Skip to main content
SpringerLink
Log in

Patterns of functional activity associated with cocaine self-administration in the rat change over time

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

Abstract

Rationale

Although imaging studies in human addicts have been valuable for identifying the neural substrates of the effects of abused drugs, few studies have used this approach in animal models where conditions can be carefully controlled.

Objective

To define the substrates that mediate the effects of cocaine in a rodent model of cocaine self-administration using the 2-[14C]deoxyglucose method and to assess changes in these patterns over the course of drug exposure.

Methods

Male Sprague-Dawley rats self-administered cocaine (0.75 mg/kg per injection; FR2; 21 injections/session) and control rats received saline infusions in the same pattern as the cocaine rats for 5 or 30 days. Metabolic mapping was applied immediately after the final session.

Results

Following 5 days of self-administration, rates of glucose utilization were decreased in the nucleus accumbens, and increased in autonomic brainstem structures and in sensorimotor regions. After 30 days of cocaine exposure, self-administration reduced glucose utilization throughout the dorsal and ventral striatum, central nucleus of the amygdala, medial forebrain bundle, and infralimbic and prelimbic prefrontal cortices. In addition, at this time point glucose utilization was no longer elevated in any autonomic or sensorimotor brain regions.

Conclusions

These data demonstrate that the distribution of functional activity associated with self-administered cocaine undergoes considerable change over the course of drug exposure. While increases in metabolic rates were largely found in autonomic and sensorimotor structures after short-term cocaine access, decreases were prominent in mesocorticolimbic regions after prolonged exposure. These differences in the patterns of brain activity that develop with long-term cocaine self-administration may play a role in the transition to habitual drug seeking behavior.

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

Similar content being viewed by others

References

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

    CAS  PubMed  Google Scholar 

  • Alheid G, DeOlmos JS, Beltramino CA (1995) Amygdala and extended amygdala. In: Paxinos G (ed) The rat nervous system. Academic Press, New York, pp 495–578

  • Ambrosio E, Tella SR, Goldberg SR, Schindler CW, Erzouki H, Elmer GI (1996) Cardiovascular effects of cocaine during operant cocaine self-administration. Eur J Pharmacol 315:43–51

    Article  CAS  PubMed  Google Scholar 

  • Borowsky B, Kuhn CM (1991) Monoamine mediation of cocaine-induced hypothalamo-pituitary-adrenal activation. J Pharmacol Exp Ther 256:204–210

    CAS  PubMed  Google Scholar 

  • Crane AM, Porrino LJ (1989) Adaptation of the quantitative 2-[14C]deoxyglucose method for use in freely moving rats. Brain Res 499:87–92

    CAS  PubMed  Google Scholar 

  • Crespo JA, Manzanares J, Oliva JM, Corchero J, Palomo T, Ambrosio E (2001) Extinction of cocaine self-administration produces a differential time-related regulation of proenkephalin gene expression in rat brain. Neuropsychopharmacology 25:185–194

    Article  CAS  PubMed  Google Scholar 

  • Dworkin SI, Smith JE (1988) Neurobehavioral pharmacology of cocaine. NIDA Res Monogr 88:185–198

    CAS  PubMed  Google Scholar 

  • Dworkin SI, Porrino LJ, Smith JE (1992) Importance of behavioral controls in the analysis of ongoing events. In: Brown RM, Frascella J (eds) Neurobiological approaches to brain-behavior interaction. NIDA Monograph, pp 173–218

  • Dworkin SI, Co C, Smith JE (1995) Rat brain neurotransmitter turnover rates altered during withdrawal from chronic cocaine administration. Brain Res 682:116–126

    CAS  PubMed  Google Scholar 

  • Erb S, Salmaso N, Rodaros D, Stewart J (2001) A role for the CRF-containing pathway from central nucleus of the amygdala to bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine seeking in rats. Psychopharmacology 158:360–365

    Google Scholar 

  • Fischman MW, Schuster CR, Resnekov L, Shick JF, Krasnegor NA, Fennell W, Freedman DX (1976) Cardiovascular and subjective effects of intravenous cocaine administration in humans. Arch Gen Psychiatry 33:983–989

    CAS  PubMed  Google Scholar 

  • Foltin RW, Fischman MW, Pedroso JJ, Pearlson GD (1988) Repeated intranasal cocaine administration: lack of tolerance to pressor effects. Drug Alcohol Depend 22:169–177

