Cover Image

Baclofen Reversed the Nicotine-Induced Anxiety-Like Behavior: A Beneficial Therapeutic Strategy for Smoking Cessation Aid

Batool Ghorbani yekta, Mobina Kordeforushani, Hoda Aryan

Background: Nicotine dependence is the most widespread form of substance abuse. Anxiety is one of the prominent symptoms in withdrawal syndromes of nicotine. Nucleus Accumbens (NAc) is a principle area which participates in several behavioral responses (e.g., anxiety), and several studies reported that receptors are involved in the modulation of anxiety. This study was aimed to examine the interaction of baclofen and nicotine on anxiety behavior in NAc shell. Materials and Methods: Rats weighing between 220 and 250g were used. The guide cannulas were implanted bilaterally into the shell of the NAc. Nicotine (0.025, 0.05 and 0.5 μg/rat) and baclofen (0.25, 0.5 and 2 μg/rat) and the co-administration of nicotine (0.025, 0.05 and 0.5μg/rat) with baclofen (0.25 μg/rat) were microinjected through the infusion cannula. The elevated plus-maze (EPM) was used to evaluate the anxiety-like parameters, and all data were recorded and analyzed. Results: Intra-NAc administration of nicotine (0.5μg/rat) decreased anxiety (P<0.001). Microinjections of baclofen (0.5 and 2 μg/rat) decreased anxiety (P< 0.001). However, there were no significant changes in anxiety-like parameters at the lowest dose of baclofen (0.25μg/rat). Co-administration of an ineffective dose of baclofen (0.25 μg/rat) with 3 doses of nicotine (0.025, 0.05 and 0.5 μg/rat) reversed the effects of nicotine in an effective dose (0.5μg/rat). Conclusion: Our result indicated that GABAergic agonist baclofen in ineffective doses could reverse the effects of nicotine on anxiety symptoms. Furthermore, our result suggested that enhancement of GABA transmission through activation of GABA-B receptors on NAc shell could reverse nicotine anxiety-related effects. It may be a strategy of treatment for smoking cessation aid.[GMJ.2017;6(2):118-27]

Nicotine; Baclofen; Smoking Cessation Aid; GABA-B Receptor Agonists

Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet (London, England). 1997;349(9064):1498-504.

Lee PR, Satcher D, Elders MJ. Special Report: Preventing Tobacco Use among Young People. A Report of the Surgeon General, 1994. Executive Summary. Tobacco Control. 1994:176-84.

Anthony JC, Warner LA, Kessler RC. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Experimental and clinical psychopharmacology. 1994;2(3):244.

Schuckit M, Helzer J, Cottler L, Crowley T, Nathan P, Woody G. Nicotine use disorder: Nicotine dependence. American Psychiatric Association DSM-IV, Diagnostic and Statistical Manual of Mental Disorders. 1994:243-7.

Kassel JD, Unrod M. Smoking, anxiety, and attention: support for the role of nicotine in attentionally mediated anxiolysis. J Abnorm Psychol. 2000;109(1):161-6.

Abercrombie ED, Keefe KA, DiFrischia DS, Zigmond MJ. Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex. J Neurochem. 1989;52(5):1655-8.

Jerlhag E, Engel JA. Ghrelin receptor antagonism attenuates nicotine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice. Drug Alcohol Depend. 2011;117(2-3):126-31.

Groenewegen HJ, Wright CI, Beijer AV. The nucleus accumbens: gateway for limbic structures to reach the motor system? Prog Brain Res. 1996;107:485-511.

Zahm DS, Brog JS. On the significance of subterritories in the "accumbens" part of the rat ventral striatum. Neuroscience. 1992;50(4):751-67.

Mombereau C, Kaupmann K, Froestl W, Sansig G, van der Putten H, Cryan JF. Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior. Neuropsychopharmacology. 2004;29(6):1050-62.

Varani AP, Pedron VT, Bettler B, Balerio GN.

Involvement of GABAB receptors in biochemical alterations induced by anxiety-related responses to nicotine in mice: genetic and pharmacological approaches. Neuropharmacology. 2014;81:31-41.

Partyka A, Klodzinska A, Szewczyk B, Wieronska JM, Chojnacka-Wojcik E, Librowski T, et al. Effects of GABAB receptor ligands in rodent tests of anxiety-like behavior. Pharmacol Rep: PR. 2007;59(6):757-62.

Jacobson LH, Cryan JF. Evaluation of the anxiolytic-like profile of the GABAB receptor positive modulator CGP7930 in rodents. Neuropharmacology. 2008;54(5):854-62.

Franklin TR, Harper D, Kampman K, et al. The GABA B agonist Baclofen reduces cigarette consumption in a preliminary double-blind placebo-controlled smoking reduction study. Drug Alcohol Depend. 2009 Jul 1;103(1-2):30-6.

