A, Yoshida M, Mizuki Y, Yamada M, Tanaka M . (1991): Psychological stress increases dopamine turnover selectively in mesoprefrontal dopamine neurons in rats: reversal by diazepam. Brain Res 557: 154–161
Kirkby DL, Jones DN, Barnes JC, Higgins GA . (1996): Effects of anticholinesterase drugs tacrine and E2020, the 5-HT3 antagonist ondansentron, and the H3 antagonist thioperamide, in models of cognition and cholinergic function. Behav Pharmacol 7: 513–525
Konstandi M, Johnson E, Lang MA, Malamas M, Marselos M . (2000): Noradrenaline, dopamine, serotonin: different effects of psychological stress on brain biogenic amines in mice and rats. Pharmacol Res 41: 341–346
Kuratsune H, Watanabe Y, Yamaguti K, Jacobsson G, Takahashi M, Machii T, Onoe H, Onoe K, Matsumura K, Valind S, Kitani T, Längström B . (1997): High uptake of [2-11C]acetyl-L-carnitine into the brain: a PET study. Biochem Biophys Res Commun 231: 488–493
Liu Y, Rosenthal RE, Stark-Reed P, Fiskum G . (1993): Inhibition of postcardiac arrest brain protein oxidation by acetyl-L-carnitine. Free Radic Biol Med 15: 667–670
Mangiavacchi S, Masi F, Scheggi S, Leggio B, De Montis MG, Gambarana C . (2001): Long-term behavioral and neurochemical effects of chronic stress exposure in rats. J Neurochem 78: 1–10
Maudhuit C, Prevot E, Dangoumau L, Martin P, Hamon M, Adrien J . (1997): Antidepressant treatment in helpless rats: effect on the electrophysiological activity of raphe dorsalis serotonergic neurons. Psychopharmacology (Berl) 130: 269–275
Meloni D, Gambarana C, De Montis MG, Dal Prá P, Taddei I, Tagliamonte A . (1993): Dizocilpine antagonizes the effect of chronic imipramine on learned helplessness in rats. Pharmacol Biochem Behav 46: 423–426
Moreau JL, Jenck F, Martin JR, Mortas P, Haefely WE . (1992): Antidepressant treatment prevents chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmentum self-stimulation behavior in rats. Eur Neuropsychopharmacol 2: 43–49
Muscat R, Sampson D, Willner P . (1990): Dopaminergic mechanism of imipramine action in an animal model of depression. Biol Psychiatry 28: 223–230
Muscat R, Papp M, Willner P . (1992): Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline. Psychopharmacology (Berl) 109: 433–438
Overmier JB, Seligman MEP . (1967): Effects of inescapable shock upon subsequent escape and avoidance learning. J Comp Physiol Psychol 63: 23–33
Pani L, Porcella A, Gessa GL . (2000): The role of stress in the pathophysiology of the dopaminergic system. Mol Psychiatry 5: 14–21
Papp M, Willner P, Muscat R . (1991): An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology (Berl) 104: 255–259
Papp M, Klimek V, Willner P . (1994): Parallel changes in dopamine D2 receptor binding in limbic forebrain associated with chronic mild stress-induced anhedonia and its reversal by imipramine. Psychopharmacology (Berl) 115: 441–446
Papp M, Moryl E, Willner P . (1996): Pharmacological validation of the chronic mild stress model of depression. Eur J Pharmacol 296: 129–136
Parnetti L, Gaiti A, Mecocci P, Cadini D, Senin U . (1997): Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer type. Eur J Clin Pharmacol 42: 89–93
Pascale A, Milano S, Corsico N, Lucchi L, Battaini F, Arrigoni Martelli E, Trabucchi M, Govoni S . (1994): Protein kinase C activation and anti-amnesic effect of acetyl-L-carnitine: in vitro and in vivo studies. Eur J Pharmacol 265: 1–7
Patacchioli FR, Amenta R, Ramacci MT, Taglialatela G, Maccari S, Angelucci L . (1989): Acetyl-L-carnitine reduces the age-dependent loss of glucocorticoid receptors in the rat hippocampus: an autoradiographic study. J Neurosci Res 23: 462–466
Paxinos G, Watson C . (1986): The rat brain in stereotaxic coordinates. New York, Academic Press
Pettegrew J, Klunk W, Panchalingam K, Kanfer JN, McClure RJ . (1995): Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease. Neurobiol Aging 16: 1–4
Pettegrew JW, Levine J, McClure RJ . (2000): Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer's disease and geriatric depression. Mol Psychiatry 5: 616–632