    CAS  PubMed  Google Scholar 

  • Galici R, Pechnick RN, Poland RE, France CP (2000) Comparison of noncontingent versus contingent cocaine administration on plasma corticosterone levels in rats. Eur J Pharmacol 387:59–62

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Goeders NE, Guerin GF (1996) Effects of surgical and pharmacological adrenalectomy on the initiation and maintenance of intravenous cocaine self-administration in rats. Brain Res 722:145–152

    CAS  PubMed  Google Scholar 

  • Graham J, Porrino LJ (1995) Neuroanatomical substrates of cocaine self-administration. In: Hammer R (ed) Neurobiology of cocaine. CRC Press, Boca Raton, pp 3–14

  • Hammer RP Jr, Cooke ES (1994) Gradual tolerance of metabolic activity is produced in mesolimbic regions by chronic cocaine treatment, while subsequent cocaine challenge activates extrapyramidal regions of rat brain. J Neurosci 14:4289–4298

    CAS  PubMed  Google Scholar 

  • Hemby SE, Co C, Koves TR, Smith JE, Dworkin SI (1997) Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat. Psychopharmacology 133:7–16

    CAS  PubMed  Google Scholar 

  • Ito R, Dalley JW, Robbins TW, Everitt BJ (2002) Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of a drug-associated cue. J Neurosci 22:6247–6253

    CAS  PubMed  Google Scholar 

  • Kiyatkin EA, Stein EA (1995) Fluctuations in nucleus accumbens dopamine during cocaine self-administration behavior: an in vivo electrochemical study. Neuroscience 64:599–617

    Article  CAS  PubMed  Google Scholar 

  • Knapp CM, Printseva B, Cottam N, Kornetsky C (2002) Effects of cue exposure on brain glucose utilization 8 days after repeated cocaine administration. Brain Res 950:119–126

    Article  CAS  PubMed  Google Scholar 

  • Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13:177–184

    PubMed  Google Scholar 

  • Lau CE, Sun L (2002) The pharmacokinetic determinants of the frequency and pattern of intravenous cocaine self-administration in rats by pharmacokinetic modeling. Drug Metab Dispos 30:254–261

    Article  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Letchworth SR, Nader MA, Smith HR, Friedman DP, Porrino LJ (2001) Progression of changes in dopamine transporter binding site density as a result of cocaine self-administration in rhesus monkeys. J Neurosci 21:2799–2807

    CAS  PubMed  Google Scholar 

  • Loewy A, Mckeller S (1980) The neuroanatomical basis of central cardiovascular control. Fed Proc 39:2945–2503

    Google Scholar 

  • London ED, Wilkerson G, Goldberg SR, Risner ME (1986) Effects of l-cocaine on local cerebral glucose utilization in the rat. Neurosci Lett 68:73–78

    Article  CAS  PubMed  Google Scholar 

  • Macey DJ, Smith HR, Nader MA, Porrino LJ (2003) Chronic cocaine self-administration upregulates the norepinephrine transporter and alters functional activity in the bed nucleus of the stria terminalis of the rhesus monkey. J Neurosci 23:12–16

    CAS  PubMed  Google Scholar 

  • Mackler SA, Eberwine JH (1991) The molecular biology of addictive drugs. Mol Neurobiol 5:45–58

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  • Mello NK, Mendelson JH (1997) Cocaine’s effects on neuroendocrine systems: clinical and preclinical studies. Pharmacol Biochem Behav 57:571–599

    CAS  PubMed  Google Scholar 

  • Mendelson JH, Teoh SK, Lukas SE, Phipps W, Ellingboe J, Palmieri SL, Schiff I (1992) Human studies on the biological basis of reinforcement: a neuroendocrine perspective. In: Jaffe JH (ed) Addictive states. Raven Press, New York, pp 131–155

  • Mendelson JH, Mello NK, Sholar MB, Siegel AJ, Mutschler N, Halpern J (2002) Temporal concordance of cocaine effects on mood states and neuroendocrine hormones. Psychoneuroendocrinology 27:71–82

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, New York

  • Piazza PV, Le Moal M (1998) The role of stress in drug self-administration. Trends Pharmacol Sci 19:67–74

    CAS  PubMed  Google Scholar 

  • Pitts DK, Marwah J (1986) Electrophysiological effects of cocaine on central monoaminergic neurons. Eur J Pharmacol 131:95–98

    CAS  PubMed  Google Scholar 

  • Pontieri FE, Colangelo V, La Riccia M, Pozzilli C, Passarelli F, Orzi F (1994) Psychostimulant drugs increase glucose utilization in the shell of the rat nucleus accumbens. Neuroreport 5:2561–2564

