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Locomotor stimulant effects of acute and repeated intrategmental injections of salsolinol in rats: role of μ-opioid receptors

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Abstract

Rationale

Microinjections of ethanol and acetaldehyde into ventral tegmental area (VTA) produce locomotor activation in rats through mechanisms dependent on the μ-opioid receptors. However, it is not clear how these drugs can interact with these receptors. It has been hypothesized that salsolinol could be the responsible for this interaction.

Objectives

The aim of the study was to investigate the ability of salsolinol to induce both motor activation and motor sensitization in rats after repeated intra-VTA administration.

Materials

Rats received one microinjection into the posterior VTA of artificial cerebrospinal fluid (aCSF; 200 nL), salsolinol (0.3–3,000.0 pmol/200 nL), or salsolinol (30.0 pmol/200 nL) with either naltrexone (13.2 nmol/200 nL) or with the antagonist of the μ-opioid receptors, β-funaltrexamine (β-FNA; 2.5 nmol/300 nL). In the sensitization experiments, four microinjections of salsolinol (30.0 pmol/200 nL) or aCSF (200 nL) were performed over a 2-week period. This period was followed by a single challenge session, in which 0.3 pmol of salsolinol was microinjected to rats. Spontaneous activity was always monitored postinjection.

Results

Intra-VTA salsolinol administration induces an increase of the spontaneous motor activity of the rats with the maximal effect at the dose of 30.0 pmol/200 nL. Salsolinol effects were blocked by the treatment with naltrexone or β-FNA. Moreover, repeated injections of salsolinol produced locomotor sensitization.

Conclusions

Salsolinol induces locomotor activity and motor sensitization after intra-VTA administration. Moreover, the implication of the μ-opioid receptors was shown since the treatment with naltrexone or β-FNA was able to suppress the salsolinol effects.

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References

  • Antkiewicz-Michaluk L, Michaluk J, Romanska I, Papla I, Vetulani J (2000a) Antidopaminergic effects of 1, 2, 3, 4-tetrahydroisoquinoline and salsolinol. J Neural Transm 107:1009–1019

    Article  CAS  PubMed  Google Scholar 

  • Antkiewicz-Michaluk L, Romanska I, Papla I, Michaluk J, Bakalarz M, Vetulani J, Krygowska-Wajs A, Szcudlik A (2000b) Neurochemical changes induced by acute and chronic administration of 1, 2, 3, 4-tetrahydroisoquinoline and salsolinol in dopaminergic structures of rat brain. Neuroscience 96:59–64

    Article  CAS  PubMed  Google Scholar 

  • Arizzi-LaFrance MN, Correa M, Aragon CM, Salamone JD (2006) Motor stimulant effects of ethanol injected into the substantia nigra pars reticulata: Importance of catalase-mediated metabolism and the role of acetaldehyde. Neuropsychopharmacology 31:997–1008

    Article  CAS  PubMed  Google Scholar 

  • Babbini M, Davis WM (1972) Time–dose relationships for locomotor activity effects of morphine after acute or repeated treatment. Br J Pharmacol 46:213–224

    CAS  PubMed  Google Scholar 

  • Bartoleni M, Gaiardi M, Gubellini G, Bacchi AA, Babbini M (1983) Long-term sensitization to the excitatory effects of morphine. Neuropharmacology 22:1193–1196

    Article  Google Scholar 

  • Baum SS, Hill R, Kiianmaa K, Rommelspacher H (1999) Effect of ethanol on (R)- and (S)-salsolinol, salsoline, and THP in the nucleus accumbens of AA and ANA rats. Alcohol 18:165–169

    Article  CAS  Google Scholar 

  • Blum D, Hamilton MG, Hirst M, Wallace JE (1978) Putative role of isoquinoline alkaloids in alcoholism: a link to opiates. Alcohol Clin Exp Res 2:113–120

    Article  CAS  PubMed  Google Scholar 

  • Cohen G, Collins M (1970) Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism. Science 27:1749–1751

    Article  Google Scholar 

  • Correa M, Arizzi MN, Betz A, Mingote S, Salamone JD (2003) Locomotor stimulant effects of intraventricular injections of low doses of ethanol in rats: acute and repeated administration. Psychopharmacology 170:368–375

    Article  CAS  PubMed  Google Scholar 

  • Davis VE, Walsh MJ (1970) Alcohol, amines, and alkaloids: a possible biochemical basis for alcohol addiction. Science 13:1005–1007

