Abstract
Rationale
The neuropeptide oxytocin (OXT) has emerged as a potential therapeutic intervention in the treatment of both alcohol use disorder (AUD) and stress-related psychiatric illnesses.
Objectives
The present study evaluates the effects of systemically administered (intraperitoneal (i.p.)) OXT treatment on alcohol relapse-like behavior in male and female mice.
Methods
Adult male and female C57BL/6J mice were trained to lever respond in operant conditioning chambers for alcohol in daily self-administration sessions. Once lever responding and alcohol intake stabilized, mice were tested under extinction conditions for 14 days before reinstatement testing. All mice underwent stress-induced reinstatement testing using either predator odor (2,3,5-trimethyl-3-thiazoline (TMT)) or the α-2 adrenergic receptor agonist yohimbine. In study 1, mice were exposed to TMT for 15 min and then immediately placed into operant conditioning chambers to examine alcohol-seeking behavior under extinction conditions. At 30 min prior to test session, separate groups of mice were injected with vehicle or OXT (0.1, 0.5, 1 mg/kg). In study 2, mice were injected with yohimbine (0.3, 0.625 mg/kg) 1 h prior to reinstatement testing. At 30 min post-yohimbine injection, mice are injected (i.p.) with vehicle or OXT (1 mg/kg).
Results
OXT attenuated alcohol-seeking behavior in a dose-related manner in male and female mice in response to acute challenge with a predator odor. Additionally, OXT administration produced a similar decrease in alcohol relapse-like behavior triggered by the pharmacological stressor yohimbine in both sexes.
Conclusions
Systemic oxytocin administration attenuates stress-induced reinstatement of alcohol seeking in male and female mice.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bahi A (2015) The oxytocin receptor impairs ethanol reward in mice. Physiol Behav 139:321–327. https://doi.org/10.1016/j.physbeh.2014.11.046
Bahi A, Al Mansouri S, Al Maamari E (2016) Nucleus accumbens lentiviral-mediated gain of function of the oxytocin receptor regulates anxiety- and ethanol-related behaviors in adult mice. Physiol Behav 164:249–258. https://doi.org/10.1016/j.physbeh.2016.06.009
Baracz SJ, Everett NA, Cornish JL (2015) The involvement of oxytocin in the subthalamic nucleus on relapse to methamphetamine-seeking behaviour. PLoS One 10:e0136132. https://doi.org/10.1371/journal.pone.0136132
Baracz SJ, Everett NA, McGregor IS, Cornish JL (2016) Oxytocin in the nucleus accumbens core reduces reinstatement of methamphetamine-seeking behaviour in rats. Addict Biol 21:316–325. https://doi.org/10.1111/adb.12198
Baskerville TA, Douglas AJ (2010) Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders. CNS Neurosci Ther 16:e92–e123. https://doi.org/10.1111/j.1755-5949.2010.00154.x
Bernheim A, Leong KC, Berini C, Reichel CM (2017) Antagonism of mGlu2/3 receptors in the nucleus accumbens prevents oxytocin from reducing cued methamphetamine seeking in male and female rats. Pharmacol Biochem Behav 161:13–21. https://doi.org/10.1016/j.pbb.2017.08.012
Blanchard DC, Griebel G, Blanchard RJ (2003) Conditioning and residual emotionality effects of predator stimuli: some reflections on stress and emotion. Prog Neuro-Psychopharmacol Biol Psychiatry 27:1177–1185. https://doi.org/10.1016/j.pnpbp.2003.09.012
Bowen MT, Carson DS, Spiro A, Arnold JC, McGregor IS (2011) Adolescent oxytocin exposure causes persistent reductions in anxiety and alcohol consumption and enhances sociability in rats. PLoS One 6:e27237. https://doi.org/10.1371/journal.pone.0027237
