Skip to main content

Advertisement

SpringerLink
Log in

Immediate and lasting effects of chronic daily methamphetamine exposure on activation of cells in hypothalamic-pituitary-adrenal axis-associated brain regions

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Chronic methamphetamine (MA) abuse leads to dependence and symptoms of withdrawal after use has ceased. Negative mood states associated with withdrawal, as well as drug reinstatement, have been linked to drug-induced disruption of the hypothalamic-pituitary-adrenal (HPA) axis. However, effects of chronic MA exposure or acute MA exposure following withdrawal on neural activation patterns within brain regions that regulate the HPA axis are unknown.

Objectives

In this study, neural activation patterns were assessed by quantification of c-Fos protein in mice exposed to different regimens of MA administration.

Methods

(Experiment 1) Adult male mice were treated with MA (5 mg/kg) or saline once or once daily for 10 days. (Experiment 2) Mice were treated with MA or saline once daily for 10 days and following a 10-day withdrawal period were re-administered a final dose of MA or saline. c-Fos was quantified in brains after the final injection.

Results

(Experiment 1) Compared to exposure to a single dose of MA (5 mg/kg), chronic MA exposure decreased the number of c-Fos expressing cells in the paraventricular hypothalamus, dorsomedial hypothalamus, central amygdala, basolateral amygdala, bed nucleus of the stria terminalis (BNST), and CA3 hippocampal region. (Experiment 2) Compared to mice receiving their first dose of MA, mice chronically treated with MA, withdrawn, and re-administered MA, showed decreased c-Fos expressing cells within the central and basolateral amygdala, BNST, and CA3.

Conclusions

HPA axis-associated amygdala, extended amygdala, and hippocampal regions endure lasting effects following chronic MA exposure and therefore may be linked to stress-related withdrawal symptoms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Acevedo SF, Pfankuch T, van Meer P, Raber J (2008) Role of histamine in short- and long-term effects of methamphetamine on the developing mouse brain. J Neurochem 107:976–986

    PubMed  CAS  PubMed Central  Google Scholar 

  • Armario A, Hidalgo J, Giralt M (1988) Evidence that the pituitary adrenal axis does not cross-adapt to stressors: comparison to other physiological variables. Neuroendocrinology 47:263–267

    Article  PubMed  CAS  Google Scholar 

  • Armario A, Vallès A, Dal-Zotto S, Márquez C, Belda X (2004) A single exposure to severe stressors causes long-term desensitisation of the physiological response to the homotypic stressor. Stress 7:157–172

    Article  PubMed  CAS  Google Scholar 

  • Belda X, Márquez C, Armario A (2004) Long-term effects of a single exposure to stress in adult rats on behavior and hypothalamic-pituitary-adrenal responsiveness: comparison of two outbred rat strains. Behav Brain Res 154:399–408

    Article  PubMed  CAS  Google Scholar 

  • Bhatnagar S, Dallman M (1998) Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress. Neuroscience 84:1025–1039

    Article  PubMed  CAS  Google Scholar 

  • Buffalari DM, Baldwin CK, Feltenstein MW, See RE (2012) Corticotrophin releasing factor (CRF) induced reinstatement of cocaine seeking in male and female rats. Physiol Behav 105:209–214

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Carson DS, Bosanquet DP, Carter CS, Pournajafi-Nazarloo H, Blaszczynski A, McGregor IS (2012) Preliminary evidence for lowered basal cortisol in a naturalistic sample of methamphetamine polydrug users. Exp Clin Psychopharmacol 20:497–503

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, Bender RA, Frotscher M, Baram TZ (2001) Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J Neurosci 21:7171–7181

    PubMed  CAS  PubMed Central  Google Scholar 

  • Cornish JL, Hunt GE, Robins L, McGregor IS (2012) Regional c-Fos and FosB/ΔFosB expression associated with chronic methamphetamine self-administration and methamphetamine-seeking behavior in rats. Neuroscience 206:100–114

    Article  PubMed  CAS  Google Scholar 

  • Danaceau JP, Deering CE, Day JE, Smeal SJ, Johnson-Davis KL, Fleckenstein AE, Wilkins DG (2007) Persistence of tolerance to methamphetamine-induced monoamine deficits. Eur J Pharmacol 559:46–54

    Article  PubMed  CAS  Google Scholar 

  • Fernández-Guasti A, Fiedler JL, Herrera L, Handa RJ (2012) Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones. Horm Metab Res 44:607–618

    Article  PubMed  PubMed Central  Google Scholar 

  • Franklin, KBJ, Paxinos, G. (1997) The Mouse Brain in Stereotaxic Coordinates. San Diego, CA: AcademicPress.

