Abstract
Rationale
The neuropeptide galanin and its receptors are expressed in brain regions implicated in the rewarding effects of natural stimuli and drugs of abuse. Galanin has been shown to attenuate neurochemical, physiological, and behavioral signs of opiate and amphetamine reinforcement.
Objective
In the current study, we present evidence that galanin modulates neurochemical and behavioral correlates of cocaine response.
Methods
Mice lacking the neuropeptide galanin (Gal −/−) and wild-type (Gal +/+) controls were used to analyze the effects of galanin in an unbiased conditioned place preference paradigm. We then examined cocaine-induced activation of extracellular signal-regulated kinase (ERK) activity as a marker of intracellular signaling in the mesolimbic dopaminergic pathway induced by acute cocaine administration
Results
Gal −/− mice showed significantly greater conditioned place preference at a threshold dose of cocaine (3 mg/kg) than Gal +/+ mice, and this was reversed by administration of the galanin receptor agonist galnon. Consistent with the results of behavioral experiments, there was a significant increase in ERK activation in the ventral tegmental area (VTA) and nucleus accumbens (NAc) of Gal −/− mice but not Gal +/+ mice following acute, systemic cocaine injection at the threshold dose. In the NAc, but not VTA, this effect was reversed by administration of galnon.
Conclusions
These data, coupled with previous studies on the effects of morphine and amphetamine, demonstrate that galanin normally attenuates drug reinforcement, potentially via modulation of the mesolimbic dopamine system.
Similar content being viewed by others
References
Antoniou K, Kehr J, Snitt K, Ogren SO (1997) Differential effects of the neuropeptide galanin on striatal acetylcholine release in anaesthetized and awake rats. Br J Pharmacol 121:1180–1186
Belfer I, Hipp H, McKnight C, Evans C, Buzas B, Bollettino A, Albaugh B, Virkkunen M, Yuan Q, Max MB, Goldman D, Enoch MA (2006) Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations. Mol Psychiatry 11:301–311
Belfer I, Hipp H, Bollettino A, McKnight C, Evans C, Virkkunen M, Albaugh B, Max MB, Goldman D, Enoch MA (2007) Alcoholism is associated with GALR3 but not two other galanin receptor genes. Genes Brain Behav 6:473–481
Berhow MT, Hiroi N, Nestler EJ (1996) Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine. J Neurosci 16:4707–4715
Burgevin MC, Loquet I, Quarteronet D, Habert-Ortoli E (1995) Cloning, pharmacological characterization, and anatomical distribution of a rat cDNA encoding for a galanin receptor. J Mol Neurosci 6:33–41
Cunningham CL, Ferree NK, Howard MA (2003) Apparatus bias and place conditioning with ethanol in mice. Psychopharmacology (Berl) 170:409–422
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 U S A 85:5274–5278
Elliott-Hunt CR, Pope RJ, Vanderplank P, Wynick D (2007) Activation of the galanin receptor 2 (GalR2) protects the hippocampus from neuronal damage. J Neurochem 100:780–789
Ellis Y, Davies JA (1994) The effect of neuropeptides on the release of neurotransmitter amino acids from rat striatum. Neuropeptides 26:65–69
Ericson E, Ahlenius S (1999) Suggestive evidence for inhibitory effects of galanin on mesolimbic dopaminergic neurotransmission. Brain Res 822:200–209
Girault JA, Valjent E, Caboche J, Herve D (2007) ERK2: a logical AND gate critical for drug-induced plasticity? Curr Opin Pharmacol 7:77–85
Gustafson EL, Smith KE, Durkin MM, Gerald C, Branchek TA (1996) Distribution of a rat galanin receptor mRNA in rat brain. Neuroreport 7:953–957
Hawes JJ, Picciotto MR (2004) Characterization of GalR1, GalR2, and GalR3 immunoreactivity in catecholaminergic nuclei of the mouse brain. J Comp Neurol 479:410–423
