Skip to main content
SpringerLink
Log in

On the positive and negative affective responses to cocaine and their relation to drug self-administration in rats

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

Abstract

Rationale

Acute cocaine administration produces an initial rewarding state followed by a dysphoric/anxiogenic “crash.”

Objective

The objective of this study was to determine whether individual differences in the relative value of cocaine’s positive and negative effects would account for variations in subsequent drug self-administration.

Methods

The dual actions of cocaine were assessed using a conditioned place test (where animals formed preferences for environments paired with the immediate rewarding effects of 1.0mg/kg i.v. cocaine or aversions of environments associated with the anxiogenic effects present 15-min postinjection) and a runway test (where animals developed approach-avoidance “retreat” behaviors about entering a goal box associated with cocaine delivery). Ranked scores from these two tests were then correlated with each other and with the escalation in the operant responding of the same subjects observed over 10 days of 1- or 6-h/day access to i.v. (0.4mg/inj) cocaine self-administration.

Results

Larger place preferences were associated with faster runway start latencies (r s = −0.64), but not with retreat frequency or run times; larger place aversions predicted slower runway start times (r s = 0.62), increased run times (r s = 0.65), and increased retreats (r s = 0.62); response escalation was observed in both the 1- and 6-h self-administration groups and was associated with increased CPPs (r s = 0.58) but not CPAs, as well as with faster run times (r s = −0.60).

Conclusions

Together, these data suggest that animals exhibiting a greater positive than negative response to acute (single daily injections of) cocaine are at the greatest risk for subsequent escalated cocaine self-administration, a presumed indicator of cocaine addiction.

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
Fig. 8

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  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

    CAS  PubMed  Google Scholar 

  • Barbieri EJ, Ferko AP, DiGregorio GJ, Ruch EK (1992) The presence of cocaine and benzoylecgonine inrat cerebrospinal fluid after intravenous administration of cocaine. Life Sci 51:1739–1746

    Article  CAS  PubMed  Google Scholar 

  • Bardo MT, Bevins RA (2000) Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl) 153:31–43

    Article  CAS  Google Scholar 

  • Bardo MT, Rowlett JK, Harris MJ (1995) Conditioned place preference using opiate and stimulant drugs: A meta-analysis. Neurosci Biobehav Rev 19:39–51

    Article  CAS  PubMed  Google Scholar 

  • Barker DJ, Simmons SJ, Servilio LC, Bercovicz D, Ma S, Root DH, Pawlak AP, West MO (2014) Ultrasonicvocalizations: evidence for an affective opponent process during cocaine self-administration. Psychopharmacology (Berl) 231:909–918

    Article  CAS  Google Scholar 

  • Ben-Shahar O, Ahmed SH, Koob GF, Ettenberg A (2004) The transition from controlled to compulsive drug use is associated with a loss of sensitization. Brain Res 995:46–54

    Article  CAS  PubMed  Google Scholar 

  • Ben-Shahar O, Moscarello JM, Jacob B, Roarty MP, Ettenberg A (2005) Prolonged daily exposure to IV cocaine results in toleranceto its stimulant effects. Pharmacol Biochem Behav 82:411–416

    Article  CAS  PubMed  Google Scholar 

  • Ben-Shahar O, Obara I, Ary AW, Ma N, Mangiardi MA, Medina RL, Szumlinski KK (2009) Extended daily access to cocaine results in distinct alterations in Homer 1b/c and NMDA receptor subunit expression within the medial prefrontal cortex. Synapse 63:598–609

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Booze RM, Lehner AF, Wallace DR, Welch MA, Mactutus CF (1997) Dose–response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized freely moving male rats. Neurotoxicol Teratol 19:7–15

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Borowski TB, Kokkinidis L (1994) Cocaine preexposure sensitizes conditioned fear in a potentiated acoustic startle paradigm. Pharmacol Biochem Behav 49:935–42

  • Browning JR, Browning DA, Maxwell AO, Dong Y, Jansen HT, Panksepp J, Sorg BA (2011) Positive affective vocalizations during cocaine and sucrose self-administration: a model for spontaneous drug desire in rats. Neuropharmacology 61:268–275