  • Giardino WJ, Pastor R, Anacker AM, Spangler E, Cote DM, Li J, Stenzel-Poore MP, Phillips TJ, Ryabinin AE (2011) Dissection of corticotropin-releasing factor system involvement in locomotor sensitivity to methamphetamine. Genes Brain Behav 10:78–89

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Girotti M, Pace TW, Gaylord RI, Rubin BA, Herman JP, Spencer RL (2006) Habituation to repeated restraint stress is associated with lack of stress-induced c-fos expression in primary sensory processing areas of the rat brain. Neuroscience 138:1067–1081

    Article  PubMed  CAS  Google Scholar 

  • Goel N, Bale TL (2010) Sex differences in the serotonergic influence on the hypothalamic-pituitary-adrenal stress axis. Endocrinology 151(4):1784–1794

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Graybiel AM, Moratalla R, Robertson HA (1990) Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum. Proc Natl Acad Sci U S A 87:6912–6916

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hamamura M, Ozawa H, Kimuro Y, Okouchi J, Higasa K, Iwaki A, Fukumaki Y (1999) Differential decreases in c-fos and aldolase C mRNA expression in the rat cerebellum afterrepeated administration of methamphetamine. Brain Res Mol Brain Res 64:119–31

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto K, Suemaru S, Takao T, Sugawara M, Makino S, Ota Z (1988) Corticotropin-releasing hormone and pituitary-adrenocortical responses in chronically stressed rats. Regul Pept 23:117–126

    Article  PubMed  CAS  Google Scholar 

  • Hauger RL, Millan MA, Lorang M, Harwood JP, Aguilera G (1988) Corticotropin-releasing factor receptors and pituitary adrenal responses during immobilization stress. Endocrinology 123:396–405

    Article  PubMed  CAS  Google Scholar 

  • Hildebrandt T, Greif R (2013) Stress and addiction. Psychoneuroendocrinology 38:1923–1927

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hope B, Kosofsky B, Hyman SE, Nestler EJ (1992) Regulation of immediate early gene expression and AP-1 binding in the rat nucleus accumbens by chronic cocaine. Proc Natl Acad Sci U S A 89:5764–8

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Inenaga K, Osaka T, Yamashita H (1987) Thermosensitivity of neurons in the paraventricular nucleus of the rat slice preparation. Brain Res 424:126–32

    Article  PubMed  CAS  Google Scholar 

  • Jang CG, Whitfield T, Schulteis G, Koob GF, Wee S (2013) A dysphoric-like state during early withdrawal from extended access to methamphetamine self-administration in rats. Psychopharmacology (Berl) 225:753–763

    Article  CAS  Google Scholar 

  • Jedynak JP, Cameron CM, Robinson TE (2012) Repeated methamphetamine administration differentially alters fos expression in caudate-putamen patch and matrix compartments and nucleus accumbens. PLoS ONE 7, e34227

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jian M, Luo YX, Xue YX, Han Y, Shi HS, Liu JF, Yan W, Wu P, Meng SQ, Deng JH, Shen HW, Shi J, Lu L (2014) eIF2α dephosphorylation in basolateral amygdala mediates reconsolidation of drug memory. J Neurosci 34:10010–10021

    Article  PubMed  Google Scholar 

  • Johnson LA, Olsen RH, Merkens LS, DeBarber A, Steiner RD, Sullivan PM, Maeda N, Raber J (2014) Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner. Neurobiol Dis 64:150–162

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Justice NJ, Yuan ZF, Sawchenko PE, Vale W (2008) Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J Comp Neurol 511:479–496

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kabbaj M, Yoshida S, Numachi Y, Matsuoka H, Devine DP, Sato M (2003) Methamphetamine differentially regulates hippocampal glucocorticoid and mineralocorticoid receptor mRNAs in Fischer and Lewis rats. Brain Res Mol Brain Res 117:8–14

    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

    Article  PubMed  CAS  Google Scholar 

  • Li SX, Yan SY, Bao YP, Lian Z, Qu Z, Wu YP, Liu ZM (2013) Depression and alterations in hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axis function in male abstinent methamphetamine abusers. Hum Psychopharmacol 28:477–483

    Article  PubMed  CAS  Google Scholar 

  • London ED, Simon SL, Berman SM, Mandelkern MA, Lichtman AM, Bramen J, Shinn AK, Miotto K, Learn J, Dong Y, Matochik JA, Kurian V, Newton T, Woods R, Rawson R, Ling W (2004) Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers. Arch Gen Psychiatry 61:73–84

