Ethanol-induced changes in synaptic amino acid neurotransmitter levels in the nucleus accumbens of differentially sensitized mice
Ethanol-induced behavioural sensitization (EBS) does not occur uniformly in mice exposed to the sensitization paradigm. This suggests innate differential responses to ethanol (EtOH) in the reward circuitry of individual animals.
To better characterize the adaptive differences between low-sensitized (LS) and high-sensitized (HS) mice, we examined excitatory amino acid (EAA) and inhibitory amino acid (IAA) neurotransmitter levels in the nucleus accumbens (NAc) during EBS expression.
Male DBA/2J mice received five ethanol (EtOH) (2.2 g/kg) or saline injections, and locomotor activity (LMA) was assessed during EBS induction. EtOH mice were classified as LS or HS on the basis of final LMA scores. Following an EtOH challenge (1.8 g/kg) 2 weeks later, LMA was re-evaluated and in vivo microdialysis samples were collected from the NAc.
Most differences in amino acid levels were observed within the first 20 min after EtOH challenge. LS mice exhibited similar glutamate levels compared with acutely treated (previously EtOH naïve) mice, and generally increased levels of the IAAs GABA, glycine, and taurine. By contrast, HS mice exhibited increased glutamate and attenuated levels of GABA, glycine, and taurine.
These data suggest that the profile of amino acid neurotransmitters in the NAc of LS and HS mice significantly differs. Elucidating these adaptive differences contributes to our understanding of factors that confer susceptibility/resilience to alcohol use disorder.
KeywordsEthanol Neurotransmitter Nucleus accumbens Alcohol Amino acid Behavioural sensitization Glutamate GABA Glycine Taurine
The authors thank Dr. Christina Nona and Roger Raymond for excellent technical assistance.
This study was supported by NSERC grant RGPIN 06615.
Compliance with ethical standards
All procedures were approved by the Animal Care Committee at the Centre for Addiction and Mental Health and were in accordance with the guidelines and practices outlined by the Canadian Council on Animal Care.
Conflicts of interest
The authors declare that they have no conflicts of interest.
- Abrahao KP, Ariwodola OJ, Butler TR, Rau AR, Skelly MJ, Carter E, Alexander NP, McCool BA, Souza-Formigoni MLO, Weiner JL (2013) Locomotor sensitization to ethanol impairs NMDA receptor-dependent synaptic plasticity in the nucleus accumbens and increases ethanol self-administration. J Neurosci 33:4834–4842. https://doi.org/10.1523/JNEUROSCI.5839-11.2013 CrossRefGoogle Scholar
- Carrara-Nascimento PF, Griffin WC 3rd, Pastrello DM, Olive MF, Camarini R (2011) Changes in extracellular levels of glutamate in the nucleus accumbens after ethanol-induced behavioral sensitization in adolescent and adult mice. Alcohol 45:451–460. https://doi.org/10.1016/j.alcohol.2011.01.002 CrossRefGoogle Scholar
- Clapp PF, Bhave SF, Hoffman PL (2018) How adaptation of the brain to alcohol leads to dependence: a pharmacological perspective. Alcohol Res Health 31:310–339Google Scholar
- Dahchour A, Quertemont E, Dewitte P (1994) Acute ethanol increases taurine but neither glutamate nor Gaba in the nucleus-accumbens of male-rats a microdialysis study. Alcohol Alcohol 29:485–487Google Scholar
- Fidler TL, Dion AM, Powers MS, Ramirez JJ, Mulgrew JA, Smitasin PJ, Crane AT, Cunningham CL (2011) Intragastric self-infusion of ethanol in high- and low-drinking mouse genotypes after passive ethanol exposure. Genes Brain Behav 10:264–275. https://doi.org/10.1111/j.1601-183X.2010.00664.x CrossRefGoogle Scholar
- Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
- Griffin WC, Ramachandra VS, Knackstedt LA, Becker HC (2015) Repeated cycles of chronic intermittent ethanol exposure increases basal glutamate in the nucleus accumbens of mice without affecting glutamate transport. Front Pharmacol 6:27. https://doi.org/10.3389/fphar.2015.00027 CrossRefGoogle Scholar
- Hitzemann B, Hitzemann R (1997) Genetics ethanol and the Fos response: a comparison of the C57BL/6J and DBA/2J inbred mouse strains. Alcohol Clin Exp Res 21:1497–1507Google Scholar
- Juarez B, Morel C, Ku SM, Liu Y, Zhang H, Montgomery S, Gregoire H, Ribeiro E, Crumiller M, Roman-Ortiz C, Walsh JJ, Jackson K, Croote DE, Zhu Y, Zhang S, Vendruscolo LF, Edwards S, Roberts A, Hodes GE, Lu Y, Calipari ES, Chaudhury D, Friedman AK, Han MH (2017) Midbrain circuit regulation of individual alcohol drinking behaviors in mice. Nat Commun 8:2220. https://doi.org/10.1038/s41467-017-02365-8 CrossRefGoogle Scholar
- Kruse LC, Linsenbardt DN, Boehm SL 2nd (2012) Positive allosteric modulation of the GABA(B) receptor by GS39783 attenuates the locomotor stimulant actions of ethanol and potentiates the induction of locomotor sensitization. Alcohol 46:455–462. https://doi.org/10.1016/j.alcohol.2012.03.004 CrossRefGoogle Scholar
- Li Z, Zharikova A, Bastian J, Esperon L, Hebert N, Mathes C, Rowland NE, Peris J (2008) High temporal resolution of amino acid levels in rat nucleus accumbens during operant ethanol self-administration: involvement of elevated glycine in anticipation. J Neurochem 106:170–181. https://doi.org/10.1111/j.1471-4159.2008.05346.x CrossRefGoogle Scholar
- Linsenbardt DN, Boehm SL 2nd (2010) Ethanol-induced locomotor sensitization in DBA/2J mice is associated with alterations in GABA(A) subunit gene expression and behavioral sensitivity to GABA(A) acting drugs. Pharmacol Biochem Behav 95:359–366. https://doi.org/10.1016/j.pbb.2010.02.014 CrossRefGoogle Scholar
- Ulrich JD, Burchett JM, Restivo JL, Schuler DR, Verghese PB, Mahan TE, Landreth GE, Castellano JM, Jiang H, Cirrito JR, Holtzman DM (2013) In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis. Mol Neurodegener 8:13. https://doi.org/10.1186/1750-1326-8-13 CrossRefGoogle Scholar
- Umhau JC, Momenan R, Schwandt ML, Singley E, Lifshitz M, Doty L, Adams LJ, Vengeliene V, Spanagel R, Zhang Y, Shen J, George DT, Hommer D, Heilig M (2010) Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. Arch Gen Psychiatry 67:1069–1077. https://doi.org/10.1001/archgenpsychiatry.2010.125 CrossRefGoogle Scholar