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Calipari ES, Ferris MJ, Jones SR (2014) Extended access of cocaine self-administration results in tolerance to the dopamine-elevating and locomotor-stimulating effects of cocaine. J Neurochem 128:224–232

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cannon DS, Leeka JK, Block AK (1994) Ethanol self-administration patterns and taste aversion learning across inbred rat strains. Pharmacol Biochem Behav 47:795–802

    Article  CAS  PubMed  Google Scholar 

  • Carr GD, Fibiger HC, Phillips AG (1989) Conditioned place preference as a measure of drug reward. In: Liebman JM, Cooper SJ (eds) The neuropharmacological basis of reward. Clarendon Press/Oxford University Press, New York, pp 264–319

    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  CAS  PubMed  Google Scholar 

  • Cunningham CL, Gremel CM, Groblewski PA (2009) Genetic influences on conditioned taste aversion. In: Reilly S, Schachtman TR (eds) Conditioned Taste Aversion: Behavioral and Neural Processes. Oxford University Place, New York, pp 387–421

    Google Scholar 

  • Dackis CA, O'Brien CP (2001) Cocaine dependence: a disease of the brain's reward centers. J Subst Abuse Treat 21:111–117

    Article  CAS  PubMed  Google Scholar 

  • Ettenberg A (2004) Opponent process properties of self-administered cocaine. Neurosci Biobehav Rev 27:721–728

    Article  CAS  PubMed  Google Scholar 

  • Ettenberg A (2009) The runway model of drug self-administration. Pharmacol Biochem Behav 91:271–277

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ettenberg A, Bernardi RE (2007) Effects of buspirone on the immediate positive and delayed negative properties of intravenous cocaine as measured in the conditioned place preference test. Pharmacol Biochem Behav 87:171–178

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ettenberg A, Geist TD (1991) Animal model for investigating the anxiogenic effects of self-administered cocaine. Psychopharmacology 103:455–461

    Article  CAS  PubMed  Google Scholar 

  • Ettenberg A, Geist TD (1993) Qualitative and quantitative differences in the operant runway behavior of rats working for cocaine and heroin reinforcement. Pharmacol Biochem Behav 44:191–198

    Article  CAS  PubMed  Google Scholar 

  • Ettenberg A, Pettit HO, Bloom FE, Koob GF (1982) Heroin and cocaine intravenous self-administration in rats: mediation by separate neural systems. Psychopharmacology 78:204–209

    Article  CAS  PubMed  Google Scholar 

  • Ettenberg A, Raven MA, Danluck DA, Necessary BD (1999) Evidence for opponent-process actions of intravenous cocaine. Pharmacol Biochem Behav 64:507–512

    Article  CAS  PubMed  Google Scholar 

  • Ettenberg A, Ofer OA, Mueller CL, Waldroup S, Cohen A (2011) Ben-Shahar O (2011) Inactivation of the dorsal raphé nucleus reduces the anxiogenic response of rats running an alley for intravenous cocaine. Pharmacol Biochem Behav 97(4):632–639. doi:10.1016/j.pbb.2010.11.008, Epub 2010 Nov 23

    Article  CAS  PubMed Central  PubMed  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  CAS  PubMed  Google Scholar 

  • Foltin RW, Fischman MW (1994) Cocaine self-administration research: treatment implications. NIDA Res Monogr 145:139–162

    CAS  PubMed  Google Scholar 

  • Gaiardi M, Bartoletti M, Bacchi A, Gubellini C, Costa M, Babbini M (1991) Role of repeated exposure to morphine in determining its affective properties: place and taste conditioning studies in rats. Psychopharmacology (Berl) 103:183–186

    Article  CAS  Google Scholar 

  • Gawin FH (1991) Cocaine addiction: psychology and neurophysiology. Science 251:1580–1586

    Article  CAS  PubMed  Google Scholar 

  • Gawin FH, Kleber HD (1986) Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations. Arch Gen Psychiatry 43:107–113

    Article  CAS  PubMed  Google Scholar 

  • Geist TD, Ettenberg A (1990) A simple method for studying intravenous drug reinforcement inthe runway. Pharmacol Biochem Behav 36:703–706

    Article  CAS  PubMed  Google Scholar 

  • Goeders NE (1988) Intracranial cocaineself-administration. NIDA Res Monogr 1988(88):199–216

