Ethanol-induced hyperactivity is associated with hypodopaminergia in the 22-TNJ ENU-mutated mouse

Tiffany A. Mathews, Bethany R. Brookshire, Evgeny A. Budygin, Kristin Hamre, Daniel Goldowitz, Sara R. Jones

Research output: Contribution to journalArticle

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Abstract

Characterization of neurochemical and behavioral responses to ethanol in phenotypically distinct mouse strains can provide insight into the mechanisms of ethanol stimulant actions. Increases in striatal dopamine (DA) levels have often been linked to ethanol-induced hyperactivity. We examined the functional status of the DA system and behavioral responsiveness to ethanol, cocaine, and a DA-receptor agonist in an N-ethyl-N-nitrosourea-mutagenized mouse strain, 22-TNJ, generated by the Integrative Neuroscience Initiative on Alcoholism Consortium. The 22-TNJ mouse strain exhibited greater locomotor responses to 2.25 g/kg ethanol and 10 mg/kg cocaine, compared with control mice. In vivo microdialysis showed low-baseline DA levels and a larger DA increase with both 2.25 g/kg ethanol and 10 mg/kg cocaine. In in vitro voltammetry studies, the 22-TNJ mice displayed increased Vmax rates for DA uptake, possibly contributing to the low-baseline DA levels found with microdialysis. Finally, 22-TNJ mice showed enhanced in vitro autoreceptor sensitivity to the D2/D3 agonist, quinpirole, and greater locomotor responses to both autoreceptor-selective and postsynaptic receptor-selective doses of apomorphine compared with controls. Taken together, these results indicate that the dopaminergic system of the 22-TNJ mouse is low functioning compared with control, with consequent receptor supersensitivity, such that mutant animals exhibit enhanced behavioral responses to DA-activating drugs, such as ethanol. Thus, the 22-TNJ mouse represents a model for a relatively hypodopaminergic system, and could provide important insights into the mechanisms of hyper-responsiveness to ethanol's stimulant actions.

Original languageEnglish (US)
Pages (from-to)421-431
Number of pages11
JournalAlcohol
Volume43
Issue number6
DOIs
StatePublished - Sep 1 2009

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Ethanol
Dopamine
Cocaine
neurosciences
alcoholism
Autoreceptors
Microdialysis
animal
drug
Ethylnitrosourea
Quinpirole
Corpus Striatum
Dopamine Agents
Apomorphine
Dopamine Agonists
Voltammetry
Neurosciences
Alcoholism
Animals
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Health(social science)
  • Biochemistry
  • Medicine(all)
  • Toxicology
  • Neurology
  • Behavioral Neuroscience

Cite this

Mathews, T. A., Brookshire, B. R., Budygin, E. A., Hamre, K., Goldowitz, D., & Jones, S. R. (2009). Ethanol-induced hyperactivity is associated with hypodopaminergia in the 22-TNJ ENU-mutated mouse. Alcohol, 43(6), 421-431. https://doi.org/10.1016/j.alcohol.2009.04.006

Ethanol-induced hyperactivity is associated with hypodopaminergia in the 22-TNJ ENU-mutated mouse. / Mathews, Tiffany A.; Brookshire, Bethany R.; Budygin, Evgeny A.; Hamre, Kristin; Goldowitz, Daniel; Jones, Sara R.

In: Alcohol, Vol. 43, No. 6, 01.09.2009, p. 421-431.

Research output: Contribution to journalArticle

Mathews, TA, Brookshire, BR, Budygin, EA, Hamre, K, Goldowitz, D & Jones, SR 2009, 'Ethanol-induced hyperactivity is associated with hypodopaminergia in the 22-TNJ ENU-mutated mouse', Alcohol, vol. 43, no. 6, pp. 421-431. https://doi.org/10.1016/j.alcohol.2009.04.006
Mathews, Tiffany A. ; Brookshire, Bethany R. ; Budygin, Evgeny A. ; Hamre, Kristin ; Goldowitz, Daniel ; Jones, Sara R. / Ethanol-induced hyperactivity is associated with hypodopaminergia in the 22-TNJ ENU-mutated mouse. In: Alcohol. 2009 ; Vol. 43, No. 6. pp. 421-431.
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