Abstract
Activation of dopaminergic (DA) neurons of the ventral tegmental area (VTA) by ethanol has been implicated in its rewarding and reinforcing effects. However, studies from our lab demonstrate that acute ethanol enhances GABA release onto VTA-DA neurons via activation of a G protein-coupled receptor, 5-HT2C, and subsequent activation of an intracellular calcium signaling pathway. Utilizing electrophysiological methods, in this chapter we present evidence which attempts to resolve the paradoxical nature of the dual excitatory and inhibitory actions of ethanol on DA neurons. Our results suggest that ethanol-excitation of VTA-DA neurons is bi-phasic and involves interplay of excitatory and inhibitory mechanisms which can fine tune the overall action of ethanol on DA neuron excitability. Overall, these results may provide insight into mechanisms underlying the development of alcohol dependence.
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References
Albanese A and Minciacchi D (1983) Organization of the ascending projections from the ventral tegmental area: a multiple fluorescent retrograde tracer study in the rat. J Comp Neurol 216:406–420.
Appel SB, Liu Z, McElvain MA and Brodie MS (2003) Ethanol excitation of dopaminergic ventral tegmental area neurons is blocked by quinidine. J Pharmacol Exp Ther 306:437–446.
Ariwodola OJ and Weiner JL (2004) Ethanol potentiation of GABAergic synaptic transmission may be self-limiting: role of presynaptic GABA(B) receptors. J Neurosci 24:10679–10686.
Brodie MS (2002) Increased ethanol excitation of dopaminergic neurons of the ventral tegmental area after chronic ethanol treatment. Alcohol Clin Exp Res 26:1024–1030.
Brodie MS, Pesold C and Appel SB (1999) Ethanol directly excites dopaminergic ventral tegmental area reward neurons. Alcohol Clin Exp Res 23:1848–1852.
Brodie MS, Shefner SA and Dunwiddie TV (1990) Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro. Brain Res 508:65–69.
Bubar MJ and Cunningham KA (2007) Distribution of serotonin 5-HT2C receptors in the ventral tegmental area. Neuroscience 146:286–297.
Cagetti E, Liang J, Spigelman I and Olsen RW (2003) Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors. Mol Pharmacol 63:53–64.
Carr DB and Sesack SR (2000) GABA-containing neurons in the rat ventral tegmental area project to the prefrontal cortex. Synapse 38:114–123.
Charara A, Smith Y and Parent A (1996) Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: Phaseolus vulgaris-leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry. J Comp Neurol 364:254–266.
Christie MJ, Bridge S, James LB and Beart PM (1985) Excitotoxin lesions suggest an aspartatergic projection from rat medial prefrontal cortex to ventral tegmental area. Brain Res 333:169–172.
Criswell HE, Ming Z, Kelm MK and Breese GR (2008) Brain regional differences in the effect of ethanol on GABA release from presynaptic terminals. J Pharmacol Exp Ther 326:596–603.
Daws LC, Montanez S, Munn JL, Owens WA, Baganz NL, Boyce-Rustay JM, Millstein RA, Wiedholz LM, Murphy DL and Holmes A (2006) Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. J Neurosci 26:6431–6438.
de Waele JP and Gianoulakis C (1993) Effects of single and repeated exposures to ethanol on hypothalamic beta-endorphin and CRH release by the C57BL/6 and DBA/2 strains of mice. Neuroendocrinology 57:700–709.
Di Giovanni G, De Deurwaerdere P, Di Mascio M, Di Matteo V, Esposito E and Spampinato U (1999) Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study. Neuroscience 91:587–597.
Di Matteo V, Di Giovanni G, Di Mascio M and Esposito E (2000) Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin(2C) receptors. Brain Res 865:85–90.
Enoch MA (2008) The role of GABA(A) receptors in the development of alcoholism. Pharmacol Biochem Behav 90:95–104.
Gessa GL, Muntoni F, Collu M, Vargiu L and Mereu G (1985) Low doses of ethanol activate dopaminergic neurons in the ventral tegmental area. Brain Res 348:201–203.
Gianoulakis C and Barcomb A (1987) Effect of acute ethanol in vivo and in vitro on the beta-endorphin system in the rat. Life Sci 40:19–28.
Goldman D, Oroszi G and Ducci F (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet 6:521–532.
