Taken from the The Science of H.E.A.T. Stack by: Caleb Stone
Alpha-Y is an analogue of yohimbine, but its potency at the subreceptors of alpha2 differs quite a bit--most notably at the alpha2b and alpha2c adrenergic subreceptors. It is 3 times more potent at alpha2b and 4 times more potent at alpha2c. It is equipotent at alpha2a (45).
Alpha-Y’s superior potency at the other receptors lets us hit them hard, while moderating activity at alpha2a. Alpha2a is the primary receptor subtype, making up 90% (46). It mediates most the classic effects of alpha2 receptor blockade such as increased NE, heart rate, blood pressure, and anxiety (47).
Alpha2a inhibition increases NE by up to 200% while increasing dopamine by only about 80% (48). Disruption of this subreceptor also increases corticosterone (rat version of cortisol) by 100-200% (49). And as we have discussed, these would have negative long-term consequences on the adipostat.
The alpha2c receptor on the other hand, plays only a minor role in the negative feedback signal on NE, but it plays a major role in certain brain areas where sympathetic innervation is low, and the dopamine system is prominent (50). These just happen to be the areas that are critical for reward, reinforcement, and metabolic control, such as the VMH, VTA, and striatum (51). In these areas, dopamine is the primary agonist at alpha2 receptors, and alpha2c makes up the majority of these receptors (52).
Thus, it will block dopamine’s negative feedback signal and increase dopaminergic tone. The dopamine precursor, L-dopa, is higher in alpha2c knockout mice (53). A2c disruption increases, and overexpression decreases, the response to amphetamine stimulation (54). Alpha2c activation (which would decrease dopamine) results in behavioral despair (depression) and elevated cortisol levels (55).
Alpha2c is also the primary subtype in skeletal muscle and an antagonist causes selective femoral vasodilation (56). If that were not handy enough, the only other place the alpha2c subreceptors are highly expressed is in the adrenal medulla, where it modulates negative feedback on epinephrine, much like alpha2a does on NE (57). In other words, in addition to the dopamine increase, Alpha-Y™ allows for a much greater increase in EP levels, with its superior effect on thermogenesis, energy expenditure, and nutrient partitioning. So, we can see that Alpha-yohimbine’s potent antagonism of alpha2c is the good ****.
The alpha2b subreceptor is prominent in development (it is the only adrenergic deletion that impacts survival), but in adults it only affects blood pressure. Namely, its activation increases the hell out of it (58, 59), especially in regard to salt loading (60, 61). Overfeeding also causes an increase in a2b receptor density, concomitant with hypertension via arginine vasopressin (62).
