Skip to main content
SpringerLink
Log in

Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats

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

Abstract

Rationale

Successful treatment of cocaine addiction is severely impeded by the propensity of users to relapse. Withdrawal severity may serve as a key predictor of susceptibility to relapse. Therefore, the identification and treatment of cocaine withdrawal symptoms such as anxiety may improve addiction treatment outcome.

Objectives

The current study examined the role of anxiety-like behavior during cocaine withdrawal and anxiolytic treatment in reinstatement of cocaine seeking in an animal model of relapse.

Methods

Male rats experienced daily IV cocaine self-administration. One group of animals received the norepinephrine α-2 agonist, guanfacine, or vehicle prior to anxiety testing 48 h after the last self-administration session. In the second group of rats, relationships between cocaine intake, anxiety-like behavior after withdrawal of cocaine, and reinstatement responding were investigated. The third and fourth groups of animals received guanfacine, yohimbine (norepinephrine α-2 antagonist), or vehicle once per day for 3 days 48 h after cessation of cocaine self-administration, followed by extinction and subsequent reinstatement induced by cocaine injections, cocaine-paired cues, and yohimbine administration.

Results

Cocaine-withdrawn rats at 48 h demonstrated higher levels of anxiety-like behavior as measured on a defensive burying task when compared to yoked saline controls, an effect reversed by guanfacine treatment. Cocaine intake was positively correlated with measures of anxiety-like behavior during early withdrawal, and this anxiety-like behavior was significantly correlated with subsequent cocaine-primed reinstatement. Yohimbine treatment during early withdrawal increased reinstatement to conditioned cues, while guanfacine treatment reduced reinstatement to yohimbine.

Conclusions

These studies suggest an important role for noradrenergic mediation of anxiety-like behavior that emerges after withdrawal of cocaine and potential risk of relapse as modeled by reinstatement, and suggest that treatment of anxiety symptoms during early abstinence may reduce the risk of relapse.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

References

  • Ahmadi J, Kampman K, Dackis C (2006) Outcome predictors in cocaine dependence treatment trials. Am J Addict 15:434–439

    Article  PubMed  Google Scholar 

  • Ahmadi J, Kampman KM, Oslin DM, Pettinati HM, Dackis C, Sparkman T (2009) Predictors of treatment outcome in outpatient cocaine and alcohol dependence treatment. Am J Addict 18:81–86

    Article  PubMed  Google Scholar 

  • Ambrose-Lanci LM, Sterling RC, Van Bockstaele EJ (2010) Cocaine withdrawal-induced anxiety in females: impact of circulating estrogen and potential use of delta-opioid receptor agonists for treatment. J Neurosci Res 88:816–824

    PubMed  CAS  Google Scholar 

  • American Psychiatric Association T (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Arlington

    Google Scholar 

  • Antkiewicz-Michaluk L, Filip M, Michaluk J, Romanska I, Patsenka A, Papla I, Przegalinski E, Vetulani J (2006) Conditioned rewarding stimulus associated with cocaine self-administration reverses the depression of catecholamine brain systems following cocaine withdrawal in rats. Int J Neuropsychopharmacol 9:37–50

    Article  PubMed  CAS  Google Scholar 

  • Aston-Jones G, Harris GC (2004) Brain substrates for increased drug seeking during protracted withdrawal. Neuropharmacology 47(Suppl 1):167–179

    Article  PubMed  CAS  Google Scholar 

  • Aujla H, Martin-Fardon R, Weiss F (2008) Rats with extended access to cocaine exhibit increased stress reactivity and sensitivity to the anxiolytic-like effects of the mGluR 2/3 agonist LY379268 during abstinence. Neuropsychopharmacology 33:1818–1826

    Article  PubMed  CAS  Google Scholar 

  • Banna KM, Back SE, Do P, See RE (2010) Yohimbine stress potentiates conditioned cue-induced reinstatement of heroin-seeking in rats. Behav Brain Res 208:144–148

    Article  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Baumann MH, Milchanowski AB, Rothman RB (2004) Evidence for alterations in alpha2-adrenergic receptor sensitivity in rats exposed to repeated cocaine administration. Neuroscience 125:683–690

