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Reinforcing properties of an intermittent, low dose of ketamine in rats: effects of sex and cycle

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Abstract

Rationale

Repeated intermittent exposure to ketamine has rapid and long-lasting antidepressant effects, but the abuse potential has only been assessed at high doses. Furthermore, while females are more susceptible to depression and more sensitive to ketamine’s antidepressant-like effects, the abuse potential for ketamine in females is unknown.

Objectives

The objectives of this study are to determine the reinforcing properties of low-dose intermittent ketamine in adult rats of both sexes and determine whether cycling gonadal hormones influence females’ response to ketamine. In male rats, we also aimed to determine whether reinstatement to intermittent ketamine is comparable to intermittent cocaine.

Methods

Male rats intravenously self-administered cocaine (0.75 mg/kg/infusion) or ketamine (0.1 mg/kg/infusion) once every fourth day, while intact cycling female rats self-administered ketamine only during preidentified stages of their 4-day estrus cycle, when gonadal hormones are either high (proestrus) or low (diestrus). After acquiring self-administration, rats underwent daily extinction training followed by cue-primed and drug-primed reinstatement to assess drug-seeking behavior.

Results

Diestrus-trained females fail to maintain ketamine self-administration and did not display reinstatement to ketamine-paired cues. Males and proestrus-trained females reinstated to ketamine-paired cues. Ketamine-primed reinstatement was dependent on simultaneous cue presentation. Male rats reinstated to cocaine priming independent of cue presentation.

Conclusion

These findings indicate that females’s responsivity to this dose of ketamine depends on stage of cycle, as only proestrus-trained females and males respond to ketamine’s reinforcing effects under this treatment paradigm.

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References

  • aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ (2010) Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 67(2):139–145. doi:10.1016/j.biopsych.2009.08.038

    Article  CAS  PubMed  Google Scholar 

  • Becker JB, Arnold AP, Berkley KJ, Blaustein JD, Eckel LA, Hampson E, ... Young E (2005) Strategies and methods for research on sex differences in brain and behavior. Endocrinology 146(4): 1650–1673. doi:10.1210/en.2004-1142

  • Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354

    Article  CAS  PubMed  Google Scholar 

  • Botanas CJ, de la Pena JB, Dela Pena IJ, Tampus R, Yoon R, Kim HJ et al (2015) Methoxetamine, a ketamine derivative, produced conditioned place preference and was self-administered by rats: evidence of its abuse potential. Pharmacol Biochem Behav 133:31–36. doi:10.1016/j.pbb.2015.03.007

    Article  CAS  PubMed  Google Scholar 

  • Carrier N, Kabbaj M (2013) Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology 70:27–34. doi:10.1016/j.neuropharm.2012.12.009

    Article  CAS  PubMed  Google Scholar 

  • Carroll ME, Batulis DK, Landry KL, Morgan AD (2005) Sex differences in the escalation of oral phencyclidine (PCP) self-administration under FR and PR schedules in rhesus monkeys. Psychopharmacology 180(3):414–426. doi:10.1007/s00213-005-2182-x

    Article  CAS  PubMed  Google Scholar 

  • Carroll ME, Roth ME, Voeller RK, Nguyen PD (2000) Acquisition of oral phencyclidine self-administration in rhesus monkeys: effect of sex. Psychopharmacology 149(4):401–408

    Article  CAS  PubMed  Google Scholar 

  • Carroll ME, Stotz DC (1983) Oral d-amphetamine and ketamine self-administration by rhesus monkeys: effects of food deprivation. J Pharmacol Exp Ther 227(1):28–34

    CAS  PubMed  Google Scholar 

  • Chen WY, Huang MC, Lin SK (2014) Gender differences in subjective discontinuation symptoms associated with ketamine use. Subst Abuse Treat Prev Policy 9:39. doi:10.1186/1747-597X-9-39

    Article  PubMed  PubMed Central  Google Scholar 

  • Cicero TJ, Aylward SC, Meyer ER (2003) Gender differences in the intravenous self-administration of mu opiate agonists. Pharmacol Biochem Behav 74(3):541–549

