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Δ⁹-THC was studied for its effects on the learning behavior of rats and mice in several experimental models of learning. Doses were selected by observation of the gross behavioral effects of THC over a wide dose range. It was found that in the pit avoidance procedure in the mouse, acutely administered doses of 2.5 mg/kg, i.p., of THC and above, significantly reduced the number of avoidances, whereas, in another active avoidance test (shuttle box) in which doses of 20 and 40 mg/kg were administered daily for 5 days, a drug state dependent enhancement of avoidance behavior acquisition was seen. In a one-trial passive avoidance situation in mice, doses of up to 20 mg/kg, i.p., of THC were ineffective with higher doses causing minimal impairment of learning. A one-trial conditioned suppression method was used in rats in which subjects were given a foot-shock in a cage previously associated with milk drinking. When shocked under 2.5 mg/kg, i.p., of THC and retested 5 days later (without drug) for drinking latency, it was found that the degree of suppression was the same in animals shocked under saline. Rats shocked under saline and retested under THC had longer latencies than controls and, finally, rats shocked and retested under THC exhibited a significantly greater degree of suppression than controls. THC does not appear to generally impair acquisition behavior.

In recent years, several studies have suggested that cardiometabolic disorders, such as diabetes, obesity, hypertension, and dyslipidemia, share strong connections with the onset of neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease (AD). However, establishing a definitive link between medical disorders with coincident pathophysiologies is difficult due to etiological heterogeneity and underlying comorbidities. For this reason, amyloid β (Aβ), a physiological peptide derived from the sequential proteolysis of amyloid precursor protein (APP), serves as a crucial link that bridges the gap between cardiometabolic and neurodegenerative disorders. Aβ normally regulates neuronal synaptic function and repair; however, the intracellular accumulation of Aβ within the brain has been observed to play a critical role in AD pathology. A portion of Aβ is believed to originate from the brain itself and can readily cross the blood-brain barrier, while the rest resides in peripheral tissues that express APP required for Aβ generation such as the liver, pancreas, kidney, spleen, skin, and lungs. Consequently, numerous organs contribute to the body pool of total circulating Aβ, which can accumulate in the brain and facilitate neurodegeneration. Although the accumulation of Aβ corresponds with the onset of neurodegenerative disorders, the direct function of periphery born Aβ in AD pathophysiology is currently unknown. This review will highlight the contributions of individual cardiometabolic diseases including cardiovascular disease (CVD), type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease (NAFLD) in elevating concentrations of circulating Aβ within the brain, as well as discuss the comorbid association of Aβ with AD pathology.

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