While several mechanisms for PPID have been proposed, Dianne McFarlane, DVM, PhD, Dipl. ACVIM, assistant professor of physiological sciences at Oklahoma State University’s Center for Veterinary Health Sciences, suggested that it is a neurodegenerative disease. This seems to be supported by the fact that her research has found almost no dopaminergic (dopamine-producing) neurons in the pars intermedia of affected horses, while there are quite a few in young horses or unaffected horses of similar age. She presented these ideas at the 2006 AAEP Convention.

The lack of dopamine is critical, as she noted that the activity of the pars intermedia is normally inhibited (controlled) by dopamine. Without dopamine, the pars intermedia produces much more hormone than it should, causing the clinical signs of PPID. Similar activity occurs in other species when dopamine is experimentally inhibited, she reported. This explains why the medication pergolide helps so many horses with PPID–it replaces dopamine activity and thus inhibits pars intermedia hormones. It also explains why another popular treatment–trilostane–doesn’t always work as well.

McFarlane explained that trilostane acts on the adrenal gland to control secretion of cortisol hormone–"stress hormone." This helps control biochemical stress, but it doesn’t act on the originating problem in the pars intermedia.

"I’m hesitant to recommend trilostane partially because it is only available compounded, and because it doesn’t act against the inciting factor," she noted. "Pergolide treats in three ways: It protects neurons, adds dopamine, and has antioxidant activity