Microinjection of Ghrelin into the Ventral Tegmental Area Potentiates Cocaine-Induced Conditioned Place Preference

Abstract

Prior work has shown that systemic cocaine pretreatment augments cocaine conditioned place preference (CPP) in rats. In contrast, ghrelin receptor antagonism attenuates cocaine and amphetamine-induced CPP. In order to further investigate ghrelins role in dopamine-mediated reward, the present report examined whether pretreament with ghrelin, administered directly into the ventral tegmental area (VTA) of the midbrain, would potentiate the rewarding properties of cocaine as measured by CPP. Adult male Sprague-Dawley rats were given access to either side of the CPP chamber in order to determine initial side preferences. The rats were then restricted to either their non-preferred or preferred side over the course of conditioning which lasted for a total of 16 consecutive days. This was followed by a final test day to then reassess preference. On days where rats were confined to their non-preferred side, ghrelin (30-300 pmol) and cocaine (0.625-10 mg/kg IP) were administered immediately prior to the conditioning trial. On alternate days rats were treated with vehicle and placed into what was initially determined to be their preferred side. CPP was calculated as the difference in percentage of total time spent in the treatment-paired compartment during the post-conditioning session and the pre-conditioning session. Our results indicated that both cocaine and ghrelin elicited CPP and that ghrelin pretreatment potentiated the effect of cocaine on place preference. Overall, these findings provide additional support for the argument that ghrelin signaling within the VTA enhances the rewarding effects of psychostimulant compounds.

Share and Cite:

