The ventral striatal complex termed the nucleus accumbens septi (NAS) is a brain structure increasingly implicated in the acquisition and expression of reinforced behaviors. In addition, there is strong evidence suggesting that the NAS, including some of its efferent and afferent connections, are critical for the brain processes leading to self-administration of both psychostimulant and narcotic analgesic drugs in rats. In the present application we plan to extend our preliminary investigations of the discharge properties of individually isolated nucleus accumbens (NAS) neurons in both the anesthetized and unanesthetized rat, and to first classify these neurons into functional categories based on: 1.) The location of NAS cells recorded within the recently specified """"""""core"""""""" vs. """"""""shell"""""""" designation; 2.) The response and topography of NAS neurons to both major afferent inputs (subiculum, amygdala, ventral tegmental area-A10, ventral pallidum) and efferents (ventral pallidum and ventral tegmental pars reticulata); 3.) The response of NAS neurons to systemically and locally applied opioids (and antagonists) with selective opioid receptor sub-type selectivity, and; 4.) The response and opioid interaction of NAS neurons with a selective number of electrophoretically applied endogenous neurotransmitters (i.e. glutamate, dopamine, acetylcholine and gamma aminobutyric acid). These studies will serve to extend our previous normative investigations of NAS cell types and begin to determine the neurochemical specificity that may underlie the observed heterogeneity of spontaneous cellular activity and cellular responsiveness we have observed in the halothane anesthetized rat. Second, in order to investigate the cellular substrate of reinforced behaviors we will extend our recordings from identified NAS neurons in anesthetized rats to unanesthetized, freely-moving rats. We will correlate the discharge of NAS neurons with on-going structured and unstructured behaviors, arousal state changes, and episodes of heroin self-administration including choice paradigms. Behavior and electrophysiological activity will be quantitated by utilizing a video/computer interface that acquires video images and precisely times behavioral events with concurrent electrophysiological and/or chemical (see below) data. This methodology allows us to construct peri-event histograms that provides the opportunity to subsequently analyze and compare similar but un-rewarded motor behaviors. This """"""""behavioral clamping"""""""" is essential in order to begin to relate cellular activity in any brain region with motivated behaviors. Video analysis of bar press events associated with heroin self-administration (see preliminary data) have indicated that NAS neuronal activity dramatically decreased for up to one minute following rewarded bar presses compared to non-rewarded similar rearing behaviors. This preliminary analysis suggests that NAS neurons can preferentially respond to complex, reward-related behaviors. In order to investigate potential circuit hierarchies we will also monitor activity of NAS efferent targets, e.g. the ventral pallidum; and afferent projection sites, e.g. the prefrontal cortex during drug-seeking behaviors and operant tasks. Thirdly, we will begin to relate cellular activity in the NAS with the release of neurotransmitters in these and other potential neural substrates of reinforced behavior, by concurrently monitoring, in situ, dialysate contralateral to recording sites during contingent and non-contingent opioid administration. In toto, these studies constitute the first attempt to correlate cellular activity with opioid self-administration involving a brain area known to be critical for this behavior.

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National Institute on Drug Abuse (NIDA)
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