    Article  PubMed  CAS  Google Scholar 

  • Belej T, Manji D, Sioutis S, Barros HM, Nobrega JN (1996) Changes in serotonin and norepinephrine uptake sites after chronic cocaine: pre- vs. post-withdrawal effects. Brain Res 736:287–296

    Article  PubMed  CAS  Google Scholar 

  • Beveridge TJ, Smith HR, Nader MA, Porrino LJ (2005) Effects of chronic cocaine self-administration on norepinephrine transporters in the nonhuman primate brain. Psychopharmacology 180:781–788

    Article  PubMed  CAS  Google Scholar 

  • Buffalari DM, See RE (2009) Guanfacine blockade of stress-induced and conditioned cue-induced cocaine-seeking in an animal model of relapse. Soc Neurosci Abstr: 35:387.5

    Google Scholar 

  • Buffalari DM, See RE (2011) Inactivation of the bed nucleus of the stria terminalis in an animal model of relapse: effects on conditioned cue-induced reinstatement and its enhancement by yohimbine. Psychopharmacology 213:19–27

    Article  PubMed  CAS  Google Scholar 

  • Carroll KM, Fenton LR, Ball SA, Nich C, Frankforter TL, Shi J, Rounsaville BJ (2004) Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial. Arch Gen Psychiatry 61:264–272

    Article  PubMed  CAS  Google Scholar 

  • Cecchi M, Khoshbouei H, Javors M, Morilak DA (2002a) Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuroscience 112:13–21

    Article  PubMed  CAS  Google Scholar 

  • Cecchi M, Khoshbouei H, Morilak DA (2002b) Modulatory effects of norepinephrine, acting on alpha 1 receptors in the central nucleus of the amygdala, on behavioral and neuroendocrine responses to acute immobilization stress. Neuropharmacology 43:1139–1147

    Article  PubMed  CAS  Google Scholar 

  • Conrad KL, McCutcheon JE, Cotterly LM, Ford KA, Beales M, Marinelli M (2010) Persistent increases in cocaine-seeking behavior after acute exposure to cold swim stress. Biol Psychiatr 68:303–305

    Article  CAS  Google Scholar 

  • Covington HE 3rd, Miczek KA (2003) Vocalizations during withdrawal from opiates and cocaine: possible expressions of affective distress. Eur J Pharmacol 467:1–13

    Article  PubMed  CAS  Google Scholar 

  • DeVries AC, Taymans SE, Sundstrom JM, Pert A (1998) Conditioned release of corticosterone by contextual stimuli associated with cocaine is mediated by corticotropin-releasing factor. Brain Res 786:39–46

    Article  PubMed  CAS  Google Scholar 

  • Economidou D, Dalley JW, Everitt BJ (2011) Selective norepinephrine reuptake inhibition by atomoxetine prevents cue-induced heroin and cocaine seeking. Biol Psychiatr 69:266–274

    Article  CAS  Google Scholar 

  • Erb S (2010) Evaluation of the relationship between anxiety during withdrawal and stress-induced reinstatement of cocaine seeking. Progr Neuro Psychopharmacol Biol Psychiatr 34:798–807

    Article  CAS  Google Scholar 

  • 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

    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 

  • Fung YK, Richard LA (1994) Behavioural consequences of cocaine withdrawal in rats. J Pharm Pharmacol 46:150–152

    Article  PubMed  CAS  Google Scholar 

  • Harris GC, Aston-Jones G (1993) Beta-adrenergic antagonists attenuate withdrawal anxiety in cocaine- and morphine-dependent rats. Psychopharmacology 113:131–136

    Article  PubMed  CAS  Google Scholar 

  • Highfield D, Yap J, Grimm JW, Shalev U, Shaham Y (2001) Repeated lofexidine treatment attenuates stress-induced, but not drug cues-induced reinstatement of a heroin-cocaine mixture (speedball) seeking in rats. Neuropsychopharmacology 25:320–331

    Article  PubMed  CAS  Google Scholar 

  • Intengan HD, Smyth DD (1997) Alpha-2a/d adrenoceptor subtype stimulation by guanfacine increases osmolar clearance. J Pharmacol Exp Therapeut 281:48–53