    Google Scholar 

  • Goeders NE (1997) A neuroendocrine role in cocaine reinforcement. Psychoneuroendocrinology 22:237–259

    Article  CAS  PubMed  Google Scholar 

  • Jhou TC, Good CH, Rowley CS, Xu SP, Wang H, Burnham NW, Hoffman AF, Lupica CR, Ikemoto S (2013) Cocaine drives aversive conditioning via delayed activation of dopamine-responsive habenular and midbrain pathways. J Neurosci 33:7501–7512

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Knackstedt LA, Samimi MM, Ettenberg A (2002) Evidence for opponent-process actions of intravenous cocaine and cocaethylene. Pharmacol Biochem Behav 72:931–936

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, LeMoal M (2006) Neurobiology of Addiction. Academic Press/Elsevier, London

    Google Scholar 

  • Koob GF, Caine B, Markou A, Pulvirenti L, Weiss F (1994) Role for the mesocortical dopamine system in the motivating effects of cocaine. NIDA Res Monogr 145:1–18

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Lambert NM, McLeod M, Schenk S (2006) Subjective responses to initial experience with cocaine: an exploration of the incentive-sensitization theory of drug abuse. Addiction 101:713–725

    Article  PubMed  Google Scholar 

  • Ma ST, Maier EY, Ahrens AM, Schallert T, Duvauchelle CL (2010) Repeated intravenous cocaine experience: development and escalation of pre-drug anticipatory 50-kHz ultrasonic vocalizations in rats. Behav Brain Res 212:109–114

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Markou A, Koob GF (1991) Postcocaine anhedonia. An animal model of cocaine withdrawal. Neuropsychopharmacology 4:17–26

    CAS  PubMed  Google Scholar 

  • Markou A, Koob GF (1992) Bromocriptine reverses the elevation in intracranial self-stimulation thresholds observed in a rat model of cocaine withdrawal. Neuropsychopharmacology 7:213–224

    CAS  PubMed  Google Scholar 

  • McReynolds JR, Peña DF, Blacktop JM, Mantsch JR (2014) Neurobiological mechanisms underlying relapse to cocaine use: contributions of CRF and noradrenergic systems and regulation by glucocorticoids. Stress 17:22–38

    Article  CAS  PubMed  Google Scholar 

  • Moldow RL, Fischman AJ (1987) Cocaine induced secretion of ACTH, beta-endorphin, and corticosterone. Peptides 8:819–822

    Article  CAS  PubMed  Google Scholar 

  • Mucha RF, van der Kooy D, O’Shaughnessy M, Bucenieks P (1982) Drug reinforcement studied by the use of place conditioning in rat. Brain Res 243:91–105

  • Mueller D, Stewart J (2000) Cocaine-induced conditioned place preference: reinstatement by priming injections of cocaine after extinction 115:39–47

  • Palamarchouk V, Smagin G, Goeders NE (2009) Self-administered and passive cocaine infusions produce different effects on corticosterone concentrations in the medial prefrontal cortex (MPC) of rats. Pharmacol Biochem Behav 94:163–168

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Paterson NE, Markou A (2003) Increased motivation for self-administrationcocaine after escalated cocaine intake. Neuroreport 14:2229–2232

    Article  CAS  PubMed  Google Scholar 

  • Port RM, Contel NR (1983) Human and animal studies of cocaine: implications for the development of behavioral pathology. In: Creese I (ed) Stimulants: Neurochemical, Behavioral and Clinical Perspectives. Raven Press, New York, pp 169–203

    Google Scholar 

  • Raven MA, Necessary BD, Danluck DA, Ettenberg A (2000) Comparison of the reinforcing and anxiogenic effects of intravenous cocaine and cocaethylene.Exp. Clin Psychopharmacol 8(1):117–124

    Article  CAS  Google Scholar 

  • Riley AL (2011) The paradox of drug taking: the role of the aversive effects of drugs. Physiol Behav 103:69–78

    Article  CAS  PubMed  Google Scholar 

  • Risinger FO, Cunningham CL (1998) Ethanol-induced conditioned taste aversion in BXD recombinant inbred mice. Alcohol Clin Exp Res 22:1234–1244

