Psychopharmacology

, Volume 204, Issue 3, pp 457–463

The role of endogenous PACAP in motor stimulation and conditioned place preference induced by morphine in mice

  • Paul Marquez
  • David Bebawy
  • Vincent Lelièvre
  • Anne-Claire Coûté
  • Christopher J. Evans
  • James A. Waschek
  • Kabirullah Lutfy
Original Investigation

Abstract

Rationale

The neuropeptide pituitary adenylyl cyclase-activating peptide (PACAP) and its receptors (PAC1 and VPAC2) are expressed in the ventral tegmental area and nucleus accumbens, raising the possibility that PACAP could be a potential modulator of the mesolimbic dopaminergic system.

Objective

The present study was designed to determine if PACAP plays a role in acute motor stimulatory and rewarding actions of morphine.

Methods

The effect of intracerebroventricular PACAP administration (0, 0.03, 0.3, 1.0, or 3.0 μg/3 μL) was studied on basal motor activity as well as on morphine (5 mg/kg)-stimulated motor activity. Motor stimulation and conditioned place preference (CPP) induced by morphine (5 or 10 mg/kg) were also determined in mice lacking PACAP and their wild-type controls.

Results

Intracerebroventricular PACAP dose-dependently suppressed basal motor activity and PACAP-deficient mice exhibited higher basal motor activity than control mice, providing evidence that the action of endogenous PACAP on basal motor activity is inhibitory. Paradoxically, low doses of PACAP which did not alter basal motor activity were found to enhance the motor stimulatory action of morphine. Furthermore, morphine-induced motor stimulation was blunted in PACAP-deficient mice. Additionally, morphine-induced CPP following a single, but not repeated, alternate-day saline/morphine (10 mg/kg) conditioning was blunted in PACAP-deficient mice compared to their wild-type littermates/controls.

Conclusion

The present results suggest that endogenous PACAP, at low doses, positively modulates the acute motor stimulatory and rewarding actions of morphine.

Keywords

Pituitary adenylyl cyclase-activating peptide (PACAP) Morphine Motor activity Conditioned place preference Reward Intracerebroventricular administration PACAP-deficient mice 