Taricco M, Adone R, Pagliacci C, Telaro E. Pharmacological interventions for spasticity following spinal cord injury. Cochrane Database Syst Rev 2000(2):Cd001131.

Addolorato G, Armuzzi A, Gasbarrini G, De Lorenzi G, Ancona C, Abenavoli L, et al. Pharmacological approaches to the management of alcohol addiction. Eur Rev Med Pharmacol Sci. 2002;6(5):89-97.

Addolorato G, Caputo F, Capristo E, Domenicali M, Bernardi M, Janiri L, et al. Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol .2002;37(5):504-8.

Johnson BA, Swift RM, Addolorato G, Ciraulo DA, Myrick H. Safety and efficacy of GABAergic medications for treating alcoholism. Alcohol Clin Exp Res. 2005;29(2):248-54..

Stallings W, Schrader S. Baclofen as prophylaxis and treatment for alcohol withdrawal: a retrospective chart review. J Okla State Med Assoc. 2007;100(9):354-60.

Corrigall WA, Coen KM, Adamson KL, Chow BL, Zhang J. Response of nicotine self-administration in the rat to manipulations of mu-opioid and gamma-aminobutyric acid receptors in the ventral tegmental area. Psychopharmacology (Berl).. 2000;149(2):107-14.

Fadda P, Scherma M, Fresu A, Collu M, Fratta W. Baclofen antagonizes nicotine-, cocaine-, and morphine-induced dopamine release in the nucleus accumbens of rat. Synapse .2003;50(1):1-6.

Fattore L, Cossu G, Martellotta MC, Fratta W. Baclofen antagonizes intravenous self-administration of nicotine in mice and rats. Alcohol and alcohol.2002;37(5):495-8.

Markou A, Paterson NE, Semenova S. Role of gamma-aminobutyric acid (GABA) and metabotropic glutamate receptors in nicotine reinforcement: potential pharmacotherapies for smoking cessation. Ann N Y Acad Sci.. 2004;1025:491-503.

Millan MJ. The neurobiology and control of anxious states. Prog Neurobiol. 2003;70(2):83-244.

Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods. 1985;14(3):149-67.

Lister RG. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology (Berl).1987;92(2):180-5.

Lister RG. Ethologically-based animal models of anxiety disorders. Pharmacol Ther. 1990;46(3):321-40.

Paxinos G, Franklin KB. The mouse brain in stereotaxic coordinates: Gulf Professional Publishing; 2004.

Ghorbani Yekta B, Ahmadzadehfar NZ, Yazdanjo S. Effect of Echinacea Purpurea Extract on Anxiety-Like Behaviors in Neonatal Rats. GMJ. 2017;6(1):52-60.

Brioni JD, O'Neill AB, Kim DJ, Decker MW. Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test. Eur J Pharmacol. 1993;238(1):1-8.

Varani AP, Moutinho LM, Bettler B, Balerio GN. Acute behavioural responses to nicotine and nicotine withdrawal syndrome are modified in GABA(B1) knockout mice. Neuropharmacology. 2012;63(5):863-72.

Ouagazzal AM, Kenny PJ, File SE. Modulation of behaviour on trials 1 and 2 in the elevated plus-maze test of anxiety after systemic and hippocampal administration of nicotine. Psychopharmacology (Berl).1999;144(1):54-60.

Benwell ME, Balfour DJ, Khadra LF. Studies on the influence of nicotine infusions on mesolimbic dopamine and locomotor responses to nicotine. Clin Investig. 1994;72(3):233-9.

Biala G, Budzynska B. Effects of acute and chronic nicotine on elevated plus maze in mice: involvement of calcium channels. Life sci. 2006;79(1):81-8.

Balerio GN, Aso E, Maldonado R. Involvement of the opioid system in the effects induced by nicotine on anxiety-like behaviour in mice. Psychopharmacology (Berl). 2005;181(2):260-9.

Varani AP, Balerio GN. GABA(B) receptors involvement in the effects induced by nicotine on anxiety-related behaviour in mice. Pharmacolol res. 2012;65(5):507-13.

Salas R, Pieri F, Fung B, Dani JA, De Biasi M. Altered anxiety-related responses in mutant mice lacking the beta4 subunit of the nicotinic receptor. J Neurosci. 2003;23(15):6255-63.

File SE, Cheeta S, Kenny PJ. Neurobiological mechanisms by which nicotine mediates different types of anxiety. Eur J Pharmacol.2000;393(1-3):231-6.

Picciotto MR, Brunzell DH, Caldarone BJ. Effect of nicotine and nicotinic receptors on anxiety and depression. Neuroreport. 2002;13(9):1097-106.

Nastiti K, Benton D, Brain PF. The effect

s of compounds acting at the benzodiazepine receptor complex on the ultrasonic calling of mouse pups. Behav Pharmacol. 1991;2(2):121-8.

Shephard RA, Wedlock P, Wilson NE. Direct evidence for mediation of an anticonflict effect of baclofen by GABAb receptors. Pharmacol Biochem Behav. 1992;41(3):651-3.

