Skip to main content
Log in

Histamine and H3 receptor-dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Neuronal histamine has a prominent role in sleep–wake control and body homeostasis, but a number of studies suggest that histamine has also a role in higher brain functions including drug reward.

Objective

The present experiments characterized the involvement of histamine and its H3 receptor in ethanol-related behaviors in mice.

Materials and methods

Male histidine decarboxylase knockout (HDC KO) and control mice were used to study the role of histamine in ethanol-induced stimulation of locomotor activity, impairment of motor coordination, and conditioned place preference (CPP). Male C57BL/6Sca mice were used to study the effects of H3 receptor antagonist in the effects of ethanol on locomotor activity.

Results

The HDC KO mice displayed a weaker stimulatory response to acute ethanol than the wild-type (WT) mice. No differences between genotypes were found after ethanol administration on accelerating rotarod. The HDC KO mice showed stronger ethanol-induced CPP than the WT mice. Binding of the GABAA receptor ligand [3H]Ro15-4513 was not markedly changed in HDC KO mouse brain and thus could not explain altered responses in KO mice. Ethanol increased the activity of C57BL/6Sca mice, and H3 receptor antagonist ciproxifan inhibited this stimulation. In CPP paradigm ciproxifan, an H3 receptor inverse agonist potentiated ethanol reward.

Conclusions

Histaminergic neurotransmission seems to be necessary for the stimulatory effect of ethanol to occur, whereas lack of histamine leads to changes that enhance the conditioned reward by ethanol. Our findings also suggest a role for histamine H3 receptor in modulation of the ethanol stimulation and reward.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Arias-Montano JA, Floran B, Garcia M, Aceves J, Young JM (2001) Histamine H(3) receptor-mediated inhibition of depolarization-induced, dopamine D(1) receptor-dependent release of [(3)H]-gamma-aminobutryic acid from rat striatal slices. Br J Pharmacol 133:165–171. doi:10.1038/sj.bjp.0704053

    Article  CAS  PubMed  Google Scholar 

  • Beardsley PM, Balster RL (1992) The intravenous self-administration of antihistamines by rhesus monkeys. Drug Alcohol Depend 30:117–126

    Article  CAS  PubMed  Google Scholar 

  • Becker HC, Jarvis MF (1996) Chronic ethanol exposure selectively increases diazepam-insensitive [3H]RO15-4513 binding in mouse cerebellum. Eur J Pharmacol 296:43–46

    Article  CAS  PubMed  Google Scholar 

  • Beninger RJ (1983) The role of dopamine in locomotor activity and learning. Brain Res 287:173–196

    CAS  PubMed  Google Scholar 

  • Brabant C, Charlier Y, Quertemont E, Tirelli E (2005) The H3 antagonist thioperamide reveals conditioned preference for a context associated with an inactive small dose of cocaine in C57BL/6J mice. Behav Brain Res 160:161–168. doi:10.1016/j.bbr.2004.11.029

    Article  CAS  PubMed  Google Scholar 

  • Brabant C, Quertemont E, Anaclet C, Lin JS, Ohtsu H, Tirelli E (2007) The psychostimulant and rewarding effects of cocaine in histidine decarboxylase knockout mice do not support the hypothesis of an inhibitory function of histamine on reward. Psychopharmacology (Berl) 190:251–263. doi:10.1007/s00213-006-0603-0

    Article  CAS  Google Scholar 

  • Clapham J, Kilpatrick GJ (1994) Thioperamide, the selective histamine H3 receptor antagonist, attenuates stimulant-induced locomotor activity in the mouse. Eur J Pharmacol 259:107–114

    Article  CAS  PubMed  Google Scholar 

  • Crabbe JC, Gallaher ES, Phillips TJ, Belknap JK (1994) Genetic determinants of sensitivity to ethanol in inbred mice. Behav Neurosci 108:186–195