References

  1. Bardo MT, Bevins RA (2000) Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl) 153:31–43CrossRefGoogle Scholar
  2. Colwell CS, Michel S, Itri J, Rodriguez W, Tam J, Lelievre V, Hu Z, Waschek JA (2004) Selective deficits in the circadian light response in mice lacking PACAP. Am J Physiol Regul Integr Comp Physiol 287:R1194–R1201PubMedGoogle Scholar
  3. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278PubMedCrossRefGoogle Scholar
  4. Fibiger HC, Phillips AG (1988) Mesocorticolimbic dopamine systems and reward. Ann N Y Acad Sci 537:206–215PubMedCrossRefGoogle Scholar
  5. Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, Inc., San Diego, California, USAGoogle Scholar
  6. Ghatei MA, Takahashi K, Suzuki Y, Gardiner J, Jones PM, Bloom SR (1993) Distribution, molecular characterization of pituitary adenylate cyclase-activating polypeptide and its precursor encoding messenger RNA in human and rat tissues. J Endocrinol 136:159–166PubMedCrossRefGoogle Scholar
  7. Harmar AJ, Sheward WJ, Morrison CF, Waser B, Gugger M, Reubi JC (2004) Distribution of the VPAC2 receptor in peripheral tissues of the mouse. Endocrinology 145:1203–1210PubMedCrossRefGoogle Scholar
  8. Hashimoto H, Nogi H, Mori K, Ohishi H, Shigemoto R, Yamamoto K, Matsuda T, Mizuno N, Nagata S, Baba A (1996) Distribution of the mRNA for a pituitary adenylate cyclase-activating polypeptide receptor in the rat brain: an in situ hybridization study. J Comp Neurol 371:567–577PubMedCrossRefGoogle Scholar
  9. Hashimoto H, Shintani N, Tanaka K, Mori W, Hirose M, Matsuda T, Sakaue M, Miyazaki J, Niwa H, Tashiro F, Yamamoto K, Koga K, Tomimoto S, Kunugi A, Suetake S, Baba A (2001) Altered psychomotor behaviors in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP). Proc Natl Acad Sci USA 98:13355–13360PubMedCrossRefGoogle Scholar
  10. Johnson SW, North RA (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12:483–488PubMedGoogle Scholar
  11. Koob GF, Swerdlow NR (1988) The functional output of the mesolimbic dopamine system. Ann N Y Acad Sci 537:216–227PubMedCrossRefGoogle Scholar
  12. Lutfy K, Do T, Maidment NT (2001) Orphanin FQ/nociceptin attenuates motor stimulation and changes in nucleus accumbens extracellular dopamine induced by cocaine in rats. Psychopharmacology (Berl) 154:1–7CrossRefGoogle Scholar
  13. Marinelli M, Aouizerate B, Barrot M, Le MM, Piazza PV (1998) Dopamine-dependent responses to morphine depend on glucocorticoid receptors. Proc Natl Acad Sci USA 95:7742–7747PubMedCrossRefGoogle Scholar
  14. Marquez P, Baliram R, Gajawada N, Friedman TC, Lutfy K (2006) Differential involvement of enkephalins in analgesic tolerance, locomotor sensitization, and conditioned place preference induced by morphine. Behav Neurosci 120:10–15PubMedCrossRefGoogle Scholar
  15. Marquez P, Baliram R, Kieffer BL, Lutfy K (2007) The mu opioid receptor is involved in buprenorphine-induced locomotor stimulation and conditioned place preference. Neuropharmacology 52:1336–1341PubMedCrossRefGoogle Scholar
  16. Marquez P, Baliram R, Dabaja I, Gajawada N, Lutfy K (2008) The role of beta-endorphin in the acute motor stimulatory and rewarding actions of cocaine in mice. Psychopharmacology (Berl) 197:443–448CrossRefGoogle Scholar
  17. Masuo Y, Ohtaki T, Masuda Y, Tsuda M, Fujino M (1992) Binding sites for pituitary adenylate cyclase activating polypeptide (PACAP): comparison with vasoactive intestinal polypeptide (VIP) binding site localization in rat brain sections. Brain Res 575:113–123PubMedCrossRefGoogle Scholar
  18. Moore MS, DeZazzo J, Luk AY, Tully T, Singh CM, Heberlein U (1998) Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signaling pathway. Cell 93:997–1007PubMedCrossRefGoogle Scholar
  19. Moser A, Scholz J, Gansle A (1999) Pituitary adenylate cyclase-activating polypeptide (PACAP-27) enhances tyrosine hydroxylase activity in the nucleus accumbens of the rat. Neuropeptides 33:492–497PubMedCrossRefGoogle Scholar
  20. Nussdorfer GG, Malendowicz LK (1998) Role of VIP, PACAP, and related peptides in the regulation of the hypothalamo–pituitary–adrenal axis. Peptides 19:1443–1467PubMedCrossRefGoogle Scholar
  21. Ogawa T, Nakamachi T, Ohtaki H, Hashimoto H, Ndummyra S, Baba A, Watanabe J, Kikuyama S, Shioda S (2005) Monoaminergic neuronal development is not affected in PACAP-gene-deficient mice. Regul Pept 126:103–108PubMedCrossRefGoogle Scholar
  22. Otto C, Martin M, Wolfer DP, Lipp HP, Maldonado R, Schutz G (2001) Altered emotional behavior in PACAP-type-I-receptor-deficient mice. Brain Res Mol Brain Res 92:78–84PubMedCrossRefGoogle Scholar
  23. Palkovits M, Somogyvari-Vigh A, Arimura A (1995) Concentrations of pituitary adenylate cyclase activating polypeptide (PACAP) in human brain nuclei. Brain Res 699:116–120PubMedCrossRefGoogle Scholar
  24. Sheward WJ, Lutz EM, Harmar AJ (1996) Expression of pituitary adenylate cyclase activating polypeptide receptors in the early mouse embryo as assessed by reverse transcription polymerase chain reaction and in situ hybridisation. Neurosci Lett 216:45–48PubMedCrossRefGoogle Scholar
  25. Sheward WJ, Lutz EM, Copp AJ, Harmar AJ (1998) Expression of PACAP, and PACAP type 1 (PAC1) receptor mRNA during development of the mouse embryo. Brain Res Dev Brain Res 109:245–253PubMedCrossRefGoogle Scholar
  26. Thiele TE, Willis B, Stadler J, Reynolds JG, Bernstein IL, McKnight GS (2000) High ethanol consumption and low sensitivity to ethanol-induced sedation in protein kinase A-mutant mice. J Neurosci 20:RC75PubMedGoogle Scholar
  27. Vaudry D, Gonzalez BJ, Basille M, Yon L, Fournier A, Vaudry H (2000) Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev 52:269–324PubMedGoogle Scholar
  28. Waschek JA, Casillas RA, Nguyen TB, Cicco-Bloom EM, Carpenter EM, Rodriguez WI (1998) Neural tube expression of pituitary adenylate cyclase-activating peptide (PACAP) and receptor: potential role in patterning and neurogenesis. Proc Natl Acad Sci USA 95:9602–9607PubMedCrossRefGoogle Scholar
  29. Wise RA (1989) Opiate reward: sites and substrates. Neurosci Biobehav Rev 13:129–133PubMedCrossRefGoogle Scholar
  30. Yoburn BC, Lutfy K, Azimuddin S, Sierra V (1990) Differentiation of spinal and supraspinal opioid receptors by morphine tolerance. Life Sci 46:343–350PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Paul Marquez
    • 1
  • David Bebawy
    • 1
  • Vincent Lelièvre
    • 2
    • 3
  • Anne-Claire Coûté
    • 2
    • 3
  • Christopher J. Evans
    • 2
  • James A. Waschek
    • 2
    • 3
  • Kabirullah Lutfy
    • 1
  1. 1.Department of Pharmaceutical SciencesWestern University of Health SciencesPomonaUSA
  2. 2.Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, David Geffen School of MedicineUniversity of California, Los AngelesLos AngelesUSA
  3. 3.Mental Retardation Research CenterUniversity of California, Los AngelesLos AngelesUSA

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