Gonzales RA and Weiss F (1998) Suppression of ethanol-reinforced behavior by naltrexone is associated with attenuation of the ethanol-induced increase in dialysate dopamine levels in the nucleus accumbens. J Neurosci 18:10663–10671.
Groenewegen HJ and Berendse HW (1990) Connections of the subthalamic nucleus with ventral striatopallidal parts of the basal ganglia in the rat. J Comp Neurol 294:607–622.
Hall FS, Sora I and Uhl GR (2001) Ethanol consumption and reward are decreased in mu-opiate receptor knockout mice. Psychopharmacology (Berl) 154:43–49.
Hiroi N and Agatsuma S (2005) Genetic susceptibility to substance dependence. Mol Psychiatry 10:336–344.
Honkanen A, Vilamo L, Wegelius K, Sarviharju M, Hyytia P and Korpi ER (1996) Alcohol drinking is reduced by a mu 1- but not by a delta-opioid receptor antagonist in alcohol-preferring rats. Eur J Pharmacol 304:7–13.
Hyytia P and Kiianmaa K (2001) Suppression of ethanol responding by centrally administered CTOP and naltrindole in AA and Wistar rats. Alcohol Clin Exp Res 25:25–33.
Jarjour S, Bai L and Gianoulakis C (2009) Effect of Acute Ethanol Administration on the Release of Opioid Peptides From the Midbrain Including the Ventral Tegmental Area. Alcohol Clin Exp Res 33:1033–1043.
Job MO, Tang A, Hall FS, Sora I, Uhl GR, Bergeson SE and Gonzales RA (2007) Mu (mu) opioid receptor regulation of ethanol-induced dopamine response in the ventral striatum: evidence of genotype specific sexual dimorphic epistasis. Biol Psychiatry 62:627–634.
Johnson SW and North RA (1992a) Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12:483–488.
Johnson SW and North RA (1992b) Two types of neurone in the rat ventral tegmental area and their synaptic inputs. J Physiol 450:455–468.
Kang MH, Spigelman I and Olsen RW (1998) Alteration in the sensitivity of GABA(A) receptors to allosteric modulatory drugs in rat hippocampus after chronic intermittent ethanol treatment. Alcohol Clin Exp Res 22:2165–2173.
Kelm MK, Criswell HE and Breese GR (2007) Calcium release from presynaptic internal stores is required for ethanol to increase spontaneous gamma-aminobutyric acid release onto cerebellum Purkinje neurons. J Pharmacol Exp Ther 323:356–364.
Kim SG, Stromberg MF, Kim MJ, Volpicelli JR and Park JM (2000) The effect of antagonists selective for mu- and delta-opioid receptor subtypes on alcohol consumption in C57BL/6 mice. Alcohol 22:85–90.
Koyama S, Brodie MS and Appel SB (2007) Ethanol inhibition of m-current and ethanol-induced direct excitation of ventral tegmental area dopamine neurons. J Neurophysiol 97:1977–1985.
Krishnan-Sarin S, Wand GS, Li XW, Portoghese PS and Froehlich JC (1998) Effect of mu opioid receptor blockade on alcohol intake in rats bred for high alcohol drinking. Pharmacol Biochem Behav 59:627–635.
Kumar S, Porcu P, Werner DF, Matthews DB, Diaz-Granados JL, Helfand RS and Morrow AL (2009) The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress. Psychopharmacology (Berl) 205:529–564.
Lasek AW, Janak PH, He L, Whistler JL and Heberlein U (2007) Downregulation of mu opioid receptor by RNA interference in the ventral tegmental area reduces ethanol consumption in mice. Genes Brain Behav 6:728–735.
Margolis EB, Fields HL, Hjelmstad GO and Mitchell JM (2008) Delta-opioid receptor expression in the ventral tegmental area protects against elevated alcohol consumption. J Neurosci 28:12672–12681.
Margolis EB, Hjelmstad GO, Bonci A and Fields HL (2003) Kappa-opioid agonists directly inhibit midbrain dopaminergic neurons. J Neurosci 23:9981–9986.
Melendez RI, Rodd-Henricks ZA, Engleman EA, Li TK, McBride WJ and Murphy JM (2002) Microdialysis of dopamine in the nucleus accumbens of alcohol-preferring (P) rats during anticipation and operant self-administration of ethanol. Alcohol Clin Exp Res 26:318–325.