    Article  CAS  PubMed  Google Scholar 

  • Crabbe JC, Metten P, Cameron AJ, Wahlsten D (2005) An analysis of the genetics of alcohol intoxication in inbred mice. Neurosci Biobehav Rev 28:785–802. doi:10.1016/j.neubiorev.2004.08.002

    Article  CAS  PubMed  Google Scholar 

  • Cunningham CL, Niehus DR, Malott DH, Prather LK (1992) Genetic differences in the rewarding and activating effects of morphine and ethanol. Psychopharmacology (Berl) 107:385–393

    Article  CAS  Google Scholar 

  • Cunningham CL, Gremel CM, Groblewski PA (2006) Drug-induced conditioned place preference and aversion in mice. Nat Protoc 1:1662–1670. doi:10.1038/nprot.2006.279

    Article  CAS  PubMed  Google Scholar 

  • Dere E, De Souza-Silva MA, Topic B, Spieler RE, Haas HL, Huston JP (2003) Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover. Learn Mem 10:510–519. doi:10.1101/lm.67603

    Article  PubMed  Google Scholar 

  • Dere E, De Souza-Silva MA, Spieler RE, Lin JS, Ohtsu H, Haas HL, Huston JP (2004) Changes in motoric, exploratory and emotional behaviours and neuronal acetylcholine content and 5-HT turnover in histidine decarboxylase-KO mice. Eur J Neurosci 20:1051–1058. doi:10.1111/j.1460-9568.2004.03546.x

    Article  CAS  PubMed  Google Scholar 

  • Di Chiara G, Imperato A (1985) Ethanol preferentially stimulates dopamine release in the nucleus accumbens of freely moving rats. Eur J Pharmacol 115:131–132

    Article  PubMed  Google Scholar 

  • Drutel G, Peitsaro N, Karlstedt K, Wieland K, Smit MJ, Timmerman H, Panula P, Leurs R (2001) Identification of rat H3 receptor isoforms with different brain expression and signaling properties. Mol Pharmacol 59:1–8

    CAS  PubMed  Google Scholar 

  • Ferrada C, Ferre S, Casado V, Cortes A, Justinova Z, Barnes C, Canela EI, Goldberg SR, Leurs R, Lluis C, Franco R (2008) Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function. Neuropharmacology 55:190–197. doi:10.1016/j.neuropharm.2008.05.008

    Article  CAS  PubMed  Google Scholar 

  • Fox GB, Esbenshade TA, Pan JB, Browman KE, Zhang M, Ballard ME, Radek RJ, Miner H, Bitner RS, Krueger KM, Yao BB, Faghih R, Rueter LE, Komater VA, Drescher KU, Buckley MJ, Sullivan JP, Cowart MD, Decker MW, Hancock AA (2005) Selective H3 receptor (H3R) blockade: broad efficacy in cognition and schizophrenia. Inflamm Res 54(Suppl 1):S23–S24. doi:10.1007/s00011-004-0410-1

    Article  CAS  PubMed  Google Scholar 

  • Frye GD, Breese GR (1981) An evaluation of the locomotor stimulating action of ethanol in rats and mice. Psychopharmacology (Berl) 75:372–379

    Article  CAS  Google Scholar 

  • Galosi R, Lenard L, Knoche A, Haas H, Huston JP, Schwarting RK (2001) Dopaminergic effects of histamine administration in the nucleus accumbens and the impact of H1-receptor blockade. Neuropharmacology 40:624–633

    Article  CAS  PubMed  Google Scholar 

  • Garcia M, Floran B, Arias-Montano JA, Young JM, Aceves J (1997) Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata. Neuroscience 80:241–249

    Article  CAS  PubMed  Google Scholar 

  • Groblewski PA, Lattal KM, Cunningham CL (2009) Effects of D-cycloserine on extinction and reconditioning of ethanol-seeking behavior in mice. Alcohol Clin Exp Res 33:772–782. doi:10.1111/j.1530-0277.2009.00895.x

