The Effects of Isoniazid on the Acquisition and Expression of Morphine-Induced Conditioned Place Preference in Mice

Document Type : Original Article


1 Assistant Professor, Department of Biology, Faculty of Basic Science, University of Maragheh, Maragheh, East Azerbaijan Province, IR Iran

2 M.Sc. Student, Department of Biology, Faculty of Basic Science, University of Maragheh, Maragheh, East Azerbaijan Province, IR Iran


Background: GABAergic drugs can modulate the rewarding properties of morphine. The objective of this study was to evaluate the effects of isoniazid, as a GABAergic agent, on the rewarding effects of morphine.
Methods: Eighteen groups of female mice (eight per group) were used in a conditioned place preference (CPP) study. On the conditioning phase of the CPP procedure, ten groups of the animals received morphine (0, 0.75, 1.5, 3, 5, and 10 mg/kg, s.c.) or isoniazid (0, 25, 50, and 75 mg/kg, i.p.) to induce CPP. Then, the effects of isoniazid on the acquisition and expression of morphine-induced CPP were evaluated. In the expression experiment, four groups of mice were conditioned with an effective dose of morphine (5mg/kg, s.c.). Then, the animals received saline or isoniazid (25, 50, and 75 mg/kg) one hour before the test, intraperitoneally. In the acquisition experiment, the other four groups received intraperitoneal saline or isoniazid (25, 50, and 75 mg/kg, i.p.) one hour before receiving the effective dose of morphine (5mg/kg, s.c.) on conditioning phase. On the test day, these animals received no treatment.
Results: Morphine but not isoniazid induced a significant CPP in mice. Morphine or isoniazid alone did not change the locomotor activity of the animals on the test day. Isoniazid pretreatment could significantly inhibit both the acquisition and expression of the morphine-induced CPP. Isoniazid also did not influence the locomotor activity of the animals in the expression and acquisition experiments.
Conclusion: Isoniazid may have a therapeutic application in morphine addiction.


