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Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats

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Abstract

Rationale

Methamphetamine is a highly addictive psychostimulant, and chronic methamphetamine users show high rates of relapse. Furthermore, prolonged methamphetamine abuse can lead to psychiatric symptoms and has been associated with various cognitive dysfunctions. However, the impact of self-administered methamphetamine on cognitive dysfunction and relapse has not been concurrently examined in an animal model.

Objectives

The present study determined the effects of short- vs. long-access contingent methamphetamine on self-administration, extinction responding, reinstatement of methamphetamine seeking, and cognitive performance on an object exploration task.

Materials and methods

Long-Evans rats self-administered methamphetamine i.v. (0.02 mg/infusion) or received saline during daily sessions (1 or 2 h) for 10 days, followed by either maintained short- (1 or 2 h) or long-access (6 h) self-administration for 14 days. Lever responding was extinguished prior to reinstatement, which consisted of presentation of drug-paired cues or a priming injection of methamphetamine (1.0 mg/kg). Animals were also tested on an object exploration task prior to self-administration and at 10–12 days after cessation of self-administration, thus providing a comparison of pre-methamphetamine exposure with post-methamphetamine exposure.

Results

Long-access methamphetamine self-administration resulted in escalation of daily intake. Furthermore, animals in both short- and long-access groups showed robust conditioned-cued and drug-primed reinstatement, with long access resulting in enhanced methamphetamine-primed reinstatement. Methamphetamine self-administration also led to access-dependent impairments on novel object recognition but failed to impair recognition of spatial reconfiguration.

Conclusions

Extended methamphetamine self-administration enhances drug-primed reinstatement and decreases novel object recognition, indicating that prolonged contingent methamphetamine increases motivation for drug seeking following withdrawal while increasing cognitive deficits.

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References

  • Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300

    Article  PubMed  CAS  Google Scholar 

  • Ahmed SH, Koob GF (1999) Long-lasting increase in the set point for cocaine self-administration after escalation in rats. Psychopharmacology 146:303–312

    Article  PubMed  CAS  Google Scholar 

  • Ahmed SH, Koob GF (2005) Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function. Psychopharmacology 180:473–490

    Article  PubMed  CAS  Google Scholar 

  • Ahmed SH, Kenny PJ, Koob GF, Markou A (2002) Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci 5:625–626

    PubMed  CAS  Google Scholar 

  • Anggadiredja K, Nakamichi M, Hiranita T, Tanaka H, Shoyama Y, Watanabe S, Yamamoto T (2004a) Endocannabinoid system modulates relapse to methamphetamine seeking: possible mediation by the arachidonic acid cascade. Neuropsychopharmacology 29:1470–1478

    Article  PubMed  CAS  Google Scholar 

  • Anggadiredja K, Sakimura K, Hiranita T, Yamamoto T (2004b) Naltrexone attenuates cue- but not drug-induced methamphetamine seeking: a possible mechanism for the dissociation of primary and secondary reward. Brain Res 1021:272–276

    Article  PubMed  CAS  Google Scholar 

  • Belcher AM, O’Dell SJ, Marshall JF (2005) Impaired object recognition memory following methamphetamine, but not p-chloroamphetamine- or d-amphetamine-induced neurotoxicity. Neuropsychopharmacology 30:2026–2034

    Article  PubMed  CAS  Google Scholar 

  • Bisagno V, Ferguson D, Luine VN (2002) Short toxic methamphetamine schedule impairs object recognition task in male rats. Brain Res 940:95–101

    Article  PubMed  CAS  Google Scholar 

  • Brecht ML, Greenwell L, Anglin MD (2005) Methamphetamine treatment: trends and predictors of retention and completion in a large state treatment system (1992–2002). J Subst Abuse Treat 29:295–306

    Article  PubMed  Google Scholar 

  • Daberkow DP, Kesner RP, Keefe KA (2005) Relation between methamphetamine-induced monoamine depletions in the striatum and sequential motor learning. Pharmacol Biochem Behav 81:198–204

    Article  PubMed  CAS  Google Scholar 

  • Dalley JW, Laane K, Pena Y, Theobald DE, Everitt BJ, Robbins TW (2005) Attentional and motivational deficits in rats withdrawn from intravenous self-administration of cocaine or heroin. Psychopharmacology 182:579–587

    Article  PubMed  CAS  Google Scholar 

  • Feltenstein MW, See RE (2008) The neurocircuitry of addiction: an overview. Br J Pharmacol (in press)

  • Feltenstein MW, Altar CA, See RE (2007) Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse. Biol Psychiatry 61:582–590

    Article  PubMed  CAS  Google Scholar 

  • Ferrario CR, Gorny G, Crombag HS, Li Y, Kolb B, Robinson TE (2005) Neural and behavioral plasticity associated with the transition from controlled to escalated cocaine use. Biol Psychiatry 58:751–759

    Article  PubMed  CAS  Google Scholar 

  • Fuchs RA, Tran-Nguyen LT, Weber SM, Khroyan TV, Neisewander JL (2002) Effects of 7-OH-DPAT on cocaine-seeking behavior and on re-establishment of cocaine self-administration. Pharmacol Biochem Behav 72:623–632

