Abstract
Rationale
Escalation of drug intake and craving are two DSM-5 hallmark symptoms of opioid use disorder (OUD).
Objectives
This study determined if escalation of intake as modeled by long access (LgA) self-administration (SA) and craving measured by reinstatement are related.
Methods
Adult male and female Sprague–Dawley rats were trained to self-administer fentanyl across 7 daily 1-h short access (ShA) sessions, followed by 21 SA sessions of either 1- or 6-h duration (ShA or LgA). Following 14 1-h extinction sessions, Experiment 1 assessed reinstatement induced by either fentanyl (10 or 30 µg/kg) or yohimbine (1 or 2 mg/kg), and Experiment 2 assessed reinstatement induced by a drug-associated cue light.
Results
Females acquired fentanyl SA faster than males. When shifted to LgA sessions, LgA rats escalated fentanyl intake, but ShA rats did not; no reliable sex difference in the rate of escalation was observed. In extinction, compared to ShA rats, LgA rats initially responded less and showed less decay of responding across sessions. A priming injection of fentanyl induced reinstatement, with LgA rats reinstating more than ShA rats at the 30 µg/kg dose. Yohimbine (1 mg/kg) also induced reinstatement, but there was no effect of access group or sex. With cue-induced reinstatement, LgA females reinstated less than LgA males and ShA females.
Conclusion
Among the different reinstatement tests assessed, escalation of fentanyl SA increased only drug-primed reinstatement, suggesting a limited relationship between escalation of drug intake and craving (reinstatement) for OUD.
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References
Ahmed SH, Walker JR, Koob GF (2000) Persistent increase in the motivation to take heroin in rats with a history of drug escalation. Neuropsychopharmacology 22:413. https://doi.org/10.1016/S0893-133X(99)00133-5
American Psychiatric A, American Psychiatric Association DSMTF (2013) Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Association, Arlington
Becker JB (2016) Sex differences in addiction. Dialogues Clin Neurosci 18:395–402
Becker JB, Koob GF (2016) Sex differences in animal models: Focus on addiction. Pharmacol Rev 68:242–263. https://doi.org/10.1124/pr.115.011163
Bertholomey ML, Nagarajan V, Torregrossa MM (2016) Sex differences in reinstatement of alcohol seeking in response to cues and yohimbine in rats with and without a history of adolescent corticosterone exposure. Psychopharmacology 233:2277–2287. https://doi.org/10.1007/s00213-016-4278-x
Carroll M, Morgan A, Lynch W, Campbell U, Dess N (2002) Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences. Psychopharmacology 161:304–313. https://doi.org/10.1007/s00213-002-1030-5
Carroll ME, Campbell UC, Heideman P (2001) Ketoconazole suppresses food restriction–induced increases in heroin self-administration in rats: sex differences experimental and clinical. Psychopharmacology 9:307–316. https://doi.org/10.1037/1064-1297.9.3.307
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
Cowan DT, Allan LG, Libretto SE, Griffiths P (2001) Opioid drugs: a comparative survey of therapeutic and “street” use. Pain Med 2:193–203. https://doi.org/10.1046/j.1526-4637.2001.01026.x
De Vries TJ, Schoffelmeer ANM, Binnekade R, Mulder AH, Vanderschuren LJMJ (1998) Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization. Eur J Neurosci 10:3565–3571. https://doi.org/10.1046/j.1460-9568.1998.00368.x
Doherty J, Ogbomnwan Y, Williams B, Frantz K (2009) Age-dependent morphine intake and cue-induced reinstatement, but not escalation in intake, by adolescent and adult male rats. Pharmacol Biochem Behav 92:164–172. https://doi.org/10.1016/j.pbb.2008.11.009
Feltenstein MW, Ghee SM, See RE (2012) Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats. Drug Alcohol Depend 121:240–246. https://doi.org/10.1016/j.drugalcdep.2011.09.001
Feltenstein MW, See RE (2006) Potentiation of cue-induced reinstatement of cocaine-seeking in rats by the anxiogenic drug yohimbine. Behav Brain Res 174:1–8. https://doi.org/10.1016/j.bbr.2006.06.039
Fox HC, Morgan PT, Sinha R (2014) Sex differences in guanfacine effects on drug craving and stress arousal in cocaine-dependent individuals. Neuropsychopharmacology 39:1527–1537. https://doi.org/10.1038/npp.2014.1
Frick KM (2020) Estrogens and memory: basic research and clinical implications. Oxford University Press, New York
Fulenwider HD et al (2020) Sex differences in oral oxycodone self-administration and stress-primed reinstatement in rats. Addict Biol 25:e12822. https://doi.org/10.1111/adb.12822
