Abstract
Rationale
A recently published study has shown that microinjections of ethanol, or its metabolite, acetaldehyde into the substantia nigra pars reticulata, are able to produce behavioral activation in rats. Another brain site that could participate in such effects is the ventral tegmental area (VTA).
Objectives
We have investigated the locomotor-activating effects of local microinjections of ethanol and acetaldehyde into the posterior VTA of rats and the role of opioid receptors in such effects.
Materials
Cannulae were placed into the posterior VTA to perform microinjections of ethanol (75 or 150 nmol) or acetaldehyde (25 or 250 nmol) in animals not previously microinjected or microinjected with either the nonselective opioid antagonist naltrexone (13.2 nmol) or the irreversible antagonist of the µ-opioid receptors β-funaltrexamine (β-FNA; 2.5 nmol). After injections, spontaneous activity was monitored for 60 min.
Results
Injections of ethanol or acetaldehyde into the VTA increased the locomotor activity of rats with maximal effects at doses of 150 nmol for ethanol and 250 nmol for acetaldehyde. These locomotor-activating effects were reduced by previously administering naltrexone (13.2 nmol) or β-FNA (2.5 nmol) into the VTA.
Conclusions
The posterior VTA is another brain region involved in the locomotor activation after the intracerebroventricular administration of ethanol or acetaldehyde. Our data indicate that opioid receptors, particularly the µ-opioid receptors, could be the target of the actions of these compounds in the VTA. These results are consistent with the hypothesis that acetaldehyde could be a mediator of some ethanol effects.
Similar content being viewed by others
References
Amit Z, Brown ZW, Rockman GE, Smith B, Amir S (1980) Acetaldehyde: a positive reinforcer mediating ethanol consumption. Adv Exp Med Biol 126:413–423
Aragon CM, Abitbol M, Amit Z (1986) Acetaldehyde may mediate reinforcement and aversion produced by ethanol. An examination using a conditioned taste-aversion paradigm. Neuropharmacology 25:79–83
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
Bontempi B, Sharp FR (1997) Systemic morphine-induced fos protein in the rat striatum and nucleus accumbens is regulated by mu opioid receptors in the substantia nigra and ventral tegmental area. J Neurosci 17:8596–8612
Camarini R, Nogueira Pires ML, Calil HM (2000) Involvement of the opioid system in the development and expression of sensitization to the locomotor-activating effect of ethanol. Int J Neuropsychopharmacol 3:303–309
Chuck TL, McLaughlin PJ, Arizzi-LaFrance MN, Salamone JD, Correa M (2006) Comparison between multiple behavioral effects of peripheral ethanol administration in rats: sedation, ataxia, and bradykinesia. Life Sci 79:154–161
Colombo G, Agabio R, Lobina C, Reali R, Vacca G, Gessa GL (1998) Stimulation of locomotor activity by voluntarily consumed ethanol in Sardinian alcohol-preferring rats. Eur J Pharmacol 357:109–113
Cornish JL, Kalivas PW (2001) Repeated cocaine administration into the rat ventral tegmental area produces behavioral sensitization to a systemic cocaine challenge. Behav Brain Res 126:205–209
Correa M, Arizzi MN, Betz A, Mingote S, Salamone JD (2003a) Open field locomotor effects in rats after intraventricular injections of ethanol and the ethanol metabolites acetaldehyde and acetate. Brain Res Bull 62:197–202
Correa M, Arizzi MN, Betz A, Mingote S, Salamone JD (2003b) Locomotor stimulant effects of intraventricular injections of low doses of ethanol in rats: acute and repeated administration. Psychopharmacology 170:368–375
Correa M, Arizzi MN, Salamone JD (2005) Behavioral stimulant effects of intracranial injections of ethanol and acetaldehyde in rats. In: Quertemont E, Grant KA, Correa M, Arizzi MN, Salamone JD, Tambour S. Aragon CMG, McBride WJ, Rodd ZA, Goldstein A, Zaffaroni A, Li TK, Pisano M, Diana M. The role of Acetaldehyde in the Central Effects of Ethanol, Alcohol Clin Exp 29:221–234 (2005)
Correa M, Arizzi MN, Salamone JD (2009). Infusions of acetaldehyde into the arcuate nucleus of the hypothalamus induce motor activity in rats. Life Sci. doi: 10.1016/j.lfs.2008.12.013
Critcher EC, Lin CI, Patel J, Myers RD (1983) Attenuation of alcohol drinking in tetrahydroisoquinoline-treated rats by morphine and naltrexone. Pharmacol Biochem Behav 18:225–229
