Elsevier

Neuroscience

Volume 154, Issue 4, 17 July 2008, Pages 1506-1516
Neuroscience

Neuropharmacology
Cocaine reward and hyperactivity in the rat: Sites of mu opioid receptor modulation

https://doi.org/10.1016/j.neuroscience.2008.04.063Get rights and content

Abstract

Opioid receptor agonists and antagonists have profound effects on cocaine-induced hyperactivity and conditioned reward. Recently, the role specifically of the mu opioid receptor has been demonstrated based on the finding that i.c.v. administration of the selective mu opioid receptor antagonist, d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), can attenuate cocaine-induced behaviors. The purpose of the present study was to determine the location of mu opioid receptors that are critical for cocaine-induced reward and hyperactivity. Adult male Sprague–Dawley rats received injections of CTAP into the caudate putamen, the rostral or caudal ventral tegmental area (VTA) or the medial shell or core of the nucleus accumbens prior to cocaine to determine the role of mu opioid receptors in cocaine-induced reward and hyperactivity. Cocaine-induced reward was assessed using an unbiased conditioned place preference procedure. Results demonstrate that animals pre-treated with CTAP into the nucleus accumbens core or rostral VTA, but not the caudal VTA, caudate putamen or medial nucleus accumbens shell, during conditioning with cocaine showed an attenuation of the development of cocaine-induced place preference. In contrast, CTAP injected into the nucleus accumbens shell but not the core attenuated the expression of cocaine place preference. Intra-nucleus accumbens core, caudate putamen or caudal VTA CTAP significantly attenuated cocaine-induced hyperactivity. In addition, the number of cFos positive cells was increased in the motor cortex, medial and ventromedial aspects of the nucleus accumbens shell, basolateral amygdala and caudal VTA during the expression of cocaine place preference, and this increase was attenuated in the animals that received intra-accumbens core CTAP during daily cocaine conditioning. These results demonstrate the importance of mu opioid receptors in the nucleus accumbens and VTA in cocaine-induced reward and hyperactivity and suggest that some aspects of the behavioral effects of cocaine are mediated by endogenous activation of mu opioid receptors in these brain regions.

Section snippets

Drugs

Cocaine HCl was generously provided by the National Institute on Drug Abuse (Bethesda, MD, USA), dissolved in sterile saline, and injected i.p. in a dose of 10 mg/kg and a volume of 1 ml/kg body weight. The dose is based on the weight of the salt. CTAP was obtained from Sigma, dissolved in sterile saline, and 0.5 μg in 0.5 μl was administered bilaterally into the brain regions of interest.

Animals and surgery

All animal procedures were approved by Temple University's Institutional Animal Care and Use Committee and

Effect of CTAP on the development of conditioned place preference

Conditioned place preference together with microinjections of the selective mu opioid receptor antagonist CTAP into five specific brain regions was employed to evaluate the role of mu opioid receptors within these regions in the development of cocaine reward. Fig. 1 shows termination sites of the tracts from the injection cannula for all regions studied. The data displayed in Fig. 2 represent the mean±S.D. in preference for the drug-paired environment for each of the five separate brain regions

Discussion

Previous studies using non-selective opioid receptor antagonists have shown that the opioid system plays a role in cocaine-induced reward (Bain and Kornetsky 1987, Corrigall and Coen 1991, Bilsky et al 1992) and hyperlocomotion (Houdi et al 1989, Kim et al 1997). In addition, a recent study by our laboratory has demonstrated that i.c.v. administration of the selective mu opioid receptor antagonist CTAP significantly attenuated acute cocaine-induced hyperactivity, and the development of

Conclusion

In summary, the results of the present study demonstrate the importance of mu opioid receptors in cocaine-induced reward and activity, and demonstrate the anatomical selectivity of mu receptors within the nucleus accumbens, VTA and caudate putamen in this regard. These data suggest that cocaine causes the release of endogenous opioid peptides and that these peptides contribute to the rewarding and locomotor-stimulating effects of cocaine. Further, the data also suggest that opioid peptides are

Acknowledgments

This work was supported by NIH/NIDA R01 DA09580 (E.M.U.). The authors would like to thank Peter Bugelski and Patricia Rafferty from Centocor Inc. Research and Development, for their expert guidance and training in immunohistochemistry.

References (50)

  • D.S. Mathon et al.

    Increased GABAergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in mu-opioid receptor knockout mice

    Neuroscience

    (2005)
  • R.L. Moldow et al.

    Cocaine induced secretion of ACTH, beta-endorphin, and corticosterone

    Peptides

    (1987)
  • L.C. Nicolaysen et al.

    Effects of cocaine on release and uptake of dopamine in vivo: differentiation by mathematical modeling

    Pharmacol Biochem Behav

    (1988)
  • H.O. Pettit et al.

    Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis

    Pharmacol Biochem Behav

    (1989)
  • N.F. Ramsey et al.

    Naltrexone affects cocaine self-administration in naive rats through the ventral tegmental area rather than dopaminergic target regions

    Eur Neuropsychopharmacol

    (1999)
  • D.C. Roberts et al.

    Disruption of cocaine self-administration following 6-hydroxydopamine lesions of the ventral tegmental area in rats

    Pharmacol Biochem Behav

    (1982)
  • B. Siegfried et al.

    Lack of morphine-induced hyperactivity in C57BL/6 mice following striatal kainic acid lesions

    Behav Brain Res

    (1982)
  • P.D. Skoubis et al.

    Blockade of ventral pallidal opioid receptors induces a conditioned place aversion and attenuates acquisition of cocaine place preference in the rat

    Neuroscience

    (2003)
  • G.E. Alexander et al.

    Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions

    Prog Brain Res

    (1990)
  • E.E. Brown et al.

    Evidence for conditional neuronal activation following exposure to a cocaine-paired environment: role of forebrain limbic structures

    J Neurosci

    (1992)
  • W.A. Corrigall et al.

    Opiate antagonists reduce cocaine but not nicotine self-administration

    Psychopharmacology (Berl)

    (1991)
  • C.A. Crawford et al.

    The effects of the kappa agonist U-50,488 on cocaine-induced conditioned and unconditioned behaviors and Fos immunoreactivity

    Psychopharmacology (Berl)

    (1995)
  • D.P. Devine et al.

    Self-administration of morphine, DAMGO, and DPDPE into the ventral tegmental area of rats

    J Neurosci

    (1994)
  • J.S. Fink et al.

    Mesolimbicocortical dopamine terminal fields are necessary for normal locomotor and investigatory exploration in rats

    Brain Res

    (1980)
  • R.P. Hammer

    Cocaine alters opiate receptor binding in critical brain reward regions

    Synapse

    (1989)
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