    Article  CAS  PubMed  Google Scholar 

  • Haas H, Panula P (2003) The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 4:121–130. doi:10.1038/nrn1034

    Article  CAS  PubMed  Google Scholar 

  • Hilakivi L, Eriksson CJ, Sarviharju M, Sinclair JD (1984) Revitalization of the AA and ANA rat lines: effects on some line characteristics. Alcohol 1:71–75

    Article  CAS  PubMed  Google Scholar 

  • Huston JP, Wagner U, Hasenohrl RU (1997) The tuberomammillary nucleus projections in the control of learning, memory and reinforcement processes: evidence for an inhibitory role. Behav Brain Res 83:97–105

    Article  CAS  PubMed  Google Scholar 

  • Hyytia P, Backstrom P, Piepponen P, Ahtee L (2003) Histamine H3-receptor antagonist thioperamide potentiates behavioral effects of cocaine. Eur J Pharm Sci 19:S21–S24

    Article  CAS  Google Scholar 

  • Koob GF, Le Moal M (2008) Addiction and the brain antireward system. Annu Rev Psychol 59:29–53. doi:10.1146/annurev.psych.59.103006.093548

    Article  PubMed  Google Scholar 

  • Korpi ER, Koikkalainen P, Vekovischeva OY, Makela R, Kleinz R, Uusi-Oukari M, Wisden W (1999) Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice. Eur J Neurosci 11:233–240

    Article  CAS  PubMed  Google Scholar 

  • Lintunen M, Hyytia P, Sallmen T, Karlstedt K, Tuomisto L, Leurs R, Kiianmaa K, Korpi ER, Panula P (2001) Increased brain histamine in an alcohol-preferring rat line and modulation of ethanol consumption by H(3) receptor mechanisms. FASEB J 15:1074–1076

    CAS  PubMed  Google Scholar 

  • Lintunen M, Raatesalmi K, Sallmen T, Anichtchik O, Karlstedt K, Kaslin J, Kiianmaa K, Korpi ER, Panula P (2002) Low brain histamine content affects ethanol-induced motor impairment. Neurobiol Dis 9:94–105. doi:10.1006/nbdi.2001.0453

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Mir MI, Pollard H, Moreau J, Arrang JM, Ruat M, Traiffort E, Schwartz JC, Palacios JM (1990) Three histamine receptors (H1, H2 and H3) visualized in the brain of human and non-human primates. Brain Res 526:322–327

    Article  CAS  PubMed  Google Scholar 

  • Masukawa Y, Suzuki T, Misawa M (1993) Differential modification of the rewarding effects of methamphetamine and cocaine by opioids and antihistamines. Psychopharmacology (Berl) 111:139–143

    Article  CAS  Google Scholar 

  • Middaugh LD, Boggan WO, Randall CL (1987) Stimulatory effects of ethanol in C57BL/6 mice. Pharmacol Biochem Behav 27:421–424

    Article  CAS  PubMed  Google Scholar 

  • Middaugh LD, Bao K, Shepherd CL (1992) Comparative effects of ethanol on motor activity and operant behavior. Pharmacol Biochem Behav 43:625–629

    Article  CAS  PubMed  Google Scholar 

  • Morisset S, Rouleau A, Ligneau X, Gbahou F, Tardivel-Lacombe J, Stark H, Schunack W, Ganellin CR, Schwartz JC, Arrang JM (2000) High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature 408:860–864. doi:10.1038/35048583

    Article  CAS  PubMed  Google Scholar 

  • Morisset S, Pilon C, Tardivel-Lacombe J, Weinstein D, Rostene W, Betancur C, Sokoloff P, Schwartz JC, Arrang JM (2002) Acute and chronic effects of methamphetamine on tele-methylhistamine levels in mouse brain: selective involvement of the D(2) and not D(3) receptor. J Pharmacol Exp Ther 300:621–628