Hawes JJ, Brunzell DH, Wynick D, Zachariou V, Picciotto MR (2005) GalR1, but not GalR2 or GalR3, levels are regulated by galanin signaling in the locus coeruleus through a cyclic AMP-dependent mechanism. J Neurochem 93:1168–1176
Hawes JJ, Narasimhaiah R, Picciotto MR (2006a) Galanin and galanin-like peptide modulate neurite outgrowth via protein kinase C-mediated activation of extracellular signal-related kinase. Eur J Neurosci 23:2937–2946
Hawes JJ, Narasimhaiah R, Picciotto MR (2006b) Galanin attenuates cyclic AMP regulatory element-binding protein (CREB) phosphorylation induced by chronic morphine and naloxone challenge in Cath.a cells and primary striatal cultures. J Neurochem 96:1160–1168
Hawes JJ, Brunzell DH, Narasimhaiah R, Langel U, Wynick D, Picciotto MR (2008) Galanin protects against behavioral and neurochemical correlates of opiate reward. Neuropsychopharmacology 33:1864–1873
Hobson SA, Holmes FE, Kerr NC, Pope RJ, Wynick D (2006) Mice deficient for galanin receptor 2 have decreased neurite outgrowth from adult sensory neurons and impaired pain-like behaviour. J Neurochem 99:1000–1010
Holmes A, Picciotto MR (2006) Galanin: a novel therapeutic target for depression, anxiety disorders and drug addiction? CNS Neurol Disord Drug Targets 5:225–232
Kinney GA, Emmerson PJ, Miller RJ (1998) Galanin receptor-mediated inhibition of glutamate release in the arcuate nucleus of the hypothalamus. J Neurosci 18:3489–3500
Kolakowski LF Jr, O’Neill GP, Howard AD, Broussard SR, Sullivan KA, Feighner SD, Sawzdargo M, Nguyen T, Kargman S, Shiao LL, Hreniuk DL, Tan CP, Evans J, Abramovitz M, Chateauneuf A, Coulombe N, Ng G, Johnson MP, Tharian A, Khoshbouei H, George SR, Smith RG, O’Dowd BF (1998) Molecular characterization and expression of cloned human galanin receptors GALR2 and GALR3. J Neurochem 71:2239–2251
Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13:177–184
Kuteeva E, Hokfelt T, Ogren SO (2005a) Behavioural characterisation of transgenic mice overexpressing galanin under the PDGF-B promoter. Neuropeptides 39:299–304
Kuteeva E, Hokfelt T, Ogren SO (2005b) Behavioural characterisation of young adult transgenic mice overexpressing galanin under the PDGF-B promoter. Regul Pept 125:67–78
Lang R, Gundlach AL, Kofler B (2007) The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease. Pharmacol Ther 115:177–207
Levran O, Londono D, O’Hara K, Nielsen DA, Peles E, Rotrosen J, Casadonte P, Linzy S, Randesi M, Ott J, Adelson M, Kreek MJ (2008) Genetic susceptibility to heroin addiction; a candidate-gene association study. Genes Brain Behav
Lewis MJ, Rada P, Johnson DF, Avena NM, Leibowitz SF, Hoebel BG (2005) Galanin and alcohol dependence: neurobehavioral research. Neuropeptides 39:317–321
Ogren SO, Pramanik A, Land T, Langel U (1993) Differential effects of the putative galanin receptor antagonists M15 and M35 on striatal acetylcholine release. Eur J Pharmacol 242:59–64
Ogren SO, Schott PA, Kehr J, Yoshitake T, Misane I, Mannstrom P, Sandin J (1998) Modulation of acetylcholine and serotonin transmission by galanin. Relationship to spatial and aversive learning. Ann N Y Acad Sci 863:342–363
Picciotto MR (2008) Galanin and addiction. Cell Mol Life Sci 65:1872–1879
Pieribone VA, Xu ZQ, Zhang X, Grillner S, Bartfai T, Hokfelt T (1995) Galanin induces a hyperpolarization of norepinephrine-containing locus coeruleus neurons in the brainstem slice. Neuroscience 64:861–874
Rada P, Avena NM, Leibowitz SF, Hoebel BG (2004) Ethanol intake is increased by injection of galanin in the paraventricular nucleus and reduced by a galanin antagonist. Alcohol 33:91–97
Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:577–582
Saar K, Mazarati AM, Mahlapuu R, Hallnemo G, Soomets U, Kilk K, Hellberg S, Pooga M, Tolf BR, Shi TS, Hokfelt T, Wasterlain C, Bartfai T, Langel U (2002) Anticonvulsant activity of a nonpeptide galanin receptor agonist. Proc Natl Acad Sci U S A 99:7136–7141