    CAS  Google Scholar 

  • Jobes ML, Ghitza UE, Epstein DH, Phillips KA, Heishman SJ, Preston KL (2011) Clonidine blocks stress-induced craving in cocaine users. Psychopharmacology 218(1):83–88

    Article  PubMed  CAS  Google Scholar 

  • Kampman KM, Volpicelli JR, Mulvaney F, Alterman AI, Cornish J, Gariti P, Cnaan A, Poole S, Muller E, Acosta T, Luce D, O'Brien C (2001) Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity. Drug Alcohol Depend 63:69–78

    Article  PubMed  CAS  Google Scholar 

  • Kampman KM, Dackis C, Lynch KG, Pettinati H, Tirado C, Gariti P, Sparkman T, Atzram M, O'Brien CP (2006) A double-blind, placebo-controlled trial of amantadine, propranolol, and their combination for the treatment of cocaine dependence in patients with severe cocaine withdrawal symptoms. Drug Alcohol Depend 85:129–137

    Article  PubMed  CAS  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 

  • Lapiz-Bluhm MD, Bondi CO, Doyen J, Rodriguez GA, Bedard-Arana T, Morilak DA (2008) Behavioural assays to model cognitive and affective dimensions of depression and anxiety in rats. J Neuroendocrinol 20:1115–1137

    Article  PubMed  CAS  Google Scholar 

  • Le AD, Funk D, Juzytsch W, Coen K, Navarre BM, Cifani C, Shaham Y (2011) Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. Psychopharmacology 218:89–99

    Article  PubMed  CAS  Google Scholar 

  • Leri F, Flores J, Rodaros D, Stewart J (2002) Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala. J Neurosci 22:5713–5718

    PubMed  CAS  Google Scholar 

  • Mantsch JR, Baker DA, Francis DM, Katz ES, Hoks MA, Serge JP (2008) Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented following long-access cocaine self-administration by rats. Psychopharmacology 195:591–603

    Article  PubMed  CAS  Google Scholar 

  • McDougle CJ, Black JE, Malison RT, Zimmermann RC, Kosten TR, Heninger GR, Price LH (1994) Noradrenergic dysregulation during discontinuation of cocaine use in addicts. Arch Gen Psychiatry 51:713–719

    Article  PubMed  CAS  Google Scholar 

  • Newton TF (2011) A perhaps unexpected role of norepinephrine in actions of MDMA. Clin Pharmacol Ther 90:215–216

    Article  PubMed  CAS  Google Scholar 

  • O'Leary TA, Rohsenow DJ, Martin R, Colby SM, Eaton CA, Monti PM (2000) The relationship between anxiety levels and outcome of cocaine abuse treatment. Am J Drug Alcohol Abuse 26:179–194

    Article  PubMed  Google Scholar 

  • Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Meth 14:149–167

    Article  CAS  Google Scholar 

  • Pinel JPJ, Treit PJ (1978) Burying as a defensive response in rats. J Comp Physiol Psychol 92:708–712

    Article  Google Scholar 

  • Platt DM, Rowlett JK, Spealman RD (2007) Noradrenergic mechanisms in cocaine-induced reinstatement of drug seeking in squirrel monkeys. J Pharmacol Exp Therapeut 322:894–902

    Article  CAS  Google Scholar 

  • Poling J, Kosten TR, Sofuoglu M (2007) Treatment outcome predictors for cocaine dependence. Am J Drug Alcohol Abuse 33:191–206

    Article  PubMed  Google Scholar 

  • Preti A (2007) New developments in the pharmacotherapy of cocaine abuse. Addict Biol 12:133–151

    Article  PubMed  CAS  Google Scholar 

  • Rudoy CA, Van Bockstaele EJ (2007) Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats. Progr Neuro Psychopharmacol Biol Psychiatr 31:1119–1129

    Article  CAS  Google Scholar 

  • Sarnyai Z, Biro E, Gardi J, Vecsernyes M, Julesz J, Telegdy G (1995) Brain corticotropin-releasing factor mediates 'anxiety-like' behavior induced by cocaine withdrawal in rats. Brain Res 675:89–97

    Article  PubMed  CAS  Google Scholar 

  • Schroeder JP, Cooper DA, Schank JR, Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM, Edwards GL, Holmes PV, Weinshenker D (2010) Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine beta-hydroxylase. Neuropsychopharmacology 35:2440–2449

