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Elevated startle during withdrawal from acute morphine: a model of opiate withdrawal and anxiety

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Abstract

Rationale

An elevated startle response has been observed in humans and animals during withdrawal from multiple substances of abuse, a phenomenon thought to reflect the anxiogenic effects of withdrawal. Although anxiety is a common symptom of opiate withdrawal, few studies have examined the effects of morphine withdrawal on acoustic startle.

Objective

To develop a procedure for assessing opiate dependence through measurement of the startle reflex in rats.

Methods

The effects of opiate withdrawal on startle were evaluated using both spontaneous and naloxone-precipitated withdrawal from an acute dose of morphine. The ability of the treatment drugs clonidine and chlordiazepoxide to block withdrawal-induced increases in startle was also tested.

Results

Spontaneous withdrawal from an injection of morphine sulfate produced a significant increase in acoustic startle 2 h (3.2 mg/kg) or 4 h (10 mg/kg) after drug administration. Morphine withdrawal (10 mg/kg morphine sulfate) precipitated by the opiate antagonist naloxone (2.5 mg/kg) also produced a significant increase in startle magnitude. This elevation of startle was blocked by both clonidine (35 μg/kg) and chlordiazepoxide (10 mg/kg).

Conclusions

These data demonstrate that both spontaneous and precipitated withdrawal from an acutely administered opiate produce anxiety-like effects on acoustic startle. This paradigm may be useful in the study of anxiety and the early mechanisms of drug dependence.

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References

  • Adams JU, Holtzman SG (1990) Pharmacologic characterization of the sensitization to the rate-decreasing effects of naltrexone induced by acute opioid pretreatment in rats. J Pharmacol Exp Ther 253:483–489

    CAS  PubMed  Google Scholar 

  • Azolosa JL, Stitzer ML, Greenwald MK (1994) Opioid physical dependence development: effects of single versus repeated morphine pretreatments and of subjects' opioid exposure history. Psychopharmacology 114:71–80

    Google Scholar 

  • Baas JM, Grillon C, Bocker KB et al. (2002) Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology 161:233–247

    PubMed  Google Scholar 

  • Basso AM, Spina M, Rivier J, Vale W, Koob GF (1999) Corticotropin-releasing factor antagonist attenuates the "anxiogenic- like" effect in the defensive burying paradigm but not in the elevated plus-maze following chronic cocaine in rats. Psychopharmacology 145:21–30

    CAS  PubMed  Google Scholar 

  • Bhattacharya SK, Chakrabarti A, Sandler M, Glover V (1995) Rat brain monoamine oxidase A and B inhibitory (tribulin) activity during drug withdrawal anxiety. Neurosci Lett 199:103–106

    Article  CAS  PubMed  Google Scholar 

  • Bickel WK, Stitzer ML, Liebson IA, Bigelow GE (1988) Acute physical dependence in man: effects of naloxone after brief morphine exposure. J Pharmacol Exp Ther 244:126–132

    CAS  PubMed  Google Scholar 

  • Davis M (1979) Morphine and naloxone: effects on conditioned fear as measured with the potentiated startle paradigm. Eur J Pharmacol 54:341–347

    CAS  PubMed  Google Scholar 

  • Davis M, Astrachan DI (1981) Spinal modulation of acoustic startle: opposite effects of clonidine and d-amphetamine. Psychopharmacology 75:219–225

    CAS  PubMed  Google Scholar 

  • Davis M, Redmond DE Jr, Baraban JM (1979) Noradrenergic agonists and antagonists: effects on conditioned fear as measured by the potentiated startle paradigm. Psychopharmacology 65:111–118

    CAS  PubMed  Google Scholar 

  • Davis M, Falls WA, Campeau S, Kim M (1993) Fear-potentiated startle: a neural and pharmacological analysis. Behav Brain Res 58:175–198

    CAS  PubMed  Google Scholar 

  • Dwoskin LP, Neal BS, Sparber SB (1983) Yohimbine exacerbates and clonidine attenuates acute morphine withdrawal in rats. Eur J Pharmacol 90:269–273

    Article  CAS  PubMed  Google Scholar 

  • Eisenberg RM (1983) Influence of clonidine on the acute dependence response elicited in naive rats by naloxone. Life Sci 32:1547–1552

    Article  CAS  PubMed  Google Scholar 

  • Falls WA, Carlson S, Turner JG, Willott JF (1997) Fear-potentiated startle in two strains of inbred mice. Behav Neurosci 111:855–861