    Google Scholar 

  • Deng Y, Maruyama W, Yamamura H, Kawai M, Dostert P, Naoi M (1996) Mechanism of enantioseparation of salsolinols, endogenous neurotoxins in human brain, with ion-pair chromatography using beta-cyclodextrin as a mobile phase additive. Anal Chem 68(17):2826–2831

    Article  CAS  PubMed  Google Scholar 

  • Devine DP, Wise RA (1994) Self-administration of morphine, DAMGO, and DPDPE into the ventral tegmental area of rats. J Neurosci 14(4):1978–1984

    CAS  PubMed  Google Scholar 

  • Devine DP, Leone P, Pocock D, Wise RA (1993) Differential involvement of ventral tegmental mu, delta and kappa opioid receptors in modulation of basal mesolimbic dopamine release: in vivo microdialysis studies. J Pharmacol Exp Ther 266(3):1236–1246

    CAS  PubMed  Google Scholar 

  • Duncan C, Deitrich RA (1980) A critical evaluation of tetrahydroisoquinoline induced ethanol preference in rats. Pharmacol Biochem Behav 13:265–281

    Article  CAS  PubMed  Google Scholar 

  • Fertel RH, Greenwald JE, Schwarz R, Wong L, Bianchine J (1980) Opiate receptor binding and analgesic effects of the tetrahydroisoquinolines salsolinol and tetrahydro-papaveroline. Res Commun Chem Pathol Pharmacol 27:3–16

    CAS  PubMed  Google Scholar 

  • Fish EW, DeBold JF, Miczek KA (2002) Repeated alcohol: behavioral sensitization and alcohol-heightened aggression in mice. Psychopharmacology 160:39–48

    Article  CAS  PubMed  Google Scholar 

  • Haber H, Dumaual N, Bare DJ, Melzig MF, McBride WJ, Lumeng L, Li TK (1999) The quantitative determination of R- and S-salsolinol in the striatum and adrenal gland of rats selectively bred for disparate alcohol drinking. Addict Biol 4:181–189

    Article  CAS  Google Scholar 

  • Hamilton MG, Blum K, Hirst M (1978) Identification of an isoquinoline alkaloid after chronic exposure to ethanol. Alcohol Clin Exp Res 2:133–137

    Article  CAS  PubMed  Google Scholar 

  • Hipólito L, Sánchez-Catalán MJ, Zanolini I, Polache A, Granero L (2008) Shell/core differences in mu- and delta-opioid receptor modulation of dopamine efflux in nucleus accumbens. Neuropharmacology 55:183–189

    Article  PubMed  Google Scholar 

  • Hipólito L, Sánchez-Catalán MJ, Granero L, Polache A (2009) Local salsolinol modulates dopamine extracellular levels from rat nucleus accumbens: shell/core differences. Neurochem Int 55:187–192

    Article  PubMed  Google Scholar 

  • Homicsko KG, Kertesz I, Radnai B, Toth BE, Toth G, Fulop F, Fekete MI, Nagy GM (2003) Binding site of salsolinol: its properties in different regions of the brain and the pituitary gland of the rat. Neurochem Int 42:19–26

    Article  CAS  PubMed  Google Scholar 

  • Jamal M, Ameno K, Ameno S, Okada N, Ijiri I (2003) In vivo study of salsolinol produced by a high concentration of acetaldehyde in the striatum and nucleus accumbens of free-moving rats. Alcohol Clin Exp Res 27(8 Suppl):79S–84S

    Article  CAS  PubMed  Google Scholar 

  • Joyce EM, Iversen SD (1979) The effect of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous motor activity in the rat. Neurosci Lett 14:207–212

    Article  CAS  PubMed  Google Scholar 

  • MacDonald AF, Billington CJ, Levine AS (2003) Effects of the opioid antagonist naltrexone on feeding induced by DAMGO in the ventral tegmental area and in the nucleus accumbens shell region in the rat. Am J Physiol Regul Integr Comp Physiol 285(5):R999–R1004

    CAS  PubMed  Google Scholar 

  • MacDonald AF, Billington CJ, Levine AS (2004) Alterations in food intake by opioid and dopamine signaling pathways between the ventral tegmental area and the shell of the nucleus accumbens. Brain Res 1018(1):78–85

