Phen-Pro's Mechanism of Action

After reviewing recent published information on serotonin (5HT) receptors and their interaction with the norepinephrine (NE) system in the hypothalamus, I find it impossible as yet to provide a reliable, detailed understanding of how Prozac extends the action of phentermine. There is a lot of information on differential drug binding to receptor proteins but not enough on where the receptors are located and what they do. One thing is clear: the control of appetite and feeding is considerably more complex and spread out through the brain than the simple hypothalamic "appestat" model. Here is what I think I know . . .

Phentermine increases the release of NE from NE-carrying neurons in the brain. Prozac acts on serotonergic neurons to increase the effective release of 5HT by inhibiting its reuptake.

In the medial hypothalamus, NE acts on alpha-2 receptors to increase hunger. 5HT inhibits this response, through HT1B receptors, by activating G-dependent adenylate cyclase which in turn activates cAMP-dependent protein kinase which inhibits tyrosine hydroxylase (TH), the rate-limiting step in NE synthesis.

In the lateral hypothalamus, NE acts in an opposite manner, through alpha-1 receptors, to reduce hunger. Here 5HT works in parallel with NE, through HT2C receptors, to reduce hunger. So it seems 5HT acts in a "push-pull" manner on the two sides of the hypothalamus. Indeed, drugs which activate only the HT2C receptor but not the HT1B receptor do not induce satiety. Only drugs that activate both receptors are fully effective in reducing hunger [Kitchener & Dourish. Psychopharmacology (Berlin) 1994; 113: 369-377]