Gallop RJ, Crits-Christoph P, Have Ten TR, Barber JP, Frank A, Griffin ML, Thase ME (2007) Differential transitions between cocaine use and abstinence for men and women. J Consult Clin Psychol 75:95–103. https://doi.org/10.1037/0022-006X.75.1.95
Grau-López L et al (2012) Risk factors for relapse in drug-dependent patients after hospital detoxification. Adicciones 24:115–122
Henry SG, Wilsey BL, Melnikow J, Iosif A-M (2015) Dose escalation during the first year of long-term opioid therapy for chronic pain. Pain Med 16:733–744. https://doi.org/10.1111/pme.12634
Hitschfeld MJ et al (2015) Female smokers have the highest alcohol craving in a residential alcoholism treatment cohort. Drug Alcohol Depend 150:179–182. https://doi.org/10.1016/j.drugalcdep.2015.02.016
Hu M, Crombag HS, Robinson TE, Becker JB (2004) Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology 29:81–85. https://doi.org/10.1038/sj.npp.1300301
Jackson LR, Robinson TE, Becker JB (2006) Sex differences and hormonal influences on acquisition of cocaine self-administration in rats. Neuropsychopharmacology 31:129–138. https://doi.org/10.1038/sj.npp.1300778
Kippin TE, Fuchs RA, Mehta RH, Case JM, Parker MP, Bimonte-Nelson HA, See RE (2005) Potentiation of cocaine-primed reinstatement of drug seeking in female rats during estrus. Psychopharmacology 182:245–252. https://doi.org/10.1007/s00213-005-0071-y
Lacy RT, Strickland JC, Feinstein MA, Robinson AM, Smith MA (2016) The effects of sex, estrous cycle, and social contact on cocaine and heroin self-administration in rats. Psychopharmacology 233:3201–3210. https://doi.org/10.1007/s00213-016-4368-9
Lê AD, Quan B, Juzytch W, Fletcher PJ, Joharchi N, Shaham Y (1998) Reinstatement of alcohol-seeking by priming injections of alcohol and exposure to stress in rats. Psychopharmacology 135:169–174. https://doi.org/10.1007/s002130050498
Le Foll B et al (2012) Varenicline decreases nicotine self-administration and cue-induced reinstatement of nicotine-seeking behaviour in rats when a long pretreatment time is used. Int J Neuropsychopharmacol 15:1265–1274. https://doi.org/10.1017/s1461145711001398
Lee B, Tiefenbacher S, Platt DM, Spealman RD (2004) Pharmacological blockade of α2-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsychopharmacology 29:686–693. https://doi.org/10.1038/sj.npp.1300391
Lenoir M, Ahmed SH (2007) Heroin-induced reinstatement is specific to compulsive heroin use and dissociable from heroin reward and sensitization. Neuropsychopharmacology 32:616–624. https://doi.org/10.1038/sj.npp.1301083
Lynch W, Roth M, Carroll M (2002) Biological basis of sex differences in drug abuse: preclinical and clinical studies. Psychopharmacology 164:121–137. https://doi.org/10.1007/s00213-002-1183-2
Lynch WJ (2006) Sex differences in vulnerability to drug self-administration experimental and clinical. Psychopharmacology 14:34–41. https://doi.org/10.1037/1064-1297.14.1.34
Lynch WJ, Carroll ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology 144:77–82. https://doi.org/10.1007/s002130050979
Lynch WJ, Carroll ME (2000) Reinstatement of cocaine self-administration in rats: sex differences. Psychopharmacology 148:196–200. https://doi.org/10.1007/s002130050042
Mantsch J, Yuferov V, Mathieu-Kia A-M, Ho A, Kreek M (2004) Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats. Psychopharmacology 175:26–36. https://doi.org/10.1007/s00213-004-1778-x
Mantsch JR, Baker DA, Funk D, Lê AD, Shaham Y (2016a) Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology 41:335–356. https://doi.org/10.1038/npp.2015.142
Mantsch JR, Vranjkovic O, Twining RC, Gasser PJ, McReynolds JR, Blacktop JM (2014) Neurobiological mechanisms that contribute to stress-related cocaine use. Neuropharmacology 76:383–394. https://doi.org/10.1016/j.neuropharm.2013.07.021
Mantsch Jr, Baker D, Funk D, Le AD, Shaham Y (2016b) Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology 41:335–356. https://doi.org/10.1038/npp.2015.142
McNally GP (2014) Extinction of drug seeking: neural circuits and approaches to augmentation. Neuropharmacology 76. https://doi.org/10.1016/j.neuropharm.2013.06.007
Morgan AD, Campbell UC, Fons RD, Carroll ME (2002) Effects of agmatine on the escalation of intravenous cocaine and fentanyl self-administration in rats. Pharmacol Biochem Behav 72:873–880. https://doi.org/10.1016/S0091-3057(02)00774-8
Rabbani M, Hajhashemi V, Mesripour A (2009) Increase in brain corticosterone concentration and recognition memory impairment following morphine withdrawal in mice. Stress 12(5):451–456. https://doi.org/10.1080/10253890802659612