    Article  PubMed  CAS  Google Scholar 

  • Fuchs RA, Evans KA, Parker MP, See RE (2004) Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats. J Neurosci 24:6600–6610

    Article  PubMed  CAS  Google Scholar 

  • Fuchs RA, Feltenstein MW, See RE (2006) The role of the basolateral amygdala in stimulus-reward memory and extinction memory consolidation and in subsequent conditioned cued reinstatement of cocaine seeking. Eur J Neurosci 23:2809–2813

    Article  PubMed  Google Scholar 

  • Hiranita T, Nawata Y, Sakimura K, Anggadiredja K, Yamamoto T (2006) Suppression of methamphetamine-seeking behavior by nicotinic agonists. Proc Natl Acad Sci USA 103:8523–8527

    Article  PubMed  CAS  Google Scholar 

  • Itzhak Y, Martin JL, Ali SF (2002) Methamphetamine-induced dopaminergic neurotoxicity in mice: long-lasting sensitization to the locomotor stimulation and desensitization to the rewarding effects of methamphetamine. Prog Neuropsychopharmacol Biol Psychiatry 26:1177–1183

    Article  PubMed  CAS  Google Scholar 

  • Kalechstein AD, Newton TF, Green M (2003) Methamphetamine dependence is associated with neurocognitive impairment in the initial phases of abstinence. J Neuropsychiatry Clin Neurosci 15:215–220

    PubMed  CAS  Google Scholar 

  • Kamei H, Nagai T, Nakano H, Togan Y, Takayanagi M, Takahashi K, Kobayashi K, Yoshida S, Maeda K, Takuma K, Nabeshima T, Yamada K (2006) Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice. Biol Psychiatry 59:75–84

    Article  PubMed  CAS  Google Scholar 

  • Kesner RP, Rogers J (2004) An analysis of independence and interactions of brain substrates that subserve multiple attributes, memory systems, and underlying processes. Neurobiol Learn Mem 82:199–215

    Article  PubMed  Google Scholar 

  • Kippin TE, Fuchs RA, See RE (2006) Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine seeking in rats. Psychopharmacology 187:60–67

    Article  PubMed  CAS  Google Scholar 

  • Kitamura O, Wee S, Specio SE, Koob GF, Pulvirenti L (2006) Escalation of methamphetamine self-administration in rats: a dose–effect function. Psychopharmacology 186:48–53

    Article  PubMed  CAS  Google Scholar 

  • Knackstedt LA, Kalivas PW (2007) Extended access to cocaine self-administration enhances drug-primed reinstatement but not behavioral sensitization. J Pharmacol Exp Ther 322:1103–1109

    Article  PubMed  CAS  Google Scholar 

  • Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, Markou A, O’Dell LE, Parsons LH, Sanna PP (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27:739–749

    Article  PubMed  CAS  Google Scholar 

  • Kruzich PJ, Xi J (2006) Differences in extinction responding and reinstatement of methamphetamine-seeking behavior between Fischer 344 and Lewis rats. Pharmacol Biochem Behav 83:391–395

    Article  PubMed  CAS  Google Scholar 

  • Lee I, Hunsaker MR, Kesner RP (2005) The role of hippocampal subregions in detecting spatial novelty. Behav Neurosci 119:145–153

    Article  PubMed  Google Scholar 

  • London ED, Berman SM, Voytek B, Simon SL, Mandelkern MA, Monterosso J, Thompson PM, Brody AL, Geaga JA, Hong MS, Hayashi KM, Rawson RA, Ling W (2005) Cerebral metabolic dysfunction and impaired vigilance in recently abstinent methamphetamine abusers. Biol Psychiatry 58:770–778

    Article  PubMed  CAS  Google Scholar 

  • Mandyam CD, Wee S, Eisch AJ, Richardson HN, Koob GF (2007) Methamphetamine self-administration and voluntary exercise have opposing effects on medial prefrontal cortex gliogenesis. J Neurosci 27:11442–11450

    Article  PubMed  CAS  Google Scholar 

  • Mantsch JR, Yuferov V, Mathieu-Kia AM, Ho A, Kreek MJ (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

    Article  PubMed  CAS  Google Scholar 

  • McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663

    PubMed  CAS  Google Scholar 

  • Meredith CW, Jaffe C, Ang-Lee K, Saxon AJ (2005) Implications of chronic methamphetamine use: a literature review. Harv Rev Psychiatry 13:141–154

    Article  PubMed  Google Scholar 

  • Moffett MC, Goeders NE (2007) CP-154,526, a CRF type-1 receptor antagonist, attenuates the cue-and methamphetamine-induced reinstatement of extinguished methamphetamine-seeking behavior in rats. Psychopharmacology 190:171–180

    Article  PubMed  CAS  Google Scholar 

  • Morgan D, Roberts DC (2004) Sensitization to the reinforcing effects of cocaine following binge-abstinent self-administration. Neurosci Biobehav Rev 27:803–812