    CAS  PubMed  Google Scholar 

  • Pontieri FE, Tanda G, Di Chiara G (1995) Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci USA 92:12304–12308

    CAS  PubMed  Google Scholar 

  • Porrino LJ (1993) Functional consequences of acute cocaine treatment depend on route of administration. Psychopharmacology 112:343–351

    CAS  PubMed  Google Scholar 

  • Porrino LJ, Lucignani G, Dow-Edwards D, Sokoloff L (1984) Correlation of dose-dependent effects of acute amphetamine administration on behavior and local cerebral metabolism in rats. Brain Res 307:311–320

    Article  CAS  PubMed  Google Scholar 

  • Porrino LJ, Domer FR, Crane AM, Sokoloff L (1988) Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats. Neuropsychopharmacology 1:109–118

    Google Scholar 

  • Porrino LJ, Lyons D, Letchworth SR, Freedland CS, Nader MA (2002) Structural and functional neuroimaging of the effects of cocaine in human and nonhuman primates. In: Massaro EJ (ed) Handbook of neurotoxicology. Humana Press, Totowa, N.J., pp 413–435

  • Resnick RB, Kestenbaum RS, Schwartz LK (1977) Acute systemic effects of cocaine in man: a controlled study by intranasal and intravenous routes. Science 195:696–698

    CAS  PubMed  Google Scholar 

  • Roberts DC, Koob GF, Klonoff P, Fibiger HC (1980) Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav 12:781–787

    CAS  PubMed  Google Scholar 

  • Roberts DC, Brebner K, Vincler M, Lynch WJ (2002) Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trials procedure. Drug Alcohol Depend 67:291–299

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916

    CAS  PubMed  Google Scholar 

  • Stein EA, Fuller SA (1992) Selective effects of cocaine on regional cerebral blood flow in the rat. J Pharmacol Exp Ther 262:327–334

    CAS  PubMed  Google Scholar 

  • Tella SR, Schindler CW, Goldberg SR (1992) Cardiovascular effects of cocaine in conscious rats: relative significance of central sympathetic stimulation and peripheral neuronal monoamine uptake and release mechanisms. J Pharmacol Exp Ther 262:602–610

    CAS  PubMed  Google Scholar 

  • Tella SR, Schindler CW, Goldberg SR (1999) Cardiovascular responses to cocaine self-administration: acute and chronic tolerance. Eur J Pharmacol 383:57–68

    CAS  PubMed  Google Scholar 

  • Thomas WL Jr, Cooke ES, Hammer RP Jr (1996) Cocaine-induced sensitization of metabolic activity in extrapyramidal circuits involves prior dopamine D1-like receptor stimulation. J Pharmacol Exp Ther 278:347–353

    CAS  PubMed  Google Scholar 

  • Tornatzky W, Miczek KA (1999) Repeated limited access to IV cocaine self-administration: conditioned autonomic rhythmicity illustrating “predictive homeostasis”. Psychopharmacology 145:144–152

    Google Scholar 

  • Volkow ND, Fowler JS (2000) Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb Cortex 10:318–325

    CAS  PubMed  Google Scholar 

  • Zhang D, Zhang L, Lou DW, Nakabeppu Y, Zhang J, Xu M (2002) The dopamine D1 receptor is a critical mediator for cocaine-induced gene expression. J Neurochem 82:1453–1464

    Article  CAS  PubMed  Google Scholar 

  • Zocchi A, Conti G, Orzi F (2001) Differential effects of cocaine on local cerebral glucose utilization in the mouse and in the rat. Neurosci Lett 306:177–180

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was funded by the National Institutes of Drug Abuse grants DA 07246 (D.M.) and DA 06634 (L.J.P.).

Author information

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Center for the Neurobiological Investigation of Drug Abuse, Wake Forest University School of Medicine, Winston Salem, NC 27157-1083, USA

    Darrel J. Macey, Wendy N. Rice, Cory S. Freedland, Christopher T. Whitlow & Linda J. Porrino

Authors
  1. Darrel J. Macey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wendy N. Rice
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cory S. Freedland
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher T. Whitlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Linda J. Porrino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Linda J. Porrino.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Macey, D.J., Rice, W.N., Freedland, C.S. et al. Patterns of functional activity associated with cocaine self-administration in the rat change over time. Psychopharmacology 172, 384–392 (2004). https://doi.org/10.1007/s00213-003-1676-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1676-7

Keywords

Search

Navigation