Robbins SJ, Ehrman RN, Childress AR, O’Brien CP (1999) Comparing levels of cocaine cue reactivity in male and female outpatients. Drug Alcohol Depend 53:223–230. https://doi.org/10.1016/S0376-8716(98)00135-5
Roth ME, Carroll ME (2004) Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration. Pharmacol Biochem Behav 78:199–207. https://doi.org/10.1016/j.pbb.2004.03.018
Rubio FJ et al (2019) Prelimbic cortex is a common brain area activated during cue-induced reinstatement of cocaine and heroin seeking in a polydrug self-administration rat model. Eur J Neurosci 49:165–178. https://doi.org/10.1111/ejn.14203
Schroeder JP, Spanos M, Stevenson JR, Besheer J, Salling M, Hodge CW (2008) Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK 1/2 phosphorylation in specific limbic brain regions: blockade by the mGluR5 antagonist MPEP. Neuropharmacology 55:546–554. https://doi.org/10.1016/j.neuropharm.2008.06.057
See R, Waters R (2011) Pharmacologically-induced stress: a cross-species probe for translational research in drug addiction and relapse. Am J Transl Res 3:81–89
Shaham Y, Rodaros D, Stewart J (1994) Reinstatement of heroin-reinforced behavior following long-term extinction: implications for the treatment of relapse to drug taking. Behav Pharmacol 5:360–364. https://doi.org/10.1097/00008877-199406000-00015
Shalev U, Grimm J, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42. https://doi.org/10.1124/pr.54.1.1
Shepard JD, Bossert JM, Liu SY, Shaham Y (2004) The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biol Psychiat 55:1082–1089. https://doi.org/10.1016/j.biopsych.2004.02.032
Singer JD, Willett JB (2003) Applied longitudinal data analysis: modeling change and event occurrence. Oxford University Press, New York. https://doi.org/10.1093/acprof:oso/9780195152968.001.0001
Smyth BP, Barry J, Keenan E, Ducray K (2010) Lapse and relapse following inpatient treatment of opiate dependence. Ir Med J 103:176–179
Stairs JD, Klein DE, Bardo TM (2006) Effects of environmental enrichment on extinction and reinstatement of amphetamine self-administration and sucrose-maintained responding. Behav Pharmacol 17:597–604. https://doi.org/10.1097/01.fbp.0000236271.72300.0e
Sutton MA, Karanian DA, Self DW (2000) Factors that determine a propensity for cocaine-seeking behavior during abstinence in rats. Neuropsychopharmacology 22:626–641. https://doi.org/10.1016/S0893-133X(99)00160-8
Towers EB, Tunstall BJ, McCracken ML, Vendruscolo LF, Koob GF (2019) Male and female mice develop escalation of heroin intake and dependence following extended access. Neuropharmacology 151:189–194. https://doi.org/10.1016/j.neuropharm.2019.03.019
Townsend EA, Negus SS, Caine SB, Thomsen M, Banks ML (2019) Sex differences in opioid reinforcement under a fentanyl vs. food choice procedure in rats. Neuropsychopharmacology 44(12):2022–2029. https://doi.org/10.1038/s41386-019-0356-1
Vendruscolo JCM et al (2018) Compulsive-like sufentanil vapor self-administration in rats. Neuropsychopharmacology 43:801–809. https://doi.org/10.1038/npp.2017.172
Wade CL, Vendruscolo LF, Schlosburg JE, Hernandez DO, Koob GF (2015) Compulsive-like responding for opioid analgesics in rats with extended access. Neuropsychopharmacology 40:421–428. https://doi.org/10.1038/npp.2014.188
Walitzer KS, Dearing RL (2006) Gender differences in alcohol and substance use relapse. Clin Psychol Rev 26:128–148. https://doi.org/10.1016/j.cpr.2005.11.003
Wee S, Specio S, Koob G (2007) Effects of dose and session duration on cocaine self-administration in rats. J Pharmacol Exp Ther 320:1134–1143. https://doi.org/10.1124/jpet.106.113340
Weiss V, Yates J, Beckmann J, Hammerslag L, Bardo M (2018) Social reinstatement: a rat model of peer-induced relapse. Psychopharmacology 235:3391–3400. https://doi.org/10.1007/s00213-018-5048-8
Yan Y, Yamada K, Nitta A, Nabeshima T (2007) Transient drug-primed but persistent cue-induced reinstatement of extinguished methamphetamine-seeking behavior in mice. Behav Brain Res 177:261–268. https://doi.org/10.1016/j.bbr.2006.11.033
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Support provided by National Institute of Health grants R01 DA053070, T32 DA035200, and T32 DA016176.
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Malone, S.G., Keller, P.S., Hammerslag, L.R. et al. Escalation and reinstatement of fentanyl self-administration in male and female rats. Psychopharmacology 238, 2261–2273 (2021). https://doi.org/10.1007/s00213-021-05850-7
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DOI: https://doi.org/10.1007/s00213-021-05850-7