Melis M, Camarini R, Ungless MA and Bonci A (2002) Long-lasting potentiation of GABAergic synapses in dopamine neurons after a single in vivo ethanol exposure. J Neurosci 22:2074–2082.
Mhatre M and Holloway F (2003) Micro1-opioid antagonist naloxonazine alters ethanol discrimination and consumption. Alcohol 29:109–116.
Ming Z, Criswell HE, Yu G and Breese GR (2006) Competing presynaptic and postsynaptic effects of ethanol on cerebellar purkinje neurons. Alcohol Clin Exp Res 30:1400–1407.
Montpied P, Ginns EI, Martin BM, Roca D, Farb DH and Paul SM (1991) gamma-Aminobutyric acid (GABA) induces a receptor-mediated reduction in GABAA receptor alpha subunit messenger RNAs in embryonic chick neurons in culture. J Biol Chem 266:6011–6014.
Oades RD and Halliday GM (1987) Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity. Brain Res 434:117–165.
Okamoto T, Harnett MT and Morikawa H (2006) Hyperpolarization-activated cation current (Ih) is an ethanol target in midbrain dopamine neurons of mice. J Neurophysiol 95:619–626.
Olive MF, Koenig HN, Nannini MA and Hodge CW (2001) Stimulation of endorphin neurotransmission in the nucleus accumbens by ethanol, cocaine, and amphetamine. J Neurosci 21:RC184.
Pfeffer AO and Samson HH (1986) Effect of pimozide on home cage ethanol drinking in the rat: dependence on drinking session length. Drug Alcohol Depend 17:47–55.
Pfeffer AO and Samson HH (1988) Haloperidol and apomorphine effects on ethanol reinforcement in free feeding rats. Pharmacol Biochem Behav 29:343–350.
Rasmussen DD, Bryant CA, Boldt BM, Colasurdo EA, Levin N and Wilkinson CW (1998) Acute alcohol effects on opiomelanocortinergic regulation. Alcohol Clin Exp Res 22:789–801.
Roberto M, Madamba SG, Moore SD, Tallent MK and Siggins GR (2003) Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons. Proc Natl Acad Sci U S A 100:2053–2058.
Roberto M, Madamba SG, Stouffer DG, Parsons LH and Siggins GR (2004) Increased GABA release in the central amygdala of ethanol-dependent rats. J Neurosci 24:10159–10166.
Roca DJ, Schiller GD, Friedman L, Rozenberg I, Gibbs TT and Farb DH (1990) gamma-Aminobutyric acidA receptor regulation in culture: altered allosteric interactions following prolonged exposure to benzodiazepines, barbiturates, and methylxanthines. Mol Pharmacol 37:710–719.
Rohrbacher J, Jarolimek W, Lewen A and Misgeld U (1997) GABAB receptor-mediated inhibition of spontaneous inhibitory synaptic currents in rat midbrain culture. J Physiol 500 (Pt 3):739–749.
Samson HH, Tolliver GA, Haraguchi M and Hodge CW (1992) Alcohol self-administration: role of mesolimbic dopamine. Ann N Y Acad Sci 654:242–253.
Sanna E, Talani G, Busonero F, Pisu MG, Purdy RH, Serra M and Biggio G (2004) Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus. J Neurosci 24:6521–6530.
Sesack SR and Pickel VM (1992) Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol 320:145–160.
Shoemaker WJ, Vavrousek-Jakuba E, Arons CD and Kwok FC (2002) The acquisition and maintenance of voluntary ethanol drinking in the rat: effects of dopaminergic lesions and naloxone. Behav Brain Res 137:139–148.
Schuckit MA, Li TK, Cloninger CR, Deitrich RA (1985) Genetics of alcoholism. Alcohol Clin Exp Res 6:475–92.
Steffensen SC, Walton CH, Hansen DM, Yorgason JT, Gallegos RA and Criado JR (2009) Contingent and non-contingent effects of low-dose ethanol on GABA neuron activity in the ventral tegmental area. Pharmacol Biochem Behav 92:68–75.