    Article  PubMed  CAS  Google Scholar 

  • Morgan D, Brebner K, Lynch WJ, Roberts DC (2002) Increases in the reinforcing efficacy of cocaine after particular histories of reinforcement. Behav Pharmacol 13:389–396

    PubMed  CAS  Google Scholar 

  • O’Dell SJ, Weihmuller FB, Marshall JF (1991) Multiple methamphetamine injections induce marked increases in extracellular striatal dopamine which correlate with subsequent neurotoxicity. Brain Res 564:256–260

    Article  PubMed  CAS  Google Scholar 

  • Paulus MP, Hozack NE, Zauscher BE, Frank L, Brown GG, Braff DL, Schuckit MA (2002) Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects. Neuropsychopharmacology 26:53–63

    Article  PubMed  CAS  Google Scholar 

  • Richards JB, Sabol KE, de Wit H (1999) Effects of methamphetamine on the adjusting amount procedure, a model of impulsive behavior in rats. Psychopharmacology 146:432–439

    Article  PubMed  CAS  Google Scholar 

  • Rogers JL, Kesner RP (2007) Hippocampal–parietal cortex interactions: evidence from a disconnection study in the rat. Behav Brain Res 179:19–27

    Article  PubMed  Google Scholar 

  • Rogers JL, See RE (2007) Selective inactivation of the ventral hippocampus attenuates cue-induced and cocaine-primed reinstatement of drug-seeking in rats. Neurobiol Learn Mem 87:688–692

    Article  PubMed  CAS  Google Scholar 

  • Roth ME, Carroll ME (2004a) Sex differences in the acquisition of IV methamphetamine self-administration and subsequent maintenance under a progressive ratio schedule in rats. Psychopharmacology 172:443–449

    Article  PubMed  CAS  Google Scholar 

  • Roth ME, Carroll ME (2004b) Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administration. Pharmacol Biochem Behav 78:199–207

    Article  PubMed  CAS  Google Scholar 

  • Schroder N, O’Dell SJ, Marshall JF (2003) Neurotoxic methamphetamine regimen severely impairs recognition memory in rats. Synapse 49:89–96

    Article  PubMed  CAS  Google Scholar 

  • See RE (2005) Neural substrates of cocaine-cue associations that trigger relapse. Eur J Pharmacol 526:140–146

    Article  PubMed  CAS  Google Scholar 

  • Shaham Y, Erb S, Stewart J (2000) Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev 33:13–33

    Article  PubMed  CAS  Google Scholar 

  • Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42

    Article  PubMed  CAS  Google Scholar 

  • Shepard JD, Bossert JM, Liu SY, Shaham Y (2004) The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biol Psychiatry 55:1082–1089

    Article  PubMed  CAS  Google Scholar 

  • Shepard JD, Chuang DT, Shaham Y, Morales M (2006) Effect of methamphetamine self-administration on tyrosine hydroxylase and dopamine transporter levels in mesolimbic and nigrostriatal dopamine pathways of the rat. Psychopharmacology 185:505–513

    Article  PubMed  CAS  Google Scholar 

  • Simon SL, Domier C, Carnell J, Brethen P, Rawson R, Ling W (2000) Cognitive impairment in individuals currently using methamphetamine. Am J Addict 9:222–231

    Article  PubMed  CAS  Google Scholar 

  • Stefanski R, Ladenheim B, Lee SH, Cadet JL, Goldberg SR (1999) Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine. Eur J Pharmacol 371:123–135

    Article  PubMed  CAS  Google Scholar 

  • Stefanski R, Lee SH, Yasar S, Cadet JL, Goldberg SR (2002) Lack of persistent changes in the dopaminergic system of rats withdrawn from methamphetamine self-administration. Eur J Pharmacol 439:59–68

    Article  PubMed  CAS  Google Scholar 

  • Vanderschuren LJ, Everitt BJ (2004) Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305:1017–1019

    Article  PubMed  CAS  Google Scholar 

  • Woods SP, Rippeth JD, Conover E, Gongvatana A, Gonzalez R, Carey CL, Cherner M, Heaton RK, Grant I (2005) Deficient strategic control of verbal encoding and retrieval in individuals with methamphetamine dependence. Neuropsychology 19:35–43

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Zhu JP, Xu W, Angulo N, Angulo JA (2006) Methamphetamine-induced striatal apoptosis in the mouse brain: comparison of a binge to an acute bolus drug administration. Neurotoxicology 27:131–136

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by the National Institute on Drug Abuse grants DA10462, DA15369 and DA22658 to RES, DA07288-16 to JLR, and NIH grant C06 RR015455.

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  1. Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, BSB416, Charleston, SC, 29425-5100, USA

    J. L. Rogers, S. De Santis & R. E. See

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  1. J. L. Rogers
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  2. S. De Santis
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  3. R. E. See
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Correspondence to R. E. See.

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Rogers, J.L., De Santis, S. & See, R.E. Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats. Psychopharmacology 199, 615–624 (2008). https://doi.org/10.1007/s00213-008-1187-7

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  • DOI: https://doi.org/10.1007/s00213-008-1187-7

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