The dopaminergic system constitutes the principal target of many psychostimulants, antidepressant, and antiparkinsonian drugs. The effects caused by these compounds are partly associated with an increased dopamine (DA) levels within the terminal areas of DA neurons and in the ventral midbrain. Therefore, several substances of abuse, antidepressants, and endogenous compounds (levodopa and trace amines [TAs]) regulate the activity of DA cells by activating D2 autoreceptors located on the terminals, soma, and dendrites. Considering our past and recent experimental studies on this issue, here we will briefly reexamine the mechanisms of action of several psychoactive drugs on DA neurons. In particular, we propose three different modalities by which the mesencephalic DA neurons can be regulated by drugs: amphetamine/TAs-like, cocaine-like, and levodopa-like. We, therefore, discuss the potential therapeutic and addictive properties of the psychoactive substances.