Stobbs SH, Ohran AJ, Lassen MB, Allison DW, Brown JE and Steffensen SC (2004) Ethanol suppression of ventral tegmental area GABA neuron electrical transmission involves N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 311:282–289.
Stromberg MF, Casale M, Volpicelli L, Volpicelli JR and O’Brien CP (1998) A comparison of the effects of the opioid antagonists naltrexone, naltrindole, and beta-funaltrexamine on ethanol consumption in the rat. Alcohol 15:281–289.
Stromberg MF, Sengpiel T, Mackler SA, Volpicelli JR, O’Brien CP and Vogel WH (2002) Effect of naltrexone on oral consumption of concurrently available ethanol and cocaine in the rat. Alcohol 28:169–179.
Svingos AL, Garzon M, Colago EE and Pickel VM (2001) Mu-opioid receptors in the ventral tegmental area are targeted to presynaptically and directly modulate mesocortical projection neurons. Synapse 41:221–229.
Theile JW, Morikawa H, Gonzales RA and Morrisett RA (2008) Ethanol enhances GABAergic transmission onto dopamine neurons in the ventral tegmental area of the rat. Alcohol Clin Exp Res 32:1040–1048.
Theile JW, Morikawa H, Gonzales RA and Morrisett RA (2009) Role of 5-hydroxytryptamine2C receptors in Ca2+-dependent ethanol potentiation of GABA release onto ventral tegmental area dopamine neurons. J Pharmacol Exp Ther 329:625–633.
Van Bockstaele EJ and Pickel VM (1995) GABA-containing neurons in the ventral tegmental area project to the nucleus accumbens in rat brain. Brain Res 682:215–221.
Walaas I and Fonnum F (1980) Biochemical evidence for gamma-aminobutyrate containing fibres from the nucleus accumbens to the substantia nigra and ventral tegmental area in the rat. Neuroscience 5:63–72.
Wanat MJ, Sparta DR, Hopf FW, Bowers MS, Melis M and Bonci A (2008) Strain Specific Synaptic Modifications on Ventral Tegmental Area Dopamine Neurons After Ethanol Exposure. Biol Psychiatry 65(8):646–53.
Weiss F, Lorang MT, Bloom FE and Koob GF (1993) Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. J Pharmacol Exp Ther 267:250–258.
Weiss F, Parsons LH, Schulteis G, Hyytia P, Lorang MT, Bloom FE and Koob GF (1996) Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytryptamine release in dependent rats. J Neurosci 16:3474–3485.
Westerink BH, Kwint HF and deVries JB (1996) The pharmacology of mesolimbic dopamine neurons: a dual-probe microdialysis study in the ventral tegmental area and nucleus accumbens of the rat brain. J Neurosci 16:2605–2611.
Xiao C and Ye JH (2008) Ethanol dually modulates GABAergic synaptic transmission onto dopaminergic neurons in ventral tegmental area: role of mu-opioid receptors. Neuroscience 153:240–248.
Xiao C, Zhang J, Krnjevic K and Ye JH (2007) Effects of ethanol on midbrain neurons: role of opioid receptors. Alcohol Clin Exp Res 31:1106–1113.
Yim CY and Mogenson GJ (1980) Electrophysiological studies of neurons in the ventral tegmental area of Tsai. Brain Res 181:301–313.
Yoshimoto K, McBride WJ, Lumeng L and Li TK (1992) Alcohol stimulates the release of dopamine and serotonin in the nucleus accumbens. Alcohol 9:17–22.
Zhu PJ and Lovinger DM (2006) Ethanol potentiates GABAergic synaptic transmission in a postsynaptic neuron/synaptic bouton preparation from basolateral amygdala. J Neurophysiol 96:433–441.
Zöllner C and Stein C (2007) Opioids. Handb Exp Pharmacol 177:31–63.
Acknowledgements
This work was supported by the following grants: R01 AA 14874 (RAG), U01 AA 16651 (RAM), F31 AA 17020 (JWT).
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Theile, J.W., Gonzales, R.A., Morrisett, R.A. (2011). Ethanol Modulation of GABAergic Inhibition in Midbrain Dopamine Neurons: Implications for the Development of Alcohol-Seeking Behaviors. In: Woodin, M., Maffei, A. (eds) Inhibitory Synaptic Plasticity. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6978-1_6
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