Acetylcholine

Acetylcholine is the neurotransmitter of the cholinergic nerves, including the parasympathetic system, and its action is terminated by the enzyme cholinesterase. 5 Peat argued that while acetylcholine is essential for learning and intelligent behavior, its role is fundamentally tied to the stress response, particularly the state of inescapable stress or "learned helplessness." 2 In this state, the body shifts away from sympathetic-adrenal activation and turns on the acetylcholine-dominant cholinergic system, which lowers blood sugar and activates histamine release, a shift Peat described as moving "towards death and away from life." 1 This parasympathetic dominance was historically overlooked in stress research until Richter observed that the hearts of hopeless rats slowed and relaxed due to vagal nerve activity, secreting acetylcholine, rather than accelerating via noradrenaline. 6

A central mechanism of acetylcholine's action, and a key to its degenerative potential, is its activation of nitric oxide synthesis. 2 Acetylcholine relaxes blood vessels by inducing cells to produce nitric oxide, a free radical that can diffuse and inhibit mitochondrial energy production in nerve cells. 2 This vasodilation via nitric oxide is a fundamentally different and more dangerous mechanism than the normal, CO2-driven regulation of blood flow, and Peat noted that nitric oxide is increasingly seen as a factor in nerve degeneration and cell death. 2 The connection between cholinergic stimulation and excitotoxic damage is further reinforced by the fact that organophosphates, which inactivate cholinesterase and prolong acetylcholine's action, increase nitric oxide formation, while protective anticholinergic drugs like atropine reduce it. 2

Peat was highly critical of the "cholinergic theory" of Alzheimer's disease, which led to treatments using cholinesterase inhibitors like Tacrine to increase acetylcholine stimulation. 2 He maintained that this approach failed and was harmful because it forced neurons to work harder without adequate energy, causing cell death, especially when combined with high cortisol or hypoglycemia. 10 Dinkov has extended this critique, stating the cholinergic theory has been "debunked" and that acetylcholine is a brain excitotoxicant very similar in effect to estrogen, manifesting its negative effects through the cholinergic and histaminergic systems. 9 Peat pointed out that drugs originally classified as anticholinergic, such as amantadine and memantine, showed actual improvement in degenerative brain diseases, though they were later reclassified as anti-glutamatergic to avoid conflict with the dominant cholinergic drug paradigm. 2

The relationship between acetylcholine and a healthy brain is nuanced by environmental context. Peat cited research from the 1960s showing that environmental enrichment increased the enzyme cholinesterase in rat brains, and that this increase, along with larger brain size, was passed on to subsequent generations. 2 This suggests that a healthy, stimulated brain upregulates the destruction of acetylcholine, rather than its accumulation. 3 Estrogen intensifies the cholinergic system, which Peat connected to its excitatory and destructive features, including premenstrual epilepsy and miscarriage via uterine contractions, while progesterone and pregnenolone act as anticholinergic, protective agents. 2 Roddy noted a personal experience where a substance that increased acetylcholine made him feel "super high strung," aligning with Peat's association of the cholinergic system with the stress response and nitric oxide. 8