    Article  CAS  PubMed  Google Scholar 

  • Martin TJ, Coller M, Co C, Smith JE (2008) Micro-opioid receptor alkylation in the ventral pallidum and ventral tegmental area, but not in the nucleus accumbens, attenuates the effects of heroin on cocaine self-administration in rats. Neuropsychopharmacology 33(5):1171–1178

    Article  CAS  PubMed  Google Scholar 

  • Matsubara K, Fukushima S, Fukui Y (1987) A systematic regional study of brain salsolinol levels during and immediately following chronic ethanol ingestion in rats. Brain Res 413:336–343

    Article  CAS  PubMed  Google Scholar 

  • Matsuzawa S, Suzuki T, Misawa M (2000) Involvement of mu-opioid receptor in the salsolinol-associated place preference in rats exposed to conditioned fear stress. Alcohol Clin Exp Res 24:366–372

    CAS  PubMed  Google Scholar 

  • Melchior CL, Myers RD (1977) Preference for alcohol evoked by tetrahydropapaveroline (THP) chronically infused in the cerebral ventricle of the rat. Pharmacol Biochem Behav 7:19–35

    Article  CAS  PubMed  Google Scholar 

  • Myers RD, Robinson DE (1999) Tetrahydropapaveroline injected in the ventral tegmental area shifts dopamine efflux differentially in the shell and core of nucleus accumbens in high-ethanol-preferring (HEP) rats. Alcohol 18:83–90

    Article  CAS  PubMed  Google Scholar 

  • Myers WD, Mackenzie L, Ng KT, Singer G, Smythe GA, Duncan MW (1985) Salsolinol and dopamine in rat medial basal hypothalamus after chronic ethanol exposure. Life Sci 36:309–314

    Article  CAS  PubMed  Google Scholar 

  • Naleid AM, Grace MK, Cummings DE, Levine AS (2005) Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens. Peptides 26(11):2274–2279

    Article  CAS  PubMed  Google Scholar 

  • Naoi M, Maruyama W, Nagy GM (2004) Dopamine-derived salsolinol derivates as endogenous monoamine oxidase inhibitors: occurrence, metabolism and function in human brains. Neurotoxicology 25:193–204

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Academic, New York

    Google Scholar 

  • Phillips TJ, Roberts AJ, Lessov CN (1997) Behavioral sensitization to ethanol: genetics and the effects of stress. Pharmacol Biochem Behav 57:487–493

    Article  CAS  PubMed  Google Scholar 

  • Rodd-Henricks ZA, Melendez RI, Zaffaroni A, Goldstein A, McBride WJ, Li TK (2002) The reinforcing effects of acetaldehyde in the posterior ventral tegmental area of alcohol-preferring rats. Pharmacol Biochem Behav 72:55–64

    Article  CAS  PubMed  Google Scholar 

  • Rodd ZA, Bell RL, Zhang Y, Goldstein A, Zaffaroni A, McBride WJ, Li TK (2003) Salsolinol produces reinforcing effects in the nucleus accumbens shell of alcohol-preferring (P) rats. Alcohol Clin Exp Res 27:440–449

    Article  CAS  PubMed  Google Scholar 

  • Rodd ZA, Melendez RI, Bell RL, Kuc KA, Zhang Y, Murphy JM, McBride WJ (2004a) Intracranial self-administration of ethanol within the ventral tegmental area of male Wistar rats: evidence for involvement of dopamine neurons. J Neurosci 24:1050–1057

    Article  CAS  PubMed  Google Scholar 

  • Rodd ZA, Bell RL, Zhang Y, Murphy JM, Goldstein A, Zaffaroni A, Li TK, McBride WJ (2004b) Regional heterogeneity for the intracranial self-administration of ethanol and acetaldehyde within the ventral tegmental area of alcohol-preferring (P) rats: involvement of dopamine and serotonin. Neuropsychopharmacology 30:330–338

    Article  Google Scholar 

  • Rodd ZA, Bell RL, Melendez RI, Kuc KA, Lumeng L, Li T-K, Murphy JM, McBride WJ (2004c) Comparison of intracranial self-administration of ethanol within the posterior ventral tegmental area between alcohol-preferring (P) and Wistar rats. Alcohol Clin Exp Res 28:1212–1219