    Article  CAS  PubMed  Google Scholar 

  • Fendt M, Mucha RF (2001) Anxiogenic-like effects of opiate withdrawal seen in the fear-potentiated startle test, an interdisciplinary probe for drug-related motivational states. Psychopharmacology 155:242–250

    Article  CAS  PubMed  Google Scholar 

  • File SE, Baldwin HA, Aranko K (1987) Anxiogenic effects in benzodiazepine withdrawal are linked to the development of tolerance. Brain Res Bull 19:607–610

    CAS  PubMed  Google Scholar 

  • Grillon C, Baas JM (2002) Comments on the use of the startle reflex in psychopharmacological challenges: impact of baseline startle on measurement of fear-potentiated startle. Psychopharmacology 164:236–238

    Article  CAS  PubMed  Google Scholar 

  • Harris AC, Hanes SL, Liszewski MC, Smith CS, Gewirtz JC (2002) Elevated acoustic startle in rats as a measure of withdrawal from acute opiate administration: effects of single and repeated withdrawals. Soc Neurosci Abstr online

    Google Scholar 

  • Helton DR, Modlin DL, Tizzano JP, Rasmussen K (1993) Nicotine withdrawal: a behavioral assessment using schedule controlled responding, locomotor activity, and sensorimotor reactivity. Psychopharmacology 113:205–210

    CAS  PubMed  Google Scholar 

  • Higgins GA, Sellers EM (1994) Antagonist-precipitated opioid withdrawal in rats: evidence for dissociations between physical and motivational signs. Pharmacol Biochem Behav 48:1–8

    CAS  PubMed  Google Scholar 

  • Jacob JJ, Michaud GM (1974) Acute physical dependence in the waking dog after a single low dose of morphine. Psychol Med 4:270–273

    CAS  PubMed  Google Scholar 

  • Kirby KC, Stitzer ML, Heishman SJ (1990) Acute opioid physical dependence in humans: effect of varying the morphine-naloxone interval II. J Pharmacol Exp Ther 255:730–737

    CAS  PubMed  Google Scholar 

  • Kishioka S, Paronis CA, Woods JH (2000) Acute dependence on, but not tolerance to, heroin and morphine as measured by respiratory effects in rhesus monkeys. Eur J Pharmacol 398:121–130

    Article  CAS  PubMed  Google Scholar 

  • Koch M (1999) The neurobiology of startle. Prog Neurobiol 59:107–128

    CAS  PubMed  Google Scholar 

  • Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278:52–58

    CAS  PubMed  Google Scholar 

  • Krystal JH, Webb E, Grillon C, Cooney N, Casal L, Morgan CA 3rd, Southwick SM, Davis M, Charney DS (1997) Evidence of acoustic startle hyperreflexia in recently detoxified early onset male alcoholics: modulation by yohimbine and m-chlorophenylpiperazine (mCPP). Psychopharmacology 131:207–215

    Article  CAS  PubMed  Google Scholar 

  • Lee Y, Lopez DE, Meloni EG, Davis M (1996) A primary acoustic startle pathway: obligatory role of cochlear root neurons and the nucleus reticularis pontis caudalis. J Neurosci 16:3775–3789

    CAS  PubMed  Google Scholar 

  • Maldonado R (1997) Participation of noradrenergic pathways in the expression of opiate withdrawal: biochemical and pharmacological evidence. Neurosci Biobehav Rev 21:91–104

    CAS  PubMed  Google Scholar 

  • Mansbach RS, Gold LH, Harris LS (1992) The acoustic startle response as a measure of behavioral dependence in rats. Psychopharmacology 108:40–46

    Google Scholar 

  • Mayo-Smith MF (1997) Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. JAMA 278:144–151

    PubMed  Google Scholar 

  • Meyer DR, Sparber SB (1977) Evidence of possible opiate dependence during the behavioral depressant action of a single dose of morphine. Life Sci 21:1087–1093

    Article  CAS  PubMed  Google Scholar 

  • Morgan CA 3rd, Southwick SM, Grillon C, Davis M, Krystal JH, Charney DS (1993) Yohimbine-facilitated acoustic startle reflex in humans. Psychopharmacology 110:342–346

    CAS  PubMed  Google Scholar 

  • Rasmussen K, Helton DR, Berger JE, Scearce E (1994) The CCK-B antagonist LY288513 blocks diazepam-withdrawal-induced increases in auditory startle response. Ann NY Acad Sci 713:374–376