De A, Boyadjieva N, Sarkar DK (2002) Role of protein kinase C in control of ethanol-modulated beta-endorphin release from hypothalamic neurons in primary cultures. J Pharmacol Exp Ther 301:119–28
Devine DP, Wise RA (1994) Self-administration of morphine, DAMGO, and DPDPE into the ventral tegmental area of rats. J Neurosci 14:1978–1984
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 266:1236–1246
Duncan PM, Cook NJ (1981) Ethanol-amphetamine interaction effects on spontaneous motor activity and fixed-interval responding. Psychopharmacology 74:256–259
Enrico P, Sirca D, Mereu M, Peana AT, Lintas A, Diana M (2008) Acetaldehyde sequestering prevents ethanol-induced stimulation of mesolimbic dopamine transmission. Drug Alcohol Depend 100:265–271
Finley JC, Lindstrom P, Petrusz P (1981) Immunocytochemical localization of beta-endorphin-containing neurons in the rat brain. Neuroendocrinology 33:28–42
Frye GD, Breese GR (1981) An evaluation of the locomotor stimulating action of ethanol in rats and mice. Psychopharmacology 75:372–379
Foddai M, Dosia G, Spiga S, Diana M (2004) Acetaldehyde increases dopaminergic neuronal activity in the VTA. Neuropsycopharmacology 29:530–536
Hall FS, Sora I, Uhl GR (2001) Ethanol consumption and reward are decreased in mu-opiate receptor knockout mice. Psychopharmacology 154:43–49
Ikemoto S (2007) Dopamine reward circuitry: Two projection systems from the ventral midbrain to the nucleus accumbens–olfactory tubercle complex. Brain Res Rev 56:27–78
Ikemoto S, Wise RA (2002) Rewarding effects of the cholinergic agents carbachol and neostigmine in the posterior ventral tegmental area. J Neurosci 22:9895–9904
Ikemoto S, Qin M, Liu ZH (2006) Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area. J Neurosci 26:723–730
Johnson SW, North RA (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12:483–488
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
Kiianmaa K, Hoffman PL, Tabakoff B (1983) Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c, C57BL/6, and DBA/2 mice. Psychopharmacology 79:291–294
Latimer LG, Duffy P, Kalivas PW (1987) Mu opioid receptor involvement in enkephalin activation of dopamine neurons in the ventral tegmental area. J Pharmacol Exp Ther 241:328–337
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:R999–R1004
Marinelli PW, Quirion R, Gianoulakis C (2003) A microdialysis profile of beta-endorphin and catecholamines in the rat nucleus accumbens following alcohol administration. Psychopharmacology 169:60–67
Marinelli PW, Quirion R, Gianoulakis C (2004) An in vivo profile of beta-endorphin release in the arcuate nucleus and nucleus accumbens following exposure to stress or alcohol. Neuroscience 127:777–784
Martin TJ, Dworkin SI, Smith JE (1995) Alkylation of mu opioid receptors by beta-funaltrexamine in vivo: comparison of the effects on in situ binding and heroin self-administration in rats. J Pharmacol Exp Ther 272:1135–1140
Masur J, Oliveira de Souza ML, Zwicker AP (1986) The excitatory effect of ethanol: Absence in rats, no tolerance and increased sensitivity in mice. Pharmacol Biochem Behav 24:1225–1228
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
Melis M, Enrico P, Peana AT, Diana M (2007) Acetaldehyde mediates alcohol activation of the mesolimbic dopamine system. Eur J Neurosci 26:2824–2833
Miquel M, Font L, Sanchis-Segura C, Aragon CM (2003) Neonatal administration of monosodium glutamate prevents the development of ethanol- but not psychostimulant-induced sensitization: a putative role of the arcuate nucleus. Eur J Neurosci 17:2163–2170
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
Myers RD, Borg S, Mossberg R (1986) Antagonism by naltrexone of voluntary alcohol selection in the chronically drinking macaque monkey. Alcohol 3:383–388
Olive MF, Koenig HN, Nannini MA, Hodge CW (2001) Stimulation of endorphin neurotransmission in the nucleus accumbens by ethanol, cocaine, and amphetamine. J Neurosci 21:RC184
Paez X, Myers RD (1990) Differential actions of RO 15-1788 and diazepam on poikilothermia, motor impairment and sleep produced by ethanol. Pharmacol Biochem Behav 36:915–922
Paivarinta P, Korpi ER (1993) Voluntary ethanol drinking increases locomotor activity in alcohol-preferring AA rats. Pharmacol Biochem Behav 44:127–132
Panagis G, Nisell M, Nomikos GG, Chergui K, Svensson TH (1996) Nicotine injections into the ventral tegmental area increase locomotion and fos-like immunoreactivity in the nucleus accumbens of the rat. Brain Res 730:133–142
