171-OR: Dopaminergic Signaling in the Ventral Tegmental Area of the Brain Mediates the Impaired Sympathoadrenal Response to Hypoglycemia

The mechanism by which recurrent hypoglycemia (RH) impairs the sympathoadrenal response to hypoglycemia remains unknown. To explore altered brain dopaminergic signaling as a mechanism, 10 weeks old rats were randomized to 3 days: 1) recurrent saline (RS), 2) insulin (2-1.2 U/kg, sc) induced RH (25-50 mg/dl), or 3) RH + antecedent dopamine receptor antagonist metoclopramide (MET, 3 mg/kg, ip). qPCR of brain biopsies demonstrated RH downregulated dopaminergic signaling, noted by decreased expression of dopamine D2 receptor (Drd2, 52%*) and increased dopamine transporter (DAT, ~1.9-fold*) in the ventral tegmental area (VTA); an effect prevented by MET (Figure 1A). To test whether recurrent dopamine activation in the VTA is sufficient to impair the sympathoadrenal response to hypoglycemia, a second rat cohort was randomized to 3-day recurrent VTA infusion of: 1) aCSF (control), or 2) Drd2 agonist bromocriptine (Bromo; 5 µg/d). During hyperinsulinemic (20 mU/kg/min) hypoglycemic (∼45 mg/dl) clamps, recurrent Bromo resulted in an increased glucose infusion rate (1.7-fold*) and blunted epinephrine response (~50%*, Figure 1B). These results demonstrate that blunted dopaminergic signaling in the VTA induced by RH contributes to the impaired sympathoadrenal response, which may be associated with recurrent brain dopaminergic activation. *p<0.05.

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