Buffalari DM, See RE (2011) Inactivation of the bed nucleus of the stria terminalis in an animal model of relapse: effects on conditioned cue-induced reinstatement and its enhancement by yohimbine. Psychopharmacology 213:19–27. https://doi.org/10.1007/s00213-010-2008-3
Burkett JP, Andari E, Johnson ZV, Curry DC, de Waal FB, Young LJ (2016) Oxytocin-dependent consolation behavior in rodents. Science 351:375–378. https://doi.org/10.1126/science.aac4785
Carson DS, Hunt GE, Guastella AJ, Barber L, Cornish JL, Arnold JC, Boucher AA, McGregor IS (2010) Systemically administered oxytocin decreases methamphetamine activation of the subthalamic nucleus and accumbens core and stimulates oxytocinergic neurons in the hypothalamus. Addict Biol 15:448–463. https://doi.org/10.1111/j.1369-1600.2010.00247.x
Chen YW, Fiscella KA, Bacharach SZ, Tanda G, Shaham Y, Calu DJ (2015) Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history. Addict Biol 20:690–700. https://doi.org/10.1111/adb.12164
Cox BM, Young AB, See RE, Reichel CM (2013) Sex differences in methamphetamine seeking in rats: impact of oxytocin. Psychoneuroendocrinology 38:2343–2353. https://doi.org/10.1016/j.psyneuen.2013.05.005
Cox BM, Bentzley BS, Regen-Tuero H, See RE, Reichel CM, Aston-Jones G (2017) Oxytocin acts in nucleus accumbens to attenuate methamphetamine seeking and demand. Biol Psychiatry 81:949–958. https://doi.org/10.1016/j.biopsych.2016.11.011
Dabrowska J, Hazra R, Ahern TH, Guo JD, McDonald AJ, Mascagni F, Muller JF, Young LJ, Rainnie DG (2011) Neuroanatomical evidence for reciprocal regulation of the corticotrophin-releasing factor and oxytocin systems in the hypothalamus and the bed nucleus of the stria terminalis of the rat: implications for balancing stress and affect. Psychoneuroendocrinology 36:1312–1326. https://doi.org/10.1016/j.psyneuen.2011.03.003
Day HE, Masini CV, Campeau S (2004) The pattern of brain c-fos mRNA induced by a component of fox odor, 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), in rats, suggests both systemic and processive stress characteristics. Brain Res 1025:139–151. https://doi.org/10.1016/j.brainres.2004.07.079
Dolen G, Darvishzadeh A, Huang KW, Malenka RC (2013) Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin. Nature 501:179–184. https://doi.org/10.1038/nature12518
Dumais KM, Veenema AH (2016) Vasopressin and oxytocin receptor systems in the brain: sex differences and sex-specific regulation of social behavior. Front Neuroendocrinol 40:1–23. https://doi.org/10.1016/j.yfrne.2015.04.003
Dumais KM, Bredewold R, Mayer TE, Veenema AH (2013) Sex differences in oxytocin receptor binding in forebrain regions: correlations with social interest in brain region- and sex- specific ways. Horm Behav 64:693–701. https://doi.org/10.1016/j.yhbeh.2013.08.012
Dumais KM, Alonso AG, Bredewold R, Veenema AH (2016) Role of the oxytocin system in amygdala subregions in the regulation of social interest in male and female rats. Neuroscience 330:138–149. https://doi.org/10.1016/j.neuroscience.2016.05.036
Endres T, Fendt M (2007) Conditioned behavioral responses to a context paired with the predator odor trimethylthiazoline. Behav Neurosci 121:594–601. https://doi.org/10.1037/0735-7044.121.3.594
Endres T, Apfelbach R, Fendt M (2005) Behavioral changes induced in rats by exposure to trimethylthiazoline, a component of fox odor. Behav Neurosci 119:1004–1010. https://doi.org/10.1037/0735-7044.119.4.1004
Fendt M, Endres T (2008) 2,3,5-Trimethyl-3-thiazoline (TMT), a component of fox odor—just repugnant or really fear-inducing? Neurosci Biobehav Rev 32:1259–1266. https://doi.org/10.1016/j.neubiorev.2008.05.010
