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

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 (ENU)-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 to 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 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 to controls. Taken together, these results indicate that the dopaminergic system of the 22-TNJ mouse is low-functioning compared to 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 hyperresponsiveness to ethanol's stimulant actions. D2 receptor; N-ethyl-N-nitrosurea; ethanol; cyclic voltammetry and microdialysis Keywords Dopamine

Ethanol-induced increases in extracellular dopamine are blunted in brain-derived neurotrophic factor heterozygous mice

“…A systemic injection of 2 g/kg ethanol significantly increased extracellular levels of dopamine in the CPu of wildtype mice between 40 and 60 min following ethanol administration. These microdialysis results from the CPu are in agreement with several mouse microdialysis studies that have shown an approximate 50 – 170% increase in extracellular dopamine levels in response to a locomotor activating dose of ethanol [17, 19, 26, 28]. One important difference between the present study and those described above is that the majority of mouse microdialysis studies have evaluated ethanol-induced elevations in extracellular dopamine in the NAc (or ventral striatum) [17, 26, 28] and not the CPu (or dorsal striatum); but see [19].…”

Mechanical Ventilation Triggers Hippocampal Apoptosis by Vagal and Dopaminergic Pathways

“…Increased dysbindin-1 expression in the hippocampi from ventilated patients suggests that this protein could play a role in the regulation of brain responses to critical illness and mechanical ventilation. Moreover, it has been described that enhanced DRD2 stimulation leads to hypodopaminergia (46). The long-term effects of these compensatory mechanisms remain to be elucidated.…”

Hypocretin/orexin knock‐out mice display disrupted behavioral and dopamine responses to cocaine

“…This timing was determined based on previous publications which tested animals 1-5 days after surgery (Narita et al, 2006; Ferris et al, 2014). Microdialysis probes (membrane length 2mm; CMA/Microdialysis) were inserted approximately 16 hr prior to the beginning of sample collections and extended 2 mm beyond the cannula tip to -4.55 V (Mathews et al, 2009). …”