L. Schuette, C. Gray and P. Currie, "Microinjection of Ghrelin into the Ventral Tegmental Area Potentiates Cocaine-Induced Conditioned Place Preference," Journal of Behavioral and Brain Science, Vol. 3 No. 8, 2013, pp. 576-580. doi: 10.4236/jbbs.2013.38060.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] P. J. Currie, A. Mirza, R. Fuld, D. Park and J. R. Vasselli, “Ghrelin Is an Orexigenic and Metabolic Signaling Peptide in the Arcuate and Paraventricular Nuclei,” American Journal of Physiology, Vol. 289, No. 2, 2005, pp. R353-R358.
[2] P. J. Currie, C. D. Coiro, R. Duenas, J. L. Guss, A. Mirza and N. Tal, “Urocortin I Inhibits the Effects of Ghrelin and Neuropeptide Y on Feeding and Energy Substrate Utilization,” Brain Research, Vol. 1385, 2001, pp. 127-134. http://dx.doi.org/10.1016/j.brainres.2011.01.114
[3] T. L. Horvath, T. Castaneda, M. Tang-Christensen, U. Pagotto and M. H. Tschop, “Ghrelin as a Potential Anti-Obesity Target,” Current Pharmaceutical Design, Vol. 9, No. 17, 2003, pp. 1383-1395.
http://dx.doi.org/10.2174/1381612033454748
[4] A. M. Wren, C. J. Small, C. R. Abbott, W. S. Dhillo, L. J. Seal, M. A. Cohen, R. L. Batterham, S. Taheri, S. A. Stanley, M. A. Ghatei and S. R. Bloom, “Ghrelin Causes Hyperphagia and Obesity in Rats,” Diabetes, Vol. 50, No. 11, 2001, pp. 2540-2547.
http://dx.doi.org/10.2337/diabetes.50.11.2540
[5] P. J. Currie, R. Khelemsky, E. M. Rigsbee, L. M. Dono, C. D. Coiro, C. D. Chapman and K. Hinchcliff, “Ghrelin Is an Orexigenic Peptide and Elicits Anxiety-Like Behaviors Following Administration into Discrete Regions of the Hypothalamus,” Behavioral Brain Research, Vol. 226, No. 1, 2012, pp. 96-105.
http://dx.doi.org/10.1016/j.bbr.2011.08.037
[6] P. J. Currie, L. M. Schuette, S. E. R. Wauson, W. N. Voss and M. J. Angeles, “Activation of Urocortin 1 and Ghrelin Signaling in the Basolateral Amygdala Induces Anxiogenesis,” NeuroReport, 2013, in press.
http://dx.doi.org/10.1097/WNR.0000000000000047
[7] C. Hansson, D. Haage, M. Taube, E. Egecioglu, N. Salome and S. L. Dickson, “Central Administration of Ghrelin Alters Emotional Responses in Rats: Behavioural, Electrophysiological, and Molecular Evidence,” Neuroscience, Vol. 180, 2011, pp. 201-211.
http://dx.doi.org/10.1016/j.neuroscience.2011.02.002
[8] S. J. Spencer, L. Xu, M. A. Clarke, M. Lemus, A. Reichenbach, B. Geenen, T. Kozicz and Z. B. Andrews, “Ghrelin Regulates the Hypothalamic-Pituitary-Adrenal Axis and Restricts Anxiety after Acute Stress,” Biological Psychiatry, Vol. 72, No. 6, 2012, pp. 457-465.
http://dx.doi.org/10.1016/j.biopsych.2012.03.010
[9] S. M. Jacoby and P. J. Currie, “SKF 83566 Attenuates the Effects of Ghrelin on Performance in the Object Location Memory Task,” Neuroscience Letters, Vol. 504, No. 3, 2011, pp. 316-320.
http://dx.doi.org/10.1016/j.neulet.2011.09.056
[10] S. E. Kanoski, S. M. Fortin, K. M. Ricks and H. J. Grill, “Ghrelin Signaling in the Ventral Hippocampus STIMULATES Learned and Motivational Aspects of Feeding via PI3K-Akt Signaling,” Biological Psychiatry, Vol. 73, No. 9, 2013, pp. 915-923.
http://dx.doi.org/10.1016/j.biopsych.2012.07.002
[11] Y. Kawahara, F. Kaneko, M. Yamada, Y. Kishikawa, H. Kawahara and A. Nishi, “Food Reward-Sensitive Interaction of Ghrelin and Opioid Receptor Pathways in the Mesolimbic Dopamine System,” Neuropharmacology, Vol. 67, 2013, pp. 395-402.
http://dx.doi.org/10.1016/j.neuropharm.2012.11.022
[12] S. J. King, A. M. Isaacs, E. O’Farrell and A. Abizaid, “Motivation to Obtain Preferred Foods Is Enhanced by Ghrelin in the Ventral Tegmental Area,” Hormones and Behavior, Vol. 60, No. 5, 2011, pp. 572-580.
http://dx.doi.org/10.1016/j.yhbeh.2011.08.006
[13] J. K. Jang, W. Y. Kim, B. R. Cho, J. W. Lee and J. H. Kim, “Microinjection of Ghrelin in the Nucleus Accumbens Core Enhances Locomotor Activity Induced by Cocaine,” Behavioural Brain Research, Vol. 248, 2013, pp. 7-11. http://dx.doi.org/10.1016/j.bbr.2013.03.049
[14] M. Palotai, Z. Bagosi, M. Jaszberenyi, K. Csabafi, R. Dochnal, M. Manczinger, G. Telegdy and G. Szabo, “Ghrelin and Nicotine Stimulate Equally the Dopamine Release in the Rat Amygdala,” Neurochemical Research, Vol. 38, No. 38, 2013, pp. 1989-1995.
http://dx.doi.org/10.1007/s11064-013-1105-1