    Article  CAS  PubMed  Google Scholar 

  • Collins GT, Woods JH (2007) Drug and reinforcement history as determinants of the response-maintaining effects of quinpirole in the rat. J Pharmacol Exp Ther 323(2):599–605. doi:10.1124/jpet.107.123042

    Article  CAS  PubMed  Google Scholar 

  • Cox BM, Young AB, See RE, Reichel CM (2013) Sex differences in methamphetamine seeking in rats: impact of oxytocin. Psychoneuroendocrinology 38(10):2343–2353. doi:10.1016/j.psyneuen.2013.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Luca MT, Badiani A (2011) Ketamine self-administration in the rat: evidence for a critical role of setting. Psychopharmacology 214(2):549–556. doi:10.1007/s00213-010-2062-x

    Article  CAS  PubMed  Google Scholar 

  • de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75(2):134–143

    Article  PubMed  Google Scholar 

  • Fattore L, Spano MS, Altea S, Angius F, Fadda P, Fratta W (2007) Cannabinoid self-administration in rats: sex differences and the influence of ovarian function. Br J Pharmacol 152(5):795–804. doi:10.1038/sj.bjp.0707465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franceschelli A, Sens J, Herchick S, Thelen C, Pitychoutis PM (2015) Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naive and “depressed” mice exposed to chronic mild stress. Neuroscience 290:49–60. doi:10.1016/j.neuroscience.2015.01.008

    Article  CAS  PubMed  Google Scholar 

  • Holm S (1979) A simple sequential rejective method procedure. Scand J Stat 6:65–70

    Google Scholar 

  • Huang X, Huang K, Zheng W, Beveridge TJ, Yang S, Li X ... Liu Y (2015) The effects of GSK-3beta blockade on ketamine self-administration and relapse to drug-seeking behavior in rats. Drug Alcohol Depend 147: 257–265. doi:10.1016/j.drugalcdep.2014.10.028

  • Jansen KL (2000) A review of the nonmedical use of ketamine: use, users and consequences. J Psychoactive Drugs 32(4):419–433. doi:10.1080/02791072.2000.10400244

    Article  CAS  PubMed  Google Scholar 

  • Jansen KL, Darracot-Cankovic R (2001) The nonmedical use of ketamine, part two: a review of problem use and dependence. J Psychoactive Drugs 33(2):151–158. doi:10.1080/02791072.2001.10400480

    Article  CAS  PubMed  Google Scholar 

  • Kabbaj M (2006) Individual differences in vulnerability to drug abuse: the high responders/low responders model. CNS Neurol Disord Drug Targets 5(5):513–520

    Article  PubMed  Google Scholar 

  • Lynch WJ, Carroll ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology 144(1):77–82

    Article  CAS  PubMed  Google Scholar 

  • Lynch WJ, Carroll ME (2000) Reinstatement of cocaine self-administration in rats: sex differences. Psychopharmacology 148(2):196–200

    Article  CAS  PubMed  Google Scholar 

  • McCarthy D, Harrigan S (1976) Dependence producing capacity of ketamine in Macaca mulatta. Anaesthesiology 399:160–168

    Google Scholar 

  • Morgan CJ, Curran HV (2012) Ketamine use: a review. Addiction 107(1):27–38. doi:10.1111/j.1360-0443.2011.03576.x

    Article  PubMed  Google Scholar 

  • Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, Iosifescu DV (2013) Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 74(4):250–256. doi:10.1016/j.biopsych.2012.06.022

    Article  CAS  PubMed  Google Scholar 

  • National Research Council (2011) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press (US). doi:10.17226/12910

  • Pinheiro J, Bates D, DebRoy S, Sarkar D, R Core Team (2016) nlme: linear and nonlinear mixed effects models. R package version 3.1–128, http://CRAN.R-project.org/packages=nlme

  • Saland SK, Schoepfer KJ, Kabbaj M (2016) Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner. Sci Rep 6:21322. doi:10.1038/srep21322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(1–2):3–20. doi:10.1007/s00213-002-1224-x

    Article  CAS  PubMed  Google Scholar 

  • Stack A, Carrier N, Dietz D, Hollis F, Sorenson J, Kabbaj M (2010) Sex differences in social interaction in rats: role of the immediate-early gene zif268. Neuropsychopharmacology 35(2):570–580. doi:10.1038/npp.2009.163