    Article  PubMed  CAS  Google Scholar 

  • Schuckit MA, Daeppen JB, Danko GP, Tripp ML, Smith TL, Li TK, Hesselbrock VM, Bucholz KK (1999) Clinical implications for four drugs of the DSM-IV distinction between substance dependence with and without a physiological component. Am J Psychiatr 156:41–49

    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 

  • Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology 158:343–359

    Article  PubMed  CAS  Google Scholar 

  • Smith RJ, Aston-Jones G (2008) Noradrenergic transmission in the extended amygdala: role in increased drug-seeking and relapse during protracted drug abstinence. Brain Struct Funct 213:43–61

    Article  PubMed  Google Scholar 

  • Smith RJ, Aston-Jones G (2011) alpha(2) Adrenergic and imidazoline receptor agonists prevent cue-induced cocaine seeking. Biol Psychiatry 70(8):712–719

    Article  PubMed  CAS  Google Scholar 

  • Sofuoglu M, Kosten TR (2006) Emerging pharmacological strategies in the fight against cocaine addiction. Expert Opin Emerg Drugs 11:91–98

    Article  PubMed  CAS  Google Scholar 

  • Sofuoglu M, Sewell RA (2009) Norepinephrine and stimulant addiction. Addict Biol 14:119–129

    Article  PubMed  CAS  Google Scholar 

  • Sofuoglu M, Gonzalez G, Poling J, Kosten TR (2003) Prediction of treatment outcome by baseline urine cocaine results and self-reported cocaine use for cocaine and opioid dependence. Am J Drug Alcohol Abuse 29:713–727

    Article  PubMed  Google Scholar 

  • Sofuoglu M, Dudish-Poulsen S, Poling J, Mooney M, Hatsukami DK (2005) The effect of individual cocaine withdrawal symptoms on outcomes in cocaine users. Addict Behav 30:1125–1134

    Article  PubMed  Google Scholar 

  • Sofuoglu M, Poling J, Waters A, Sewell A, Hill K, Kosten T (2008) Disulfiram enhances subjective effects of dextroamphetamine in humans. Pharmacol Biochem Behav 90:394–398

    Article  PubMed  CAS  Google Scholar 

  • Stoops WW, Blackburn JW, Hudson DA, Hays LR, Rush CR (2008) Safety, tolerability and subject-rated effects of acute intranasal cocaine administration during atomoxetine maintenance. Drug Alcohol Depend 92:282–285

    Article  PubMed  CAS  Google Scholar 

  • Uhlen S, Wikberg JE (1991) Delineation of rat kidney alpha 2A- and alpha 2B-adrenoceptors with [3 H]RX821002 radioligand binding: computer modelling reveals that guanfacine is an alpha 2A-selective compound. Eur J Pharmacol 202:235–243

    Article  PubMed  CAS  Google Scholar 

  • Yang XM, Gorman AL, Dunn AJ, Goeders NE (1992) Anxiogenic effects of acute and chronic cocaine administration: neurochemical and behavioral studies. Pharmacol Biochem Behav 41:643–650

    Article  PubMed  CAS  Google Scholar 

  • Zhang XY, Kosten TA (2005) Prazosin, an alpha-1 adrenergic antagonist, reduces cocaine-induced reinstatement of drug-seeking. Biol Psychiatr 57:1202–1204

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by National Institute on Drug Abuse grants DA16511 and DA21690 (RES), 1F32 DA025411-01 (DMB), and NIH grant C06 RR015455. The authors thank Shannon Ghee and Bernard Smalls for technical assistance and data collection.

Author information

Authors and Affiliations

  1. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Deanne M. Buffalari

  2. Department of Neurosciences, Medical University of South Carolina, BSB416B, 173 Ashley Avenue, Charleston, SC, 29425, USA

    Chelsey K. Baldwin & Ronald E. See

Authors
  1. Deanne M. Buffalari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chelsey K. Baldwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald E. See
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ronald E. See.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buffalari, D.M., Baldwin, C.K. & See, R.E. Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats. Psychopharmacology 223, 179–190 (2012). https://doi.org/10.1007/s00213-012-2705-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-012-2705-1

Keywords

Search

Navigation