The goal of this study was to clarify the role of the nucleus accumbens septi (NAS) in the expression of cocaine self-administration behaviors. Rats were trained in a continuous reinforcement schedule to press a lever to activate a pump that provided an intravenous injection of cocaine. Once the rats were trained, neuronal activity in the NAS was monitored during cocaine self-administration with chronic recording techniques using permanently implanted microwires. In the NAS, 19% of 181 neurons exhibited either increased or decreased firing rates seconds prior to lever pressing (termed “anticipatory responses”), and 48% had altered, predominantly decreased, firing rates for a few minutes after lever pressing (“postcocaine responses”). Two-thirds of the neurons with anticipatory responses had postcocaine responses. Neurons with either of these response patterns were localized histologically to both core and shell regions of the NAS, with no statistically significant differences in the proportion of response types in either area. Analysis of videotaped cocaine self- administration behaviors revealed that anticipatory responses were specifically associated either with the animal orienting toward and pressing the lever or only with movements directly related to pressing the lever. Anticipatory-like phasic spike activity was not observed during similar movements unrelated to lever pressing. In some animals, D1 (SCH 23390) or D2 (pimozide