[15] K. P. Skibicka, R. H. Shirazi, C. Rabasa-Papio, M. Alvarez-Crespo, C. Neuber, H. Vogel and S. L. Dickson, “Divergent Circuitry Underlying Food Reward and Intake Effects of Ghrelin: Dopaminergic VTA-Accumbens Projection Mediates Ghrelin’s Effects on Food Reward but Not Food Intake,” Neuropharmacology, Vol. 73, 2013, pp. 274-283.
http://dx.doi.org/10.1016/j.neuropharm.2013.06.004
[16] W. A. Banks, M. Tschop, S. M. Robinson and M. L. Heiman, “Extent and Direction of Ghrelin Transport across the Blood-Brain Barrier Is Determined by Its Unique Primary Structure,” Journal of Pharmacology and Experimental Therapeutics, Vol. 302, No. 2, 2002, pp. 822-827. http://dx.doi.org/10.1124/jpet.102.034827
[17] A. M. Naleid, M. K. Grace, D. E. Cummings and A. S. Levine, “Ghrelin Induces Feeding in the Mesolimbic Reward Pathway between the Ventral Tegmental Area and the Nucleus Accumbens,” Peptides, Vol. 26, No. 11, 2005, pp. 2274-2279.
http://dx.doi.org/10.1016/j.peptides.2005.04.025
[18] P. J. Wellman, C. N. Hollas and A. E. Elliott, “Systemic Ghrelin Sensitizes Cocaine-Induced Hyperlocomotion in Rats,” Regulatory Peptides, Vol. 146, No. 1-3, 2008, pp. 33-37.
http://dx.doi.org/10.1016/j.regpep.2007.07.007
[19] K. W. Davis, P.J. Wellman and P. S. Clifford, “Augmented Cocaine Conditioned Place Preference in Rats Pretreated with Systemic Ghrelin,” Regulatory Peptides, Vol. 140, No. 3, 2007, pp. 148-152.
http://dx.doi.org/10.1016/j.regpep.2006.12.003
[20] E. Jerlhag, E. Egecioglu, S. L. Dickson and J. A. Engel, “Ghrelin Receptor Antagonism Attenuates Cocaineand Amphetamine-Induced Locomotor Stimulation, Accumbal Dopamine Release, and Conditioned Place Preference,” Psychopharmacology, Vol. 211, No. 4, 2010, pp. 415-422. http://dx.doi.org/10.1007/s00213-010-1907-7
[21] L. M. Schuette, C. C. Gray, S. E. R. Wauson, K. R. Davis and P. J. Currie, “Mesotelencephalic Ghrelinergic Signaling in Reward and Limbic Function,” Program No. 707.18. 2012 Neuroscience Meeting Planner, New Orleans, Society for Neuroscience, 2012, Online.
[22] G. Paxinos and C. Watson, “The Rat Brain in Stereotaxic Coordinates,” Academic Press, New York, 2007.
[23] D. Quarta, C. DiFrancesco, S. Melotto, L. Mangiarini, C. Heidbreder and G. Hedou, “Systemic Administration of Ghrelin Increases Extracellular Dopamine in the Shell but Not the Core Subdivision of the Nucleus Accumbens,” Neurochemistry International, Vol. 54, No. 2, 2009, pp. 89-94. http://dx.doi.org/10.1016/j.neuint.2008.12.006
[24] Z. Y. Weinberg, M. L. Nicholson and P. J. Currie, “6-Hydroxydopamine Lesions of the Ventral Tegmental Area Suppress Ghrelin’s Ability to Elicit Food-Rein-forced behavior,” Neuroscience Letters, Vol. 499, No. 2, 2011, 70-73. http://dx.doi.org/10.1016/j.neulet.2011.05.034
[25] E. Jerlhag, S. Landgren, E. Eqecioglu, S. L. Dickson and J. A. Engel, “The Alcohol-Induced Locomotor Stimulation and Accumbal Dopamine Release Is Suppressed in Ghrelin Knockout Mice,” Alcohol, Vol. 45, No. 4, 2011, pp. 341-347.
http://dx.doi.org/10.1016/j.alcohol.2010.10.002
[26] A. Abizaid, Y. S. Mineur, R. H. Roth, J. D. Elsworth, M. W. Sleeman, M. R. Picciotto and T. L. Horvath, “Reduced Locomotor Responses to Cocaine in Ghrelin-Deficient Mice,” Neuroscience, Vol. 192, 2011, pp. 500-506.
http://dx.doi.org/10.1016/j.neuroscience.2011.06.001
[27] P. S. Clifford, J. Rodriguez, D. Schul, S. Hughes. T. Kniffin, N. Hart, S. Eitan, L. Brunel. J. A. Fehrentz, J. Martinez and P. J. Wellman, “Attenuation of Cocaine-Induced Locomotor Sensitization in Rats Sustaining Genetic or Pharmacologic Antagonism of Ghrelin Receptors,” Addiction Biology, Vol. 17, No. 6, 2011, pp. 956-963. http://dx.doi.org/10.1111/j.1369-1600.2011.00339.x
[28] E. Egecioglu, E. Jerlhag, N. Salome, K. P. Skibicka, D. Haage, M. Bohlooly-Y, D. Andersson, M. Bjursell, D. Perrisoud, J. A. Engel and S. L. Dickson, “Ghrelin Increases Intake of Rewarding Food in Rodents,” Addiction Biology, Vol. 15, No. 3, 2010, pp. 304-311.
http://dx.doi.org/10.1111/j.1369-1600.2010.00216.x
[29] Y. Kawahara, F. Kaneko, M. Yamada, Y. Kishikawa, H. Kawahara and A. Nishi, “Food Reward-Sensitive Interaction of Ghrelin and Opioid Receptor Pathways in Mesolimbic Dopamine System,” Neuropharmacology, Vol. 67, 2013, pp. 395-402.
http://dx.doi.org/10.1016/j.neuropharm.2012.11.022

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.