    Article  PubMed  Google Scholar 

  • Swalve N, Smethells JR, Carroll ME (2016) Sex differences in the acquisition and maintenance of cocaine and nicotine self-administration in rats. Psychopharmacology 233(6):1005–1013. doi:10.1007/s00213-015-4183-8

    Article  CAS  PubMed  Google Scholar 

  • Trujillo KA, Smith ML, Sullivan B, Heller CY, Garcia C, Bates M (2011) The neurobehavioral pharmacology of ketamine: implications for drug abuse, addiction, and psychiatric disorders. ILAR J 52(3):366–378. doi:10.1093/ilar.52.3.366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trujillo KA, Zamora JJ, Warmoth KP (2008) Increased response to ketamine following treatment at long intervals: implications for intermittent use. Biol Psychiatry 63(2):178–183. doi:10.1016/j.biopsych.2007.02.014

    Article  CAS  PubMed  Google Scholar 

  • van der Kam EL, de Vry J, Tzschentke TM (2007) Effect of 2-methyl-6-(phenylethynyl) pyridine on intravenous self-administration of ketamine and heroin in the rat. Behav Pharmacol 18(8):717–724. doi:10.1097/FBP.0b013e3282f18d58

    Article  PubMed  Google Scholar 

  • Venniro M, Mutti A, Chiamulera C (2015) Pharmacological and non-pharmacological factors that regulate the acquisition of ketamine self-administration in rats. Psychopharmacology 232(24):4505–4514. doi:10.1007/s00213-015-4077-9

    Article  CAS  PubMed  Google Scholar 

  • Wright KN, Hollis F, Duclot F, Dossat AM, Strong CE, Francis TC ... Kabbaj M (2015) Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner. J Neurosci 35(23): 8948–8958. doi:10.1523/jneurosci.5227-14.2015

  • Young AM, Woods JH (1981) Maintenance of behavior by ketamine and related compounds in rhesus monkeys with different self-administration histories. J Pharmacol Exp Ther 218(3):720–727

    CAS  PubMed  Google Scholar 

  • Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI … Gould TD (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533(7604): 481–486. doi: 10.1038/nature17998

  • Zarate CA Jr., Singh JB, Carlson PL, Brutsche NE, Ameli R, Luckenbaugh DA ... Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8): 856–864. doi:10.1001/archpsyc.63.8.856

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Acknowledgements

This research was supported by R01MH 087583 and R01MH 099085 to MK. Special thanks to Samantha Pavlock, Elsa Johnson, and Amanda Dossat for their technical assistance. KNW and MK designed the experiments. KNW, CES, and MNA carried out the behavioral testing. KNW, NCB, and MK performed the data analysis. KNW and MK wrote the manuscript. All authors provided editorial input for the final draft.

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Authors and Affiliations

  1. Program in Neuroscience, Department of Biomedical Sciences, Florida State University, Tallahassee, FL, USA

    Katherine N. Wright, Caroline E. Strong, Marjorie N. Addonizio & Mohamed Kabbaj

  2. Department of Behavioral Sciences and Social Medicine, Florida State University, Tallahassee, FL, USA

    Naomi C. Brownstein

  3. Department of Statistics, Florida State University, Tallahassee, FL, USA

    Naomi C. Brownstein

  4. College of Medicine, Department of Biomedical Sciences, Florida State University, 1115 W. Call St., Tallahassee, FL, 32306, USA

    Mohamed Kabbaj

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  1. Katherine N. Wright
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  2. Caroline E. Strong
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  3. Marjorie N. Addonizio
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  4. Naomi C. Brownstein
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  5. Mohamed Kabbaj
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Corresponding author

Correspondence to Mohamed Kabbaj.

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All protocols were approved by the Florida State University Institutional Animal Care and Use Committee.

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The authors declare that they have no conflicts of interest.

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Wright, K.N., Strong, C.E., Addonizio, M.N. et al. Reinforcing properties of an intermittent, low dose of ketamine in rats: effects of sex and cycle. Psychopharmacology 234, 393–401 (2017). https://doi.org/10.1007/s00213-016-4470-z

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  • DOI: https://doi.org/10.1007/s00213-016-4470-z

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