    CAS  PubMed  Google Scholar 

  • Rassnick S, Koob GF, Geyer MA (1992) Responding to acoustic startle during chronic ethanol intoxication and withdrawal. Psychopharmacology 106:351–358

    Google Scholar 

  • Risdahl JM, Chao C, Murtaugh MP, Peterson PK, Molitor TW (1992) Acute and chronic morphine administration in swine. Pharmacol Biochem Behav 43:799–800

    Article  CAS  PubMed  Google Scholar 

  • Schulteis G, Koob GF (1996) Reinforcement processes in opiate addiction: a homeostatic model. Neurochem Res 21:1437–1454

    CAS  PubMed  Google Scholar 

  • Schulteis G, Heyser CJ, Koob GF (1997) Opiate withdrawal signs precipitated by naloxone following a single exposure to morphine: potentiation with a second morphine exposure. Psychopharmacology 129:56–65

    Google Scholar 

  • Schulteis G, Yackey M, Risbrough V, Koob GF (1998) Anxiogenic-like effects of spontaneous and naloxone-precipitated opiate withdrawal in the elevated plus-maze. Pharmacol Biochem Behav 60:727–731

    CAS  PubMed  Google Scholar 

  • Schulteis G, Heyser CJ, Koob GF (1999) Differential expression of response-disruptive and somatic indices of opiate withdrawal during the initiation and development of opiate dependence. Behav Pharmacol 10:235–242

    CAS  PubMed  Google Scholar 

  • Sparber SB, Gellert VF, Lichtblau L, Eisenberg R (1978) The use of operant behavior methods to study aggression and effects of acute and chronic morphine administration in rats. In: Adler ML, Manara L, Samanin R (eds) Factors affecting the action of narcotics. Raven Press, New York, pp 63–91

  • Stine SM, Grillon CG, Morgan CA 3rd, Kosten TR, Charney DS, Krystal JH (2001) Methadone patients exhibit increased startle and cortisol response after intravenous yohimbine. Psychopharmacology 154:274–281

    Article  CAS  PubMed  Google Scholar 

  • Swerdlow NR, Geyer MA, Vale WW, Koob GF (1986) Corticotropin-releasing factor potentiates acoustic startle in rats: blockade by chlordiazepoxide. Psychopharmacology 88:147–152

    Google Scholar 

  • Vandergriff J, Kallman MJ, Rasmussen K (2000) Moxonidine, a selective imidazoline-1 receptor agonist, suppresses the effects of ethanol withdrawal on the acoustic startle response in rats. Biol Psychiatry 47:874–879

    Article  CAS  PubMed  Google Scholar 

  • Walker DL, Davis M (1997) Anxiogenic effects of high illumination levels assessed with the acoustic startle response. Biol Psychiatry 42:461–471

    CAS  PubMed  Google Scholar 

  • Walker DL, Davis M (2002) Light-enhanced startle: further pharmacological and behavioral characterization. Psychopharmacology 159:304–310

    Google Scholar 

  • Winslow JT, Parr LA, Davis M (2002) Acoustic startle, prepulse inhibition, and fear-potentiated startle measured in rhesus monkeys. Biol Psychiatry 51:859–866

    Article  PubMed  Google Scholar 

  • Yoburn BC, Chen J, Huang T, Inturrisi CE (1985) Pharmacokinetics and pharmacodynamics of subcutaneous morphine pellets in the rat. J Pharmacol Exp Ther 235:282–286

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank David Atkinson, Stephanie Hanes, and Michelle Pilat and for their assistance in conducting the experiments. In addition, we thank Drs. Lisa Schrott, Monica Luciana, and Megan Gunnar of the University of Minnesota for helpful discussion of the manuscript. This work was supported by the National Institute on Drug Abuse T32 DA07097 and the University of Minnesota.

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  1. Department of Psychology, University of Minnesota, 75 East River Road, Minneapolis, MN, 55455, USA

    Andrew C. Harris & Jonathan C. Gewirtz

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  1. Andrew C. Harris
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  2. Jonathan C. Gewirtz
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Correspondence to Jonathan C. Gewirtz.

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Harris, A.C., Gewirtz, J.C. Elevated startle during withdrawal from acute morphine: a model of opiate withdrawal and anxiety. Psychopharmacology 171, 140–147 (2004). https://doi.org/10.1007/s00213-003-1573-0

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  • DOI: https://doi.org/10.1007/s00213-003-1573-0

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