    Article  PubMed  Google Scholar 

  • Lowy MT (1990) MK-801 antagonizes methamphetamine-induced decreases in hippocampal and striatal corticosteroid receptors. Brain Res 533:348–52

    Article  PubMed  CAS  Google Scholar 

  • Martin TA, Jayanthi S, McCoy MT, Brannock C, Ladenheim B, Garrett T, Lehrmann E, Becker KG, Cadet JL (2012) Methamphetamine causes differential alterations in gene expression and patterns of histone acetylation/hypoacetylation in the rat nucleus accumbens. PLoS ONE 7, e34236

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • McCoy MT, Jayanthi S, Wulu JA, Beauvais G, Ladenheim B, Martin TA, Krasnova IN, Hodges AB, Cadet JL (2011) Chronic methamphetamine exposure suppresses the striatal expression of members of multiple families of immediate early genes (IEGs) in the rat: normalization by an acute methamphetamine injection. Psychopharmacology (Berl) 215:353–365

    Article  CAS  PubMed Central  Google Scholar 

  • Melia KR, Ryabinin AE, Schroeder R, Bloom FE, Wilson MC (1994) Induction and habituation of immediate early gene expression in rat brain by acute and repeated restraint stress. J Neurosci 14:5929–5938

    PubMed  CAS  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 (Berl) 190:171–180

    Article  CAS  Google Scholar 

  • Moratalla R, Robertson HA, Graybiel AM (1992) Dynamic regulation of NGFI-A (zif268, egr1) gene expression in the striatum. J Neurosci 12:2609–2622

    PubMed  CAS  Google Scholar 

  • Myles BJ, Sabol KE (2008) The effects of methamphetamine on core body temperature in the rat--part 2: an escalating regimen. Psychopharmacology (Berl) 198:313–322

    Article  CAS  Google Scholar 

  • Myles BJ, Jarrett LA, Broom SL, Speaker HA, Sabol KE (2008) The effects of methamphetamine on core body temperature in the rat--part 1: chronic treatment and ambient temperature. Psychopharmacology (Berl) 198:301–311

    Article  CAS  Google Scholar 

  • Nawata Y, Kitaichi K, Yamamoto T (2012) Increases of CRF in the amygdala are responsible for reinstatement of methamphetamine-seeking behavior induced by footshock. Pharmacol Biochem Behav 10:297–302

    Article  Google Scholar 

  • Pham K, Nacher J, Hof PR, McEwen BS (2003) Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur J Neurosci 17(4):879–86

    Article  PubMed  Google Scholar 

  • Raber J (1998) Detrimental effects of chronic hypothalamic-pituitary-adrenal axis activation. From obesity to memory deficits. Mol Neurobiol 18:1–22

    Article  PubMed  CAS  Google Scholar 

  • Reichel CM, Schwendt M, McGinty JF, Olive MF, See RE (2011) Loss of object recognition memory produced by extended access to methamphetamine self-administration is reversed by positive allosteric modulation of metabotropic glutamate receptor 5. Neuropsychopharmacology 36:782–92

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Reichel CM, Ramsey LA, Schwendt M, McGinty JF, See RE (2012) Methamphetamine-induced changes in the object recognition memory circuit. Neuropharmacology 62:1119–1126

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Rendell PG, Mazur M, Henry JD (2009) Prospective memory impairment in former users of methamphetamine. Psychopharmacology (Berl) 203:609–16

    Article  CAS  Google Scholar 

  • Santos TB, Céspedes IC, Viana MB (2014) Chronic corticosterone administration facilitates aversive memory retrieval and increases GR/NOS immunoreactivity. Behav Brain Res 267:46–54

    Article  PubMed  CAS  Google Scholar 

  • Shoener JA, Baig R, Page KC (2006) Prenatal exposure to dexamethasone alters hippocampal drive on hypothalamic-pituitary-adrenal axis activity in adult male rats. Am J Physiol Regul Integr Comp Physiol 290:1366–1373

    Article  Google Scholar 

  • Silva CD, Neves AF, Dias AI, Freitas HJ, Mendes SM, Pita I, Viana SD, de Oliveira PA, Cunha RA, Fontes Ribeiro CA, Prediger RD, Pereira FC (2014) A single neurotoxic dose of methamphetamine induces a long-lasting depressive-like behaviour in mice. Neurotox Res 25:295–304

    Article  PubMed  CAS  Google Scholar 

  • Stephan FK, Nunez AA (1977) Elimination of circadian rhythms in drinking, activity, sleep, and temperature by isolation of the suprachiasmatic nuclei. Behav Biol 20:1–61