    Article  CAS  PubMed  Google Scholar 

  • Roberts DC, Corcoran ME, Fibiger HC (1977) On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine. Pharmacol Biochem Behav 6:615–620

    Article  CAS  PubMed  Google Scholar 

  • Rogerio R, Takahashi RN (1992) Anxiogenic properties of cocaine in the rat evaluated with the elevated plus-maze. Pharmacol Biochem Behav 43:631–633

    Article  CAS  PubMed  Google Scholar 

  • Simon P, Dupuis R, Costentin J (1994) Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav Brain Res 61:59–64

    Article  CAS  PubMed  Google Scholar 

  • Su ZI, Kichaev G, Wenzel J, Ben-Shahar O, Ettenberg A (2012) Weakening of negative relative to positive associations with cocaine-paired cues contributes to cue-induced responding after drug removal. Pharmacol Biochem Behav 100:458–463

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Su Z-I, Wenzel JM, Ettenberg A, Ben-Shahar O (2013) Prior extended daily access to cocaine elevates the reward threshold in a Conditioned Place Preference test. Addict Biol 18:222–229

    Article  PubMed Central  PubMed  Google Scholar 

  • Tzschentke TM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog in Neurobiol 56:61–672

    Article  Google Scholar 

  • Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462

    Article  CAS  PubMed  Google Scholar 

  • Van Dyke C, Byck R (1982) Cocaine. Scientific American 246:128–141

    Article  PubMed  Google Scholar 

  • Verendeev A, Riley AL (2012) Conditioned taste aversion and drugs of abuse: history and interpretation. Neurosci Biobehav Rev 36:2193–2205

    Article  PubMed  Google Scholar 

  • Wenzel JM, Cotten SW, Dominguez HM, Lane JE, Shelton K, Su ZI, Ettenberg A (2014) Noradrenergic β-receptor antagonism within the central nucleus of the amygdala or bed nucleus of the stria terminalis attenuates the negative/anxiogenic effects of cocaine. J Neurosci 34:3467–3474

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • White NM, Carr GD (1985) The conditioned place preference is affected by two independent reinforcement processes. Pharmacol Biochem Beha 23:37–42

    Article  CAS  Google Scholar 

  • Williamson S, Gossop M, Powis B, Griffiths P, Fountain J, Strang J (1997) Adverse effects of stimulant drugs in a community sample of drug users. Drug Alcohol Depend 44:87–94

    Article  CAS  PubMed  Google Scholar 

  • Willick ML, Kokkinidis L (1995) Cocaine enhances the expression of fear-potentiated startle: evaluation of state-dependent extinction and the shock-sensitization of acoustic startle. Behav Neurosci 109:929–938

    Article  CAS  PubMed  Google Scholar 

  • Wise RA, Newton P, Leeb K, Burnette B, Pocock D, Justice JB Jr (1995) Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaineself-administration in rats. Psychopharmacology (Berl) 120:10–20

    Article  CAS  Google Scholar 

  • Woolverton WL (1992) Determinants of cocaineself-administration by laboratory animals. Ciba Found Symp 166:149–161

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

Download references

Funding

Funding for this research was provided by National Institute of Drug Abuse grants DA05041 and 033370 awarded to AE. The data described herein were collected as part of the undergraduate honors theses of VF and KK. We thank Dr. Osnat Ben-Shahar for her invaluable assistance and advice. The authors have no conflicts of interest to report.

Author information

Authors and Affiliations

  1. Behavioral Pharmacology Laboratory, Department of Psychological and Brain Sciences, University of California, Santa Barbara, CA, 93106-9660, USA

    Aaron Ettenberg, Vira Fomenko, Konstantin Kaganovsky, Kerisa Shelton & Jennifer M. Wenzel

Authors
  1. Aaron Ettenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vira Fomenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Konstantin Kaganovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kerisa Shelton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jennifer M. Wenzel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aaron Ettenberg.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ettenberg, A., Fomenko, V., Kaganovsky, K. et al. On the positive and negative affective responses to cocaine and their relation to drug self-administration in rats. Psychopharmacology 232, 2363–2375 (2015). https://doi.org/10.1007/s00213-015-3873-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-015-3873-6

Keywords

Search

Navigation