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

Ethanol-induced hyperactivity is associated with hypodopaminergia in the 22-TNJ ENU-mutated mouse
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 2.25g/kg ethanol and 10mg/kg cocaine, compared with control mice. In vivo microdialysis showed low-baseline DA levels and a larger DA increase with both 2.25g/kg ethanol and 10mg/kg cocaine. In in vitro voltammetry studies, the 22-TNJ mice displayed increased V(max) 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.
- University of British Columbia Canada
- Wayne State University United States
- University of Tennessee Health Science Center United States
- Wayne State College United States
- Tennessee State University United States
Quinpirole, Ethanol, Receptors, Dopamine D2, Dopamine, Microdialysis, Putamen, Hyperkinesis, Motor Activity, Mice, Mutant Strains, Nucleus Accumbens, Mice, Cocaine, Ethylnitrosourea, Models, Animal, Animals, Caudate Nucleus
Quinpirole, Ethanol, Receptors, Dopamine D2, Dopamine, Microdialysis, Putamen, Hyperkinesis, Motor Activity, Mice, Mutant Strains, Nucleus Accumbens, Mice, Cocaine, Ethylnitrosourea, Models, Animal, Animals, Caudate Nucleus
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