Fendt M, Endres T, Lowry CA, Apfelbach R, McGregor IS (2005) TMT-induced autonomic and behavioral changes and the neural basis of its processing. Neurosci Biobehav Rev 29:1145–1156. https://doi.org/10.1016/j.neubiorev.2005.04.018
Ferland CL, Reichel CM, McGinty JF (2016) Effects of oxytocin on methamphetamine-seeking exacerbated by predator odor pre-exposure in rats. Psychopharmacology 233:1015–1024. https://doi.org/10.1007/s00213-015-4184-7
Gimpl G, Fahrenholz F (2001) The oxytocin receptor system: structure, function, and regulation. Physiol Rev 81:629–683. https://doi.org/10.1152/physrev.2001.81.2.629
Greenwald MK, Lundahl LH, Steinmiller CL (2013) Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals. Psychopharmacology 225:811–824. https://doi.org/10.1007/s00213-012-2868-9
Hammock EA, Levitt P (2013) Oxytocin receptor ligand binding in embryonic tissue and postnatal brain development of the C57BL/6J mouse. Front Behav Neurosci 7:195. https://doi.org/10.3389/fnbeh.2013.00195
Hansson AC, Koopmann A, Uhrig S, Bühler S, Domi E, Kiessling E, Ciccocioppo R, Froemke RC, Grinevich V, Kiefer F, Sommer WH, Vollstädt-Klein S, Spanagel R (2018) Oxytocin reduces alcohol cue-reactivity in alcohol-dependent rats and humans. Neuropsychopharmacology 43:1235–1246. https://doi.org/10.1038/npp.2017.257
Ivell R, Walther N (1999) The role of sex steroids in the oxytocin hormone system. Mol Cell Endocrinol 151:95–101
Janitzky K, D’Hanis W, Krober A, Schwegler H (2015) TMT predator odor activated neural circuit in C57BL/6J mice indicates TMT-stress as a suitable model for uncontrollable intense stress. Brain Res 1599:1–8. https://doi.org/10.1016/j.brainres.2014.12.030
Jurek B, Slattery DA, Hiraoka Y, Liu Y, Nishimori K, Aguilera G, Neumann ID, van den Burg EH (2015) Oxytocin regulates stress-induced Crf gene transcription through CREB-regulated transcription coactivator 3. J Neurosci 35:12248–12260. https://doi.org/10.1523/JNEUROSCI.1345-14.2015
King CE, Griffin WC, Luderman LN, Kates MM, McGinty JF, Becker HC (2017) Oxytocin reduces ethanol self-administration in mice. Alcohol Clin Exp Res 41:955–964. https://doi.org/10.1111/acer.13359
Kohtz AS, Lin B, Smith ME, Aston-Jones G (2018) Attenuated cocaine-seeking after oxytocin administration in male and female rats. Psychopharmacology 235:2051–2063. https://doi.org/10.1007/s00213-018-4902-z
Landgraf R, Neumann ID (2004) Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 25:150–176. https://doi.org/10.1016/j.yfrne.2004.05.001
Le AD, Funk D, Coen K, Li Z, Shaham Y (2013) Role of corticotropin-releasing factor in the median raphe nucleus in yohimbine-induced reinstatement of alcohol seeking in rats. Addict Biol 18:448–451. https://doi.org/10.1111/j.1369-1600.2011.00374.x
Lee MR, Rohn MC, Tanda G, Leggio L (2016) Targeting the oxytocin system to treat addictive disorders: rationale and progress to date. CNS Drugs 30:109–123. https://doi.org/10.1007/s40263-016-0313-z
Lee MR, Scheidweiler KB, Diao XX, Akhlaghi F, Cummins A, Huestis MA, Leggio L, Averbeck BB (2018) Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay. Mol Psychiatry 23:115–122. https://doi.org/10.1038/mp.2017.27
Leong KC, Zhou L, Ghee SM, See RE, Reichel CM (2016) Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats. Exp Clin Psychopharmacol 24:55–64. https://doi.org/10.1037/pha0000058
Leong KC, Freeman LR, Berini CR, Ghee SM, See RE, Reichel CM (2017) Oxytocin reduces cocaine cued Fos activation in a regionally specific manner. Int J Neuropsychopharmacol 20:844–854. https://doi.org/10.1093/ijnp/pyx058
Leong KC, Cox S, King C, Becker H, Reichel CM (2018) Oxytocin and rodent models of addiction. Int Rev Neurobiol 140:201–247. https://doi.org/10.1016/bs.irn.2018.07.007