Pastor R, Aragon CM (2008) Ethanol injected into the hypothalamic arcuate nucleus induces behavioural stimulation in rats: an effect prevented by catalase inhibition and naltrexone. Behav Pharmacol 19(7):698–705
Pastor R, Sanchis-Segura C, Aragon CM (2005) Effect of selective antagonism of mu(1)-, mu(1/2)-, mu(3)-, and delta-opioid receptors on the locomotor-stimulating actions of ethanol. Drug Alcohol Depend 78:289–295
Pastorcic M, Boyadjieva N, Sarkar DK (1994) Comparison of the effects of alcohol and acetaldehyde on proopiomelanocortin mRNA levels and beta-endorphin secretion from hypothalamic neurons in primary cultures. Mol Cell Neurosci 5:580–586
Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Academic, New York
Perugini M, Vezina P (1994) Amphetamine administered to the ventral tegmental area sensitizes rats to the locomotor effects of nucleus accumbens amphetamine. J Pharmacol Exp Ther 270:690–696
Reddy BV, Sarkar DK (1993) Effect of alcohol, acetaldehyde, and salsolinol on beta-endorphin secretion from the hypothalamic neurons in primary cultures. Alcohol Clin Exp Res 17:1261–1267
Reddy BV, Boyadjieva N, Sarkar DK (1995) Effect of ethanol, propanol, butanol, and catalase enzyme blockers on beta-endorphin secretion from primary cultures of hypothalamic neurons: evidence for a mediatory role of acetaldehyde in ethanol stimulation of beta-endorphin release. Alcohol Clin Exp Res 19:339–344
Rodd ZA, Bel RL, Zhang Y, Murphy JM, Goldstein A, Zaffaroni A, Li TK, McBride WJ (2004) 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
Rodd ZA, Bell RL, Kuc KA, Zhang Y, Murphy JM, McBride WJ (2005) Intracranial self-administration of cocaine within the posterior ventral tegmental area of wistar rats: evidence for involvement of serotonin-3 receptors and dopamine neurons. J Pharmacol Exp Ther 313:134–145
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
Rodd-Henricks ZA, McKinzie DL, Crile RS, Murphy JM, McBride WJ (2000) Regional heterogeneity for the intracranial self-administration of ethanol within the ventral tegmental area of female wistar rats. Psychopharmacology 149:217–224
Sanchis C, Aragón CM (2007) What we drink when we drink? The role of the acetaldehyde in the alcohol consumption. Adicciones 19:5–11
Sanchis-Segura C, Aragon CM (2002) Consequences of monosodium glutamate or goldthioglucose arcuate nucleus lesions on ethanol-induced locomotion. Drug Alcohol Depend 68:189–194
Sanchis-Segura C, Correa M, Aragon CM (2000) Lesion on the hypothalamic arcuate nucleus by estradiol valerate results in a blockade of ethanol-induced locomotion. Behav Brain Res 114:57–63
Sanchis-Segura C, Pastor R, Aragon CM (2004) Opposite effects of acute versus chronic naltrexone administration on ethanol-induced locomotion. Behav Brain Res 153:61–67
Vezina P (1993) Amphetamine injected into the ventral tegmental area sensitizes the nucleus accumbens dopaminergic response to systemic amphetamine: an in vivo microdialysis study in the rat. Brain Res 605:332–337
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 75:301–307
Webb B, Burnett PW, Walker DW (2002) Sex differences in ethanol-induced hypnosis and hypothermia in young Long–Evans rats. Alcohol Clin Exp Res 26:695–704
Zangen A, Ikemoto S, Zadina JE, Wise RA (2002) Rewarding and psychomotor stimulant effects of endomorphin-1: anteroposterior differences within the ventral tegmental area and lack of effect in nucleus accumbens. J Neurosci 22:7225–7233
Zangen A, Solinas M, Ikemoto S, Goldberg SR, Wise RA (2006) Two brain sites for cannabinoid reward. J Neurosci 26:4901–4907
Acknowledgments
This work was supported by Fundación para el Estudio, Prevención y Asistencia a las Drogodependencias (FEPAD), Generalitat Valenciana, Spain and the Spanish Ministry of Science and Innovation (BFU 2007-67912-C02-02). MJSC and LH are recipients of predoctoral fellowships from the Cinc Segles Program, Universitat de València.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sánchez-Catalán, M.J., Hipólito, L., Zornoza, T. et al. Motor stimulant effects of ethanol and acetaldehyde injected into the posterior ventral tegmental area of rats: role of opioid receptors. Psychopharmacology 204, 641–653 (2009). https://doi.org/10.1007/s00213-009-1495-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-009-1495-6