Petty F, Kramer G, Wilson L . (1992): Prevention of learned helplessness: in vivo correlation with cortical serotonin. Pharmacol Biochem Behav 43: 361–367
Petty F, Kramer G, Wilson L, Jordan S . (1994): In vivo serotonin release and learned helplessness. Psychiatry Res 52: 285–293
Prickaerts J, Blokland A, Honig W, Meng F, Jolles J . (1995): Spatial discrimination learning and choline acetyltransferase activity in streptozocin-treated rats: effects of chronic treatment with acetyl-L-carnitine. Brain Res 674: 142–146
Rao KV, Mawal YR, Qureshi IA . (1997): Progressive decrease of cerebral cytochrome C oxidase activity in sparse-fur mice: role of acetyl-L-carnitine in restoring the ammonia-induced cerebral energy depletion. Neurosci Lett 224: 83–86
Richardson AJ, Ross MA . (2000): Fatty acid metabolism in neurodevelopmental disorder: a new perspective on associations between attention-deficit/hyperactivity disorder, dyslexia, dyspraxia and the autistic spectrum. Prostaglandins Leukot Essent Fatty Acids 63: 1–9
Richardson AJ, Puri BK . (2000): The potential role of fatty acids in attention-deficit/hyperactivity disorder. Prostaglandins Leukot Essent Fatty Acids 63: 79–87
Rosenthal RE, Williams R, Bogaert YE, Getson PR, Fiskum G . (1992): Prevention of postischemic canine neurological injury through potentiation of brain energy metabolism by acetyl-L-carnitine. Stroke 23: 1312–1318
Rouge-Pont F, Piazza PV, Kharouby M, Le Moal M, Simon H . (1993): Higher and longer stress-induced increase in dopamine concentrations in the nucleus accumbens of animals predisposed to amphetamine self-administration. A microdialysis study. Brain Res 602: 169–174
Sorg BA, Kalivas PW . (1993): Effects of cocaine and footshock stress on extracellular dopamine levels in the medial prefrontal cortex. Neuroscience 53: 695–703
Tempesta E, Janiri L, Pirrongelli C . (1985): Stereospecific effects of acetylcarnitine on the spontaneous activity of brainstem neurones and their response to acetylcholine and serotonin. Neuropharmacology 24: 43–50
Tidey JW, Miczek KA . (1996): Social defeat stress selectively alters mesocorticolimbic dopamine release: an in vivo microdialysis study. Brain Res 721: 140–149
Villa RF, Turpeenoja L, Benzi G, Giuffrida SM . (1988): Action of L-acetylcarnitine on age-dependent modifications of mitochondrial membrane proteins from rat cerebellum. Neurochem Res 13: 909–916
Willner P . (1997): Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology (Berl) 134: 319–329
Yoshioka M, Matsumoto M, Togashi H, Saito H . (1996): Effect of conditioned fear stress on dopamine release in the rat prefrontal cortex. Neurosci Let 209: 201–203
Acknowledgements
This research was supported by a grant from the University of Siena (PAR 2000). The authors wish to thank Ms. Colleen Pisaneschi for editing the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tolu, P., Masi, F., Leggio, B. et al. Effects of Long-term Acetyl-L-carnitine Administration in Rats: I. Increased Dopamine Output in Mesocorticolimbic Areas and Protection toward Acute Stress Exposure. Neuropsychopharmacol 27, 410–420 (2002). https://doi.org/10.1016/S0893-133X(02)00306-8
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(02)00306-8
Keywords
This article is cited by
-
Use of Acetyl-L-Carnitine in Gerontological Practice
Neuroscience and Behavioral Physiology (2019)
-
Acetyl-l-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats
Molecular Neurobiology (2018)
-
ALCAR Exerts Neuroprotective and Pro-Neurogenic Effects by Inhibition of Glial Activation and Oxidative Stress via Activation of the Wnt/β-Catenin Signaling in Parkinsonian Rats
Molecular Neurobiology (2016)
-
Antidepressant-like effect of artemin in mice: a mechanism for acetyl-l-carnitine activity on depression
Psychopharmacology (2011)
-
Acetyl-l-carnitine reduces impulsive behaviour in adolescent rats
Psychopharmacology (2004)