    Article  CAS  PubMed  Google Scholar 

  • Munzar P, Tanda G, Justinova Z, Goldberg SR (2004) Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release. Neuropsychopharmacology 29:705–717. doi:10.1038/sj.npp.1300380

    Article  CAS  PubMed  Google Scholar 

  • Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder JC (1993) Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A 90:8424–8428

    Article  CAS  PubMed  Google Scholar 

  • Ohtsu H, Tanaka S, Terui T, Hori Y, Makabe-Kobayashi Y, Pejler G, Tchougounova E, Hellman L, Gertsenstein M, Hirasawa N, Sakurai E, Buzas E, Kovacs P, Csaba G, Kittel A, Okada M, Hara M, Mar L, Numayama-Tsuruta K, Ishigaki-Suzuki S, Ohuchi K, Ichikawa A, Falus A, Watanabe T, Nagy A (2001) Mice lacking histidine decarboxylase exhibit abnormal mast cells. FEBS Lett 502:53–56

    Article  CAS  PubMed  Google Scholar 

  • Oishi R, Shishido S, Yamori M, Saeki K (1994) Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain. Naunyn Schmiedebergs Arch Pharmacol 349:140–144

    Article  CAS  PubMed  Google Scholar 

  • Parmentier R, Ohtsu H, Djebbara-Hannas Z, Valatx JL, Watanabe T, Lin JS (2002) Anatomical, physiological, and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J Neurosci 22:7695–7711

    CAS  PubMed  Google Scholar 

  • Phillips TJ, Shen EH (1996) Neurochemical bases of locomotion and ethanol stimulant effects. Int Rev Neurobiol 39:243–282

    Article  CAS  PubMed  Google Scholar 

  • Pillot C, Heron A, Cochois V, Tardivel-Lacombe J, Ligneau X, Schwartz JC, Arrang JM (2002a) A detailed mapping of the histamine H(3) receptor and its gene transcripts in rat brain. Neuroscience 114:173–193

    Article  CAS  PubMed  Google Scholar 

  • Pillot C, Ortiz J, Heron A, Ridray S, Schwartz JC, Arrang JM (2002b) Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat. J Neurosci 22:7272–7280. doi:20026704

    CAS  PubMed  Google Scholar 

  • Pillot C, Heron A, Schwartz JC, Arrang JM (2003) Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, modulates the effects of methamphetamine on neuropeptide mRNA expression in rat striatum. Eur J Neurosci 17:307–314

    Article  PubMed  Google Scholar 

  • Randall CL, Carpenter JA, Lester D, Friedman HJ (1975) Ethanol-induced mouse strain differences in locomotor activity. Pharmacol Biochem Behav 3:533–535

    Article  CAS  PubMed  Google Scholar 

  • Risinger FO, Oakes RA (1996) Dose- and conditioning trial-dependent ethanol-induced conditioned place preference in Swiss-Webster mice. Pharmacol Biochem Behav 55:117–123

    Article  CAS  PubMed  Google Scholar 

  • Risinger FO, Dickinson SD, Cunningham CL (1992) Haloperidol reduces ethanol-induced motor activity stimulation but not conditioned place preference. Psychopharmacology (Berl) 107:453–456

    Article  CAS  Google Scholar 

  • Risinger FO, Malott DH, Prather LK, Niehus DR, Cunningham CL (1994) Motivational properties of ethanol in mice selectively bred for ethanol-induced locomotor differences. Psychopharmacology (Berl) 116:207–216

    Article  CAS  Google Scholar 

  • Risinger FO, Freeman PA, Greengard P, Fienberg AA (2001) Motivational effects of ethanol in DARPP-32 knock-out mice. J Neurosci 21:340–348

    CAS  PubMed  Google Scholar 

  • Rouleau A, Heron A, Cochois V, Pillot C, Schwartz JC, Arrang JM (2004) Cloning and expression of the mouse histamine H3 receptor: evidence for multiple isoforms. J Neurochem 90:1331–1338. doi:10.1111/j.1471-4159.2004.02606.x

