D-2 dopamine autoreceptor selective drugs: do they really exist?

The catecholamine dopamine plays an important role as a neurotransmitter or neurohormone in the brain and pituitary gland. Dopamine exerts its effects through activation of two types of receptors called D-1 and D-2. These receptors are distinguished by their different pharmacological characteristics and signal transduction mechanism(s). Release of dopamine inhibits the activity of dopaminergic neurons through activation of so-called dopamine autoreceptors which are of the D-2 type. In general, these receptors occur both in the soma-dendritic region of the dopaminergic neuron, where they are involved in the inhibition of the firing rate and on the dopaminergic terminals where they mediate the inhibition of dopamine synthesis and release. D-2 receptors occur also on the target cells of dopaminergic neurons both in the brain (postsynaptic D-2 receptors) and pituitary gland. On the basis of data gathered from in vivo (behavioral- as well as electrophysiological) studies it has been concluded that D-2 agonists are much more potent at dopamine autoreceptors as compared to postsynaptic D-2 receptors, indicating the possibility of a pharmacological distinction between these differentially located D-2 receptors. This concept led to the introduction of a whole group of drugs allegedly displaying a selective agonist profile at the dopamine autoreceptor. In contrast, biochemical (in vitro) studies with brain tissue as well as the pituitary gland, did not reveal any significant difference between the pharmacological profiles of autoreceptors and postsynaptic D-2 receptors. In the present minireview a balanced discussion is presented of these in vivo and in vitro findings and it is concluded that both autoreceptors as well as postsynaptic D-2 receptors are similar if not identical entities.