This is a new five-year grant that proposes to use in vivo and in vitro electrophysiological recordings to examine the functional interactions among cortical afferents and the dopamine (DA) system within the nucleus accumbens of rats. Although initial studies into schizophrenia were directed at a role for DA in the etiology of this disorder, interest has recently been focused on a cortical locus of pathology, with emphasis on the prefrontal cortex and the hippocampus. Moreover, owing to the genetic linkage of schizophrenia, one topic of concentration has been the study of neonatal lesions of the ventral hippocampus and its impact system function in the adult organism. One region in which the hippocampus, prefrontal cortex, and the mesolimbic DA system overlap in particular appears to have a functional role if gating prefrontal cortical throughput within this structure. In addition, the DA system appears to play a role as well in that is has been shown by us and others to affect both the afferent processes and the response of nucleus accumbens cells to these inputs. We propose to evaluate this functional interaction and how it may be selectively altered by neonatal disruption according to the following specific aims: (1) to characterize the physiology and pharmacology of the responses evoked in accumbens neurons in vitro by stimulation of prefrontal cortical, hippocampal, and amygdalar afferents. (2) To examine the pharmacology of DA actions on each of these afferent systems in vitro. (3) to characterize the response properties and types of interaction between pairs of afferents to accumbens neurons recorded in vivo. (4) To examine how the DA system affects the afferent-evoked responses and their interactions in vivo, and how these interactions may be altered by psychotropic drugs. The first 4 aims will provide a comprehensive characterization of the nature of the interactions among these cortical afferents and their modulation by DA in the normal adult rat, to provide the necessary baseline data set for the last specific aim: (5) To compare the effects of neonatal versus adult lesions of the ventral hippocampus on the interaction between excitatory afferents to the accumbens neurons and their regulation by DA. In this way, we will gain a better understanding of the nature of these cortical interactions within the nucleus accumbens, how these systems are modulated by DA, and how they may undergo a compensatory reorganization as a consequence of neonatal damage to the ventral hippocampus.
Showing the most recent 10 out of 92 publications