    Article  CAS  PubMed  Google Scholar 

  • Ryu JH, Yanai K, Iwata R, Ido T, Watanabe T (1994) Heterogeneous distributions of histamine H3, dopamine D1 and D2 receptors in rat brain. Neuroreport 5:621–624

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Lemus E, Arias-Montano JA (2004) Histamine H3 receptor activation inhibits dopamine D1 receptor-induced cAMP accumulation in rat striatal slices. Neurosci Lett 364:179–184. doi:10.1016/j.neulet.2004.04.045

    Article  CAS  PubMed  Google Scholar 

  • Shannon HE, Su TP (1982) Effects of the combination of tripelennamine and pentazocine at the behavioral and molecular levels. Pharmacol Biochem Behav 17:789–795

    Article  CAS  PubMed  Google Scholar 

  • Shoblock J, O’Donnell P (2000) Histamine modulation of nucleus accumbens neurons. Ann N Y Acad Sci 909:270–272

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T, Takamori K, Misawa M, Onodera K (1995) Effects of the histaminergic system on the morphine-induced conditioned place preference in mice. Brain Res 675:195–202

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T, Mori T, Takamori K, Onodera K, Misawa M (1996) Effects of H(1)-antagonists on discriminative stimulus effects of cocaine and methamphetamine in rats. Behav Pharmacol 7:111–118

    Article  CAS  PubMed  Google Scholar 

  • Tambour S, Didone V, Tirelli E, Quertemont E (2006) Locomotor effects of ethanol and acetaldehyde after peripheral and intraventricular injections in Swiss and C57BL/6 J mice. Behav Brain Res 172:145–154. doi:10.1016/j.bbr.2006.05.010

    Article  CAS  PubMed  Google Scholar 

  • Toyota H, Dugovic C, Koehl M, Laposky AD, Weber C, Ngo K, Wu Y, Lee DH, Yanai K, Sakurai E, Watanabe T, Liu C, Chen J, Barbier AJ, Turek FW, Fung-Leung WP, Lovenberg TW (2002) Behavioral characterization of mice lacking histamine H(3) receptors. Mol Pharmacol 62:389–397

    Article  CAS  PubMed  Google Scholar 

  • Tzschentke TM (2007) Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol 12:227–462. doi:10.1111/j.1369-1600.2007.00070.x

    Article  CAS  PubMed  Google Scholar 

  • Wagner U, Segura-Torres P, Weiler T, Huston JP (1993) The tuberomammillary nucleus region as a reinforcement inhibiting substrate: facilitation of ipsihypothalamic self-stimulation by unilateral ibotenic acid lesions. Brain Res 613:269–274

    Article  CAS  PubMed  Google Scholar 

  • Wahlsten D, Metten P, Phillips TJ, Boehm SL 2nd, Burkhart-Kasch S, Dorow J, Doerksen S, Downing C, Fogarty J, Rodd-Henricks K, Hen R, McKinnon CS, Merrill CM, Nolte C, Schalomon M, Schlumbohm JP, Sibert JR, Wenger CD, Dudek BC, Crabbe JC (2003) Different data from different labs: lessons from studies of gene-environment interaction. J Neurobiol 54:283–311. doi:10.1002/neu.10173

    Article  PubMed  Google Scholar 

  • Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Anni-Maija Linden, Ph.D., for the guidance with the behavioral studies and Tiia Ojala, Cand. Med., for technical help with the experiments. This work was supported by grants from the Academy of Finland and the Finnish Foundation for Alcohol Studies.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Saara Nuutinen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nuutinen, S., Karlstedt, K., Aitta-aho, T. et al. Histamine and H3 receptor-dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice. Psychopharmacology 208, 75–86 (2010). https://doi.org/10.1007/s00213-009-1710-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1710-5

Keywords

Navigation