Schneider ER, Rada P, Darby RD, Leibowitz SF, Hoebel BG (2007) Orexigenic peptides and alcohol intake: differential effects of orexin, galanin, and ghrelin. Alcohol Clin Exp Res 31:1858–1865
Tsuda K, Tsuda S, Nishio I, Masuyama Y, Goldstein M (1998) Effects of galanin on dopamine release in the central nervous system of normotensive and spontaneously hypertensive rats. Am J Hypertens 11:1475–1479
Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583–587
Valjent E, Corvol JC, Pages C, Besson MJ, Maldonado R, Caboche J (2000) Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J Neurosci 20:8701–8709
Valjent E, Caboche J, Vanhoutte P (2001) Mitogen-activated protein kinase/extracellular signal-regulated kinase induced gene regulation in brain: a molecular substrate for learning and memory? Mol Neurobiol 23:83–99
Valjent E, Pages C, Herve D, Girault JA, Caboche J (2004) Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 19:1826–1836
Valjent E, Pascoli V, Svenningsson P, Paul S, Enslen H, Corvol JC, Stipanovich A, Caboche J, Lombroso PJ, Nairn AC, Greengard P, Herve D, Girault JA (2005) Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc Natl Acad Sci U S A 102:491–496
Valjent E, Corbille AG, Bertran-Gonzalez J, Herve D, Girault JA (2006) Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference. Proc Natl Acad Sci U S A 103:2932–2937
Vanderschuren LJ, Schoffelmeer AN, Mulder AH, De Vries TJ (1999) Dopaminergic mechanisms mediating the long-term expression of locomotor sensitization following pre-exposure to morphine or amphetamine. Psychopharmacology (Berl) 143:244–253
Vossler MR, Yao H, York RD, Pan MG, Rim CS, Stork PJ (1997) cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89:73–82
Wang HY, Wild KD, Shank RP, Lee DH (1999) Galanin inhibits acetylcholine release from rat cerebral cortex via a pertussis toxin-sensitive G(i)protein. Neuropeptides 33:197–205
Waters SM, Krause JE (2000) Distribution of galanin-1, -2 and -3 receptor messenger RNAs in central and peripheral rat tissues. Neuroscience 95:265–271
Wittau N, Grosse R, Kalkbrenner F, Gohla A, Schultz G, Gudermann T (2000) The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to G(q), G(i) and G(12) proteins. Oncogene 19:4199–4209
Wu WP, Hao JX, Lundstrom L, Wiesenfeld-Hallin Z, Langel U, Bartfai T, Xu XJ (2003) Systemic galnon, a low-molecular weight galanin receptor agonist, reduces heat hyperalgesia in rats with nerve injury. Eur J Pharmacol 482:133–137
Wynick D, Small CJ, Bloom SR, Pachnis V (1998) Targeted disruption of the murine galanin gene. Ann N Y Acad Sci 863:22–47
Zachariou V, Parikh K, Picciotto MR (1999) Centrally administered galanin blocks morphine place preference in the mouse. Brain Res 831:33–42
Zachariou V, Brunzell DH, Hawes J, Stedman DR, Bartfai T, Steiner RA, Wynick D, Langel U, Picciotto MR (2003) The neuropeptide galanin modulates behavioral and neurochemical signs of opiate withdrawal. Proc Natl Acad Sci U S A 100:9028–9033
Zubrzycka M, Janecka A (2008) Interactions of galanin with endomorphin-2, vasopressin and oxytocin in nociceptive modulation of the trigemino-hypoglossal reflex in rats. Physiol Res 57:769–776
Acknowledgements
This work was supported by grants DA15425 and DA00436 from the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Additional information
Roopashree Narasimhaiah and Helen M. Kamens contributed equally to this manuscript.
Rights and permissions
About this article
Cite this article
Narasimhaiah, R., Kamens, H.M. & Picciotto, M.R. Effects of galanin on cocaine-mediated conditioned place preference and ERK signaling in mice. Psychopharmacology 204, 95–102 (2009). https://doi.org/10.1007/s00213-008-1438-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-008-1438-7