    Article  PubMed  CAS  Google Scholar 

  • Substance Abuse and Mental Health Services Administration (SAMHSA) (2012) Results from the 2011 National Survey on Drug Use and Health: Summary of National Findings. In: NSDUH Series H-44, HHS Publication No. (SMA) 12–4713. Substance Abuse and Mental Health Services Administration, Rockville, MD

  • Umemoto S, Noguchi K, Kawai Y, Senba E (1994) Repeated stress reduces the subsequent stress-induced expression of Fos in rat brain. Neurosci Lett 167:101–104

    Article  PubMed  CAS  Google Scholar 

  • Uno H, Tarara R, Else JG, Suleman MA, Sapolsky RM (1989) (1989) Hippocampal damage associated with prolonged and fatal stress in primates. J Neurosci 9(5):1705–1711

    PubMed  CAS  Google Scholar 

  • Zahm DS, Becker ML, Freiman AJ, Strauch S, Degarmo B, Geisler S, Meredith GE, Marinelli M (2010) Fos after single and repeated self-administration of cocaine and saline in the rat: emphasis on the Basal forebrain and recalibration of expression. Neuropsychopharmacology 35:445–63

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zaretskaia MV, Zaretsky DV, Shekhar A, DiMicco JA (2002) Chemical stimulation of the dorsomedial hypothalamus evokes non-shivering thermogenesis in anesthetized rats. Brain Res 928:113–125

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Zhang L, Jiao H, Zhang Q, Zhang D, Lou D, Katz JL, Xu M (2006) c-Fos facilitates the acquisition and extinction of cocaine-induced persistent changes. J Neurosci 26:13287–13296

    Article  PubMed  CAS  Google Scholar 

  • Zhu H, Mingler MK, McBride ML, Murphy AJ, Valenzuela DM, Yancopoulos GD, Williams MT, Vorhees CV, Rothenberg ME (2010) Abnormal response to stress and impaired NPS-induced hyperlocomotion, anxiolytic effect and corticosterone increase in mice lacking NPSR1. Psychoneuroendocrinology 35:1119–1132

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zorrilla EP, Heilig M, de Wit H, Shaham Y (2013) Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism. Drug Alcohol Depend 128:175–86

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zuloaga DG, Siegel JA, Acevedo SF, Agam M, Raber J (2013) Developmental methamphetamine exposure results in short- and long-term alterations in hypothalamic-pituitary-adrenal-axis-associated proteins. Dev Neurosci 35:338–346

    Article  PubMed  CAS  Google Scholar 

  • Zuloaga DG, Johnson LA, Agam M, Raber J (2014) Sex differences in activation of the hypothalamic-pituitary-adrenal axis by methamphetamine. J Neurochem 129:495–508

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zuloaga DG, Iancu O, Weber S, Etzel D, Marzulla T, Stewart B, Allen CN, Raber J (2015a) Enhanced functional connectivity involving the ventromedial hypothalamus following methamphetamine exposure. Front Neurosci 9:326

  • Zuloaga DG, Jacobskind JS, Raber J (2015b) Methamphetamine and the hypothalamic-pituitary-adrenal axis. Front Neurosci 9:178

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors acknowledge Tessa Marzulla, Tara Kugelman, and Chi Phan for their expert technical assistance. Funding was provided by NIDA T32DA007262, an Oregon Health and Science University Tartar Award, and the Oregon Health and Science University development account of Dr. Raber.

Author information

Authors and Affiliations

  1. Department of Behavioral Neuroscience, Oregon Health and Science University Portland, Portland, OR, 97239, USA

    Damian G. Zuloaga, Lance A. Johnson, Sydney Weber & Jacob Raber

  2. Department of Psychology, University at Albany, Albany, NY, 12222, USA

    Damian G. Zuloaga

  3. Department of Neurology, Oregon Health and Science University Portland, Portland, OR, 97239, USA

    Jacob Raber

  4. Department of Radiation Medicine, Oregon Health and Science University Portland, Portland, OR, 97239, USA

    Jacob Raber

  5. Division of Neuroscience, ONPRC, Oregon Health and Science University Portland, Portland, OR, 97239, USA

    Jacob Raber

Authors
  1. Damian G. Zuloaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lance A. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sydney Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacob Raber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Damian G. Zuloaga.

Ethics declarations

Conflict of Interest

The authors report no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zuloaga, D.G., Johnson, L.A., Weber, S. et al. Immediate and lasting effects of chronic daily methamphetamine exposure on activation of cells in hypothalamic-pituitary-adrenal axis-associated brain regions. Psychopharmacology 233, 381–392 (2016). https://doi.org/10.1007/s00213-015-4114-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-015-4114-8

Keywords

Search

Navigation