Imaging neurochemical endophenotypes: promises and pitfalls

A large number of polymorphisms in genes coding for neurotransmitter receptors and transporters have been associated with neuropsychiatric conditions, although few of these associations have been consistently replicated. These proteins are critical targets of psychoactive drugs and the clarification of the functional significance of these polymorphisms might offer important leads for drug development and therapeutic applications. Brain imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) provide the means to monitor the expression and function of many of these proteins in the living human brain. This paper reviews brain imaging studies designed to evaluate the significance of polymorphisms in genes coding for important drug targets (e.g., the serotonin transporter [SERT], the dopamine transporter [DAT] and the dopamine D-2 receptor) in terms of expression or function. These studies illustrate the unique opportunities, as well as the pitfalls, generated by combining genetic analysis with brain imaging studies.