Recent studies suggest a link between blood pressure (BP) and executive functions including working memory, response inhibition, and attention. Older adults and children with hypertension exhibit deficits in working memory and attention; however, it is not clear whether a common mechanism could link the elevation in BP and the cognitive abnormalities. The expression of the Calcyon (Caly), a protein which regulates receptor endocytosis, is increased in the brain of the spontaneously hypertensive rat (SHR), a widely accepted animal model of essential hypertension and attention deficit hyperactivity disorder. We hypothesize that Caly up-regulation in forebrain elevates BP under normal physiological response by altering adrenergic transmission. Radio-telemetry transmitters were implanted in CalOE transgenic mice in which Caly is up-regulated, and in tTA littermate controls. Mean arterial pressure was significantly higher in CalOE mice compared to tTA control (121± 1 vs. 108±1 mmHg, P<0.05). Consistent with deficits in executive functions, CalOE mice were also more active and less able to extinguish a learned behavior than tTA controls. Silencing the transgene with doxycycline treatment improved learning deficits and prevented the elevation in BP in CalOE mice. Plasma nor-epinephrine levels were higher in CalOE vs. tTA control mice (20±2 vs. 13±4 ng/ml). In the brain, dopamine levels were significantly lower in CalOE mice vs. control (0.2 ± 0.02 vs. 0.5±0.08 ng/mg) together with decreased dopamine D1 receptor expression whereas urinary dopamine excretion levels were higher in CalOE vs. control (0.5± 0.1 vs. 0.1± .04 μg/day, P<0.05). These data suggest that up-regulation of Caly in brain could increase BP and compromise inhibitory control mechanisms under normal physiological condition via the differential regulation of adrenergic transmission.