    Article  PubMed  Google Scholar 

  • Rodd ZA, Bell RL, McQueen VK, Davids MR, Hsu CC, Murphy JM, Li T-K, Lumeng L, McBride WJ (2005) Prolonged increase in the sensitivity of the posterior ventral tegmental area to the reinforcing effects of ethanol following repeated exposure to cycles of ethanol access and deprivation. J Pharmacol Exp Ther 315:648–657

    Article  CAS  PubMed  Google Scholar 

  • Rodd ZA, Oster SM, Ding ZM, Toalston JE, Deehan G, Bell RL, Li TK, McBride WJ (2008) The reinforcing properties of salsolinol in the ventral tegmental area: evidence for regional heterogeneity and the involvement of serotonin and dopamine. Alcohol Clin Exp Res 32:230–239

    Article  CAS  PubMed  Google Scholar 

  • Rojkovicova T, Mechref Y, Starkey JA, Wu G, Bell RL, McBride WJ, Novotny MV (2008) Quantitative chiral analysis of salsolinol in different brain regions of rats genetically predisposed to alcoholism. J Chromatogr B Analyt Technol Biomed Life Sci 863:206–214

    Article  CAS  PubMed  Google Scholar 

  • Rommelspacher H, Baum S, Dufeu P, Schmidt LG (1995) Determination of (R)- and (S)-salsolinol sulfate and dopamine sulfate levels in plasma of nonalcoholics and alcoholics. Alcohol 12:309–315

    Article  CAS  PubMed  Google Scholar 

  • Sánchez-Catalán MJ, Hipólito L, Zornoza T, Polache A, Granero L (2009) Motor stimulant effects of ethanol and acetaldehyde injected into the posterior ventral tegmental area of rats: role of opioid receptors. Psychopharmacology 204(4):641–653

    Article  PubMed  Google Scholar 

  • Sjoquist B, Liljequist S, Engel J (1982) Increased salsolinol levels in rat striatum and limbic forebrain following chronic ethanol treatment. J Neurochem 39:259–262

    Article  CAS  PubMed  Google Scholar 

  • Starkey JA, Mechref Y, Muzikar J, McBride WJ, Novotny MV (2006) Determination of salsolinol and related catecholamines through on-line preconcentration and liquid chromatography/atmospheric pressure photoionization mass spectrometry. Anal Chem 78:3342–3347

    Article  CAS  PubMed  Google Scholar 

  • Szekacs D, Bodnar I, Vizi ES, Nagy GM, Fekete MIK (2007) The role of catecholamines in the prolactin release induced by salsolinol. Neurochem Int 51:319–322

    Article  CAS  PubMed  Google Scholar 

  • Toth BE, Bodnar I, Homicsko KG, Fulop F, Fekete MI, Nagy GM (2002) Physiological role of salsolinol: its hypophysiotrophic function in the regulation of pituitary prolactin secretion. Neurotoxicol Teratol 24:655–666

    Article  CAS  PubMed  Google Scholar 

  • Vasko MR, Domino EF (1978) Tolerance development to the biphasic effects of morphine on locomotor activity and brain acetylcholine in the rat. J Pharmacol Exp Ther 207:848–858

    CAS  PubMed  Google Scholar 

  • Vezina P, Stewart J (1984) Conditioning and place-specific sensitization of increases in activity induced by morphine in the VTA. Pharmacol Biochem Behav 20:925–934

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Ameno K, Jamal M, Kumihashi M, Uekita I, Ameno S, Ijiri I (2007) Effect of direct infusion of acetaldehyde on dopamine and dopamine-derived salsolinol in the striatum of free-moving rats using a reverse microdialysis technique. Arch Toxicol 81:121–126

    Article  CAS  PubMed  Google Scholar 

  • Ward SJ, Martin TJ, Roberts DC (2003) Beta-funaltrexamine affects cocaine self-administration in rats responding on a progressive ratio schedule of reinforcement. Pharmacol Biochem Behav 75(2):301–307

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Spanish Ministry of Science and Innovation (BFU 2007-67912-C02-02). LH and MJSC are recipients of predoctoral fellowships from the Cinc Segles Program, Universitat de València.

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Correspondence to Luis Granero.

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Hipólito, L., Sánchez-Catalán, MJ., Zornoza, T. et al. Locomotor stimulant effects of acute and repeated intrategmental injections of salsolinol in rats: role of μ-opioid receptors. Psychopharmacology 209, 1–11 (2010). https://doi.org/10.1007/s00213-009-1751-9

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  • DOI: https://doi.org/10.1007/s00213-009-1751-9

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