The long term goal of this research is to increase our understanding of plasticity in neurons postsynaptic to dopamine- terminals in limbic or paralimbic brain regions. Dopaminergic mechanisms and limbic and paralimbic brain regions are related to the etiology of schizophrenia and affective disorders. The anterior cingulate cortex is a paralimbic region that is dopamine- enriched and forms an interface between the DARPP-32 and ARPP-21, in dopaminocptive neurons in anterior cingulate cortex, is suggested in this proposal. DARPP-32 and ARPP-21 are enriched in dopaminoceptive cells containing the D-1 dopamine receptor, and will be studied with neuroanatomical and neurochemical methods. DARPP-32 is regulated by dopamine and it is very likely that ARPP- 21 is also regulated by that transmitter agent. Both phosphoprotein are present in anterior cingulate cortex; ARPP-21 is enriched in neurons in the upper layers of carted that receive the superficial plexus of dopaminergic axon terminals and DARpp-32 is enriched in neurons in the deep layers that receive the deep plexus of dopaminergic axon terminals. DARPP-32 acts as a """"""""third messenger"""""""" for dopaminergic activation of the dopamine D-1 receptor (dopamine is the first messenger and cyclic AMP is the second messenger), and these is very likely true for ARPP-21 as well. The goals of the specific aims of this proposal are to define the morphology of DARPP-32- and ARPP-21- containing neurons in the singulate carte of untreated (""""""""normal"""""""") rats, to determine whether or not these neurons receive classical dopaminergic synapses, to determine whether decreased dopaminergic input can induce a compensatory increase in the synthesis os mRNA for DARPP-32 and ARPP-21, and to assess the effects of decreased dopaminergic input on the """"""""Golgi-morphology"""""""" of the DAEPP-32- and ARPP-21-containing neurons. Changes in the Golgi-morphology of these cells many also reflect an attempt to re-establish homeostasis. The techniques employed will include light and electron microscopic immunocytochemistry, double staining immunocytochemistry, combined Golgi staining and immunocytochemistry, in situ hybridization, and biochemical analysis with Western blotting. The study of dopamine and dopamine-regulated phosphoprotein anterior cingulate cortex should increase our knowledge of dopaminergic function in cortex and demonstrate whether these two phosphoprotein, and the cells that contain them, can be altered by decrease dopaminergic activity.
| Ouimet, C C; LaMantia, A S; Goldman-Rakic, P et al. (1992) Immunocytochemical localization of DARPP-32, a dopamine and cyclic-AMP-regulated phosphoprotein, in the primate brain. J Comp Neurol 323:209-18 |
| Ouimet, C C (1991) DARPP-32, a dopamine and cyclic AMP-regulated phosphoprotein, is present in corticothalamic neurons of the rat cingulate cortex. Brain Res 562:85-92 |