Ketelaars CE, Bollen EL, Rigter H, Bruinvels J. GABA-B receptor activation and conflict behaviour. Life sci. 1988;42(8):933-42.

Di Chiara G. Role of dopamine in the behavioural actions of nicotine related to addiction .Eur J Pharmacol. 2000;393(1-3):295-314.

Dani JA, Ji D, Zhou FM. Synaptic plasticity and nicotine addiction. Neuron. 2001;31(3):349-52.

Grady S, Marks MJ, Wonnacott S, Collins AC. Characterization of nicotinic receptor-mediated [3H]dopamine release from synaptosomes prepared from mouse striatum. J neurochem. 1992;59(3):848-56.

Pezze MA, Feldon J. Mesolimbic dopaminergic pathways in fear conditioning. Prog Neurobiol. 2004;74(5):301-20.

Benwell ME, Balfour DJ. The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity. Br J Pharmacol. 1992;105(4):849-56.

Wonnacott S. Presynaptic nicotinic ACh receptors. Trends Neurosci. 1997;20(2):92-8.

Benowitz NL. Neurobiology of nicotine addiction: implications for smoking cessation treatment. Am J Med. 2008;121(4 Suppl 1):S3-10.

Koob GF. Neural mechanisms of drug reinforcement. Ann N Y Acad Sci. 1992;654:171-91.

ueller AL, Brodie MS. Intracellular recording from putative dopamine-containing neurons in the ventral tegmental area of Tsai in a brain slice preparation. J Neurosci Methods.. 1989;28(1-2):15-22.

Xi ZX, Stein EA. Nucleus accumbens dopamine release modulation by mesolimbic GABAA receptors-an in vivo electrochemical study. Brain Res. 1998;798(1-2):156-65.

File SE, Zharkovsky A, Gulati K. Effects of baclofen and nitrendipine on ethanol withdrawal responses in the rat. Neuropharmacology. 1991;30(2):183-90.

Sandoval MR, Palermo-Neto J. Central nervous system supersensitivity and withdrawal from long-term treatment with barbital. Neuropharmacology. 1985;24(12):1247-51.

Diaz SL, Kemmling AK, Rubio MC, Balerio GN. Lack of sex-related differences in the prevention by baclofen of the morphine withdrawal syndrome in mice. Behav Pharmacol. 2001;12(1):75-9.

Diaz SL, Kemmling AK, Balerio GN. Baclofen reestablishes striatal and cortical dopamine concentrations during naloxone-precipitated withdrawal. Neurochem Int. 2003;42(4):293-8.

Le Foll B, Wertheim CE, Goldberg SR. Effects of baclofen on conditioned rewarding and discriminative stimulus effects of nicotine in rats. Neurosci lett. 2008;443(3):236-40.

Andrews N, File SE. Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioural evidence. Psychopharmacology (Berl). 1993;112(1):21-5.

Cryan JF, Kaupmann K. Don't worry 'B' happy!: a role for GABA(B) receptors in anxiety and depression. Trends Pharmacol Sci. 2005;26(1):36-43

Colombo G, Agabio R, Carai MA, Lobina C, Pani M, Reali R, et al. Ability of baclofen in reducing alcohol intake and withdrawal severity: I--Preclinical evidence. Alcohol Clin Exp Res. 2000;24(1):58-66.

Drake RG, Davis LL, Cates ME, Jewell ME, Ambrose SM, Lowe JS. Baclofen treatment for chronic posttraumatic stress disorder. Ann Pharmacother. 2003;37(9):1177-81.

Breslow MF, Fankhauser MP, Potter RL, Meredith KE, Misiaszek J, Hope DG, Jr. Role of gamma-aminobutyric acid in antipanic drug efficacy. Am J Psychiatry. 1989 Mar;146(3):353-6.

Hinderer SR. The supraspinal anxiolytic effect of baclofen for spasticity reduction. Am J Phys Med Rehabil. 1990;69(5):254-8.

Fattore L, Spano MS, Cossu G, Scherma M, Fratta W, Fadda P. Baclofen prevents drug-induced reinstatement of extinguished nicotine-seeking behaviour and nicotine place preference in rodents. Eur Neuropsychopharmacol. 2009;19(7):487-98.

Roberts DC, Andrews MM. Baclofen suppression of cocaine self-administration: demonstration using a discrete trials procedure. Psychopharmacology (Berl). 1997;131(3):271-7.

Spano MS, Fattore L, Fratta W, Fadda P. The GABAB receptor agonist baclofen prevents heroin-induced reinstatement of heroin-seeking behavior in rats. Neuropharmacology. 2007;52(7):1555-62.

Paterson NE, Froestl W, Markou A. The GABAB receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat. Psychopharmacology (Berl). 2004;172(2):179-86.


  • There are currently no refbacks.