Li K, Nakajima M, Ibanez-Tallon I, Heintz N (2016) A cortical circuit for sexually dimorphic oxytocin-dependent anxiety behaviors. Cell 167:60–72 e11. https://doi.org/10.1016/j.cell.2016.08.067
Love TM (2014) Oxytocin, motivation and the role of dopamine. Pharmacol Biochem Behav 119:49–60. https://doi.org/10.1016/j.pbb.2013.06.011
MacFadyen K, Loveless R, DeLucca B, Wardley K, Deogan S, Thomas C, Peris J (2016) Peripheral oxytocin administration reduces ethanol consumption in rats. Pharmacol Biochem Behav 140:27–32. https://doi.org/10.1016/j.pbb.2015.10.014
Mantsch JR, Baker DA, Funk D, Le AD, Shaham Y (2016) Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology 41:335–356. https://doi.org/10.1038/npp.2015.142
Martinon D, Dabrowska J (2018) Corticotropin-releasing factor receptors modulate oxytocin release in the dorsolateral bed nucleus of the stria terminalis (BNST) in male rats. Front Neurosci 12:183. https://doi.org/10.3389/fnins.2018.00183
McGregor IS, Bowen MT (2012) Breaking the loop: oxytocin as a potential treatment for drug addiction. Horm Behav 61:331–339. https://doi.org/10.1016/j.yhbeh.2011.12.001
McGregor IS, Schrama L, Ambermoon P, Dielenberg RA (2002) Not all ‘predator odours’ are equal: cat odour but not 2,4,5 trimethylthiazoline (TMT; fox odour) elicits specific defensive behaviours in rats. Behav Brain Res 129:1–16
Morrow BA, Redmond AJ, Roth RH, Elsworth JD (2000) The predator odor, TMT, displays a unique, stress-like pattern of dopaminergic and endocrinological activation in the rat. Brain Res 864:146–151
Myers EA, Rinaman L (2005) Trimethylthiazoline supports conditioned flavor avoidance and activates viscerosensory, hypothalamic, and limbic circuits in rats. Am J Phys Regul Integr Comp Phys 288:R1716–R1726. https://doi.org/10.1152/ajpregu.00479.2004
Nakajima M, Gorlich A, Heintz N (2014) Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons. Cell 159:295–305. https://doi.org/10.1016/j.cell.2014.09.020
Neumann ID, Landgraf R (2012) Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 35:649–659. https://doi.org/10.1016/j.tins.2012.08.004
Neumann ID, Wigger A, Torner L, Holsboer F, Landgraf R (2000) Brain oxytocin inhibits basal and stress-induced activity of the hypothalamo-pituitary-adrenal axis in male and female rats: partial action within the paraventricular nucleus. J Neuroendocrinol 12:235–243
Patchev VK, Schlosser SF, Hassan AH, Almeida OF (1993) Oxytocin binding sites in rat limbic and hypothalamic structures: site-specific modulation by adrenal and gonadal steroids. Neuroscience 57:537–543
Pedersen CA, Smedley KL, Leserman J, Jarskog LF, Rau SW, Kampov-Polevoi A, Casey RL, Fender T, Garbutt JC (2013) Intranasal oxytocin blocks alcohol withdrawal in human subjects. Alcohol Clin Exp Res 37:484–489. https://doi.org/10.1111/j.1530-0277.2012.01958.x
Peris J, MacFadyen K, Smith JA, de Kloet AD, Wang L, Krause EG (2017) Oxytocin receptors are expressed on dopamine and glutamate neurons in the mouse ventral tegmental area that project to nucleus accumbens and other mesolimbic targets. J Comp Neurol 525:1094–1108. https://doi.org/10.1002/cne.24116
Peters S, Slattery DA, Uschold-Schmidt N, Reber SO, Neumann ID (2014) Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice. Psychoneuroendocrinology 42:225–236. https://doi.org/10.1016/j.psyneuen.2014.01.021
Peters ST, Bowen MT, Bohrer K, McGregor IS, Neumann ID (2017) Oxytocin inhibits ethanol consumption and ethanol-induced dopamine release in the nucleus accumbens. Addict Biol 22:702–711. https://doi.org/10.1111/adb.12362