Wiffen PJ, Wee B, Moore RA. Oral morphine for cancer pain. Cochrane Database Syst Rev 2016; 4:CD003868.
Volkow ND, Jones EB, Einstein EB, Wargo EM. Prevention and treatment of opioid misuse and addiction: a review. JAMA Psychiatry 2019; 76(2):208-16.
Compton WM, Volkow ND. Major increases in opioid analgesic abuse in the United States: concerns and strategies. Drug Alcohol Depend 2006; 81(2):103-7.
Tzschentke TM. Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 1998; 56(6):613-72.
Becker A, Grecksch G, Brödemann R, Kraus J, Peters B, Schroeder H, et al. Morphine self-administration in µ-opioid receptor-deficient mice. Naunyn Schmiedebergs Arch Pharmacol 2000; 361(6):584-9.
Xi ZX, Stein EA. GABAergic mechanisms of opiate reinforcement. Alcohol Alcohol 2002; 37(5):485-94.
McClung CA. The molecular mechanisms of morphine addiction. Rev Neurosci 2006; 17(4):393-402.
Negus SS, Miller LL. Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev 2014; 66(3):869-917.
Bardo M, Bevins RA. Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl) 2000; 153(1):31-43.
Koob GF. Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 1992; 13(5):177-84.
Sahraei H, Barzegari AA, Shams J, Zarrindast MR, Haeri-Rohani A, Ghoshooni H, et al. Theophylline inhibits tolerance and sensitization induced by morphine: a conditioned place preference paradigm study in female mice. Behav Pharmacol 2006; 17(7):621-8.
Zarrindast MR, Fattahi Z, Rostami P, Rezayof A. Role of the cholinergic system in the rat basolateral amygdala on morphine-induced conditioned place preference. Pharmacol Biochem Behav 2005; 82(1):1-10.
Manzanedo C, Aguilar MA, Rodrı́guez-Arias M, Miñarro J. Effects of dopamine antagonists with different receptor blockade profiles on morphine-induced place preference in male mice. Behav Brain Res 2001; 121(1-2):189-97.
Manzanedo C, Aguilar MA, Do Couto BR, Rodríguez-Arias M, Miñarro J. Involvement of nitric oxide synthesis in sensitization to the rewarding effects of morphine. Neurosci Lett 2009; 464(1):67-70.
Sahraei H, Amiri YA, Haeri-Rohani A, Sepehri H, Salimi SH, Pourmotabbed A, et al. Different effects of GABAergic receptors located in the ventral tegmental area on the expression of morphine-induced conditioned place preference in rat. Eur J Pharmacol 2005; 524(1-3):95-101.
Sahraei H, Ghazzaghi H, Zarrindast MR, Ghoshooni H, Sepehri H, Haeri-Rohan A. The role of alpha-adrenoceptor mechanism (s) in morphine-induced conditioned place preference in female mice. Pharmacol Biochem Behav 2004; 78(1):135-41.
Rezayof A, Zarrindast MR, Sahraei H, Haeri-Rohani A. Involvement of dopamine receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats. J Psychopharmacol 2003; 17(4):415-23.
Murray JF, Schraufnagel DE, Hopewell PC. Treatment of tuberculosis. A historical perspective. Ann Am Thorac Soc 2015; 12(12):1749-59.
Casey RE, Wood JD. Isonicotinic acid hydrazide-induced changes in the metabolism of γ-aminobutyric acid in the brain of four species. Comp Biochem Physiol B 1973; 45(4):741-8.
Wood JD, Peesker SJ. A correlation between changes in GABA metabolism and isonicotinic acid hydrazide-induced seizures. Brain Res 1972; 45(2):489-98.
Perry T, Hansen S. Sustained drug-induced elevation of brain GABA in the rat. J Neurochem 1973; 21(5):1167-75.
Perry TL, Urquhart N, Hansen S, Kennedy J. Gamma-aminobutyric acid: drug-induced elevation in monkey brain. J Neurochem 1974; 23(2):443-5.
Zarrindast MR, Rezayof A. Morphine-induced place preference: interactions with neurotransmitter systems. Iranian Journal of Pharmaceutical Research 2007; 6(1):3-15.
Olmstead MC, Franklin KB. The development of a conditioned place preference to morphine: effects of microinjections into various CNS sites. Behav Neurosci 1997; 111(6):1324-34.
Lorenz TH, Calden G, Ousley JL. A study of the effects of isoniazid on the emotions of tuberculous patients. Am Rev Tuberc 1953; 68(4):523-34.
Arbex MA, Varella Mde C, Siqueira HR, Mello FA. Antituberculosis drugs: drug interactions, adverse effects, and use in special situations-part 1: first-line drugs. J Bras Pneumol 2010; 36(5):626-40.
Jackson SL. Psychosis due to isoniazid. Br Med J 1957; 2(5047):743-6.
Rezayof A, Razavi S, Haeri-Rohani A, Rassouli Y, Zarrindast MR. GABAA receptors of hippocampal CA1 regions are involved in the acquisition and expression of morphine-induced place preference. Eur Neuropsychopharmacol 2007; 17(1):24-31.
Zarrindast MR, Ahmadi S, Haeri-Rohani A, Rezayof A, Jafari MR, Jafari-Sabet M. GABAA receptors in the basolateral amygdala are involved in mediating morphine reward. Brain Res 2004; 1006(1):49-58.
Asehinde S, Ajayi A, Bakre A, Omorogbe O, Adebesin A, Umukoro S. Effects of jobelyn® on isoniazid-induced seizures, biomarkers of oxidative stress and glutamate decarboxylase activity in mice. Basic Clin Neurosci 2018; 9(6):389-96.
Westerink BH, Kwint HF, deVries JB. The pharmacology of mesolimbic dopamine neurons: a dual-probe microdialysis study in the ventral tegmental area and nucleus accumbens of the rat brain. Journal of Neuroscience 1996; 16(8):2605-11.
Xi ZX, Stein EA. Increased mesolimbic GABA concentration blocks heroin self-administration in the rat. J Pharmacol Exp Ther 2000; 294(2):613-9.
Gerasimov MR, Ashby CR Jr, Gardner EL, Mills MJ, Brodie JD, Dewey SL. Gamma‐vinyl GABA inhibits methamphetamine, heroin, or ethanol‐induced increases in nucleus accumbens dopamine. Synapse 1999; 34(1):11-9.
Ashby CR Jr, Rohatgi R, Ngosuwan J, Borda T, Gerasimov MR, Morgan AE, et al. Implication of the GABAb receptor in gamma vinyl‐GABA's inhibition of cocaine‐induced increases in nucleus accumbens dopamine. Synapse 1999; 31(2):151-3.
Mu P, Yu LC. Valproic acid sodium inhibits the morphine-induced conditioned place preference in the central nervous system of rats. Neurosci Lett 2007; 426(3):135-8.
Cicek E, Sutcu R, Gokalp O, Yilmaz HR, Ozer MK, Uz E, et al. The effects of isoniazid on hippocampal NMDA receptors: protective role of erdosteine. Mol Cell Biochem 2005; 277(1-2):131-5.
Tsien JZ, Huerta PT, Tonegawa S. The essential role of hippocampal CA1 NMDA receptor–dependent synaptic plasticity in spatial memory. Cell 1996; 87(7):1327-38.
Morris RG. NMDA receptors and memory encoding. Neuropharmacology 2013; 74:32-40.
Nakazawa K, McHugh TJ, Wilson MA, Tonegawa S. NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci 2004; 5(5):361-72.