Pharmacology of mesocortical dopamine neurons

The current information on the pharmacology and function of the DA innervation to the prefrontal cortex is a synthesis of data from several initially distinct areas of research. Some possible functions of the mesocortical DA system are suggested from the extensive studies conducted on the role of the prefrontal cortex in behavior, and also from the data on prefrontal cortical modulation of the output of subcortical DA systems. Meanwhile, anatomical, behavioral, biochemical, and electrophysiological studies on mesocortical DA neurons have largely resulted from interest in determining the site(s) and mechanism(s) of action of various psychotropic drugs, and particularly the antipsychotic drugs (DA antagonists). An interrelated field of study has investigated the functional role of DA autoreceptors. The mesocortical DA system possesses many unique characteristics compared to the nigrostriatal/mesolimbic DA systems, including 1) a higher DA turnover rate, 2) a higher rate and different pattern of neuronal discharge, 3) a greatly diminished responsiveness to DA agonists and antagonists, 4) a lack of tolerance to the effect of chronically administered DA antagonists, and 5) a selective activation by footshock stress. These characteristics may be due to the fact that the DA cells projecting to the prefrontal cortex lack DA autoreceptors, an important site for the physiological and pharmacological modulation of subcortical DA systems. This contention is further supported by recent studies on two distinct DA systems innervating, respectively, the anterior cingulate and piriform cortices: the former system, which lacks DA autoreceptors, responds much like the prefrontal cortical DA sy stem; the latter system, which possesses functional DA autoreceptors, manifests a pharmacological responsiveness similar to the nigrostriatal/mesolimbic DA systems (11, 14, 118, 119, 38). Autoreceptors may be an important target for future rational drug design. For example, DA agonists more selective for DA autoreceptors (65, 72) may be useful agents in the treatment of schizophrenia. If, however, these drugs prove ineffective in schizophrenic patients, it might help to explain the equivocal results obtained to date in the treatment of schizophrenia with low (autoreceptor-specific) doses of less selective DA agonists (for a review, see Ref. 97). A lack of clinical efficacy of DA autoreceptor agonists might also suggest that if a DA system is indirectly involved in schizophrenia the site of therapeutic action of antipsychotic drugs is a DA system (such as that innervating the prefrontal cortex) that lacks autoreceptors.