Qi J, Yang JY, Wang F, Zhao YN, Song M, Wu CF (2009) Effects of oxytocin on methamphetamine-induced conditioned place preference and the possible role of glutamatergic neurotransmission in the medial prefrontal cortex of mice in reinstatement. Neuropharmacology 56:856–865. https://doi.org/10.1016/j.neuropharm.2009.01.010
Ring RH, Malberg JE, Potestio L, Ping J, Boikess S, Luo B, Schechter LE, Rizzo S, Rahman Z, Rosenzweig-Lipson S (2006) Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications. Psychopharmacology 185:218–225. https://doi.org/10.1007/s00213-005-0293-z
Shaham Y, Shalev U, Lu L, de Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168:3–20. https://doi.org/10.1007/s00213-002-1224-x
Shalev U, Erb S, Shaham Y (2010) Role of CRF and other neuropeptides in stress-induced reinstatement of drug seeking. Brain Res 1314:15–28. https://doi.org/10.1016/j.brainres.2009.07.028
Slattery DA, Neumann ID (2010) Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats. Neuropharmacology 58:56–61. https://doi.org/10.1016/j.neuropharm.2009.06.038
Tan Y, Singhal S, Hiller H, Harden S, Nguyen D, Colon-Perez C, Febo M, Wang L, Cahill K, de Kloet A, Frazier C, Krause E (2017) Optogenetic excitation of neurons in the prefrontal cortex that express oxytocin receptors eliminates preference for social novelty in male mice. Society for Neuroscience Abstract No 783.12, 2017
Umhau JC, Schwandt ML, Usala J, Geyer C, Singley E, George DT, Heilig M (2011) Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate. Neuropsychopharmacology 36:1178–1186. https://doi.org/10.1038/npp.2010.253
Veinante P, Freund-Mercier MJ (1997) Distribution of oxytocin- and vasopressin-binding sites in the rat extended amygdala: a histoautoradiographic study. J Comp Neurol 383:305–325
Weber RA, Logan CN, Leong KC, Peris J, Knackstedt L, Reichel CM (2018) Regionally specific effects of oxytocin on reinstatement of cocaine seeking in male and female rats. Int J Neuropsychopharmacol 21:677–686. https://doi.org/10.1093/ijnp/pyy025
Windle RJ, Shanks N, Lightman SL, Ingram CD (1997) Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats. Endocrinology 138:2829–2834. https://doi.org/10.1210/endo.138.7.5255
Windle RJ, Kershaw YM, Shanks N, Wood SA, Lightman SL, Ingram CD (2004) Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity. J Neurosci 24:2974–2982. https://doi.org/10.1523/JNEUROSCI.3432-03.2004
Zanos P, Georgiou P, Wright SR, Hourani SM, Kitchen I, Winsky-Sommerer R, Bailey A (2014) The oxytocin analogue carbetocin prevents emotional impairment and stress-induced reinstatement of opioid-seeking in morphine-abstinent mice. Neuropsychopharmacology 39:855–865. https://doi.org/10.1038/npp.2013.285
Zhou L, Ghee SM, See RE, Reichel CM (2015) Oxytocin differentially affects sucrose taking and seeking in male and female rats. Behav Brain Res 283:184–190. https://doi.org/10.1016/j.bbr.2015.01.050
Funding
This study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (U01 AA014095, U24 AA020929, P50 AA0107061, F31 AA026483) and VA Medical Research (I01BX000813).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All experimental protocols were approved by the Medical University of South Carolina Institutional Animal Care and Use Committee and consistent with guidelines of the NIH Guide for the Care and Use of Laboratory Animals.
Conflict of interest
The authors declare that they do not have conflicts of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
King, C.E., Becker, H.C. Oxytocin attenuates stress-induced reinstatement of alcohol seeking behavior in male and female mice. Psychopharmacology 236, 2613–2622 (2019). https://doi.org/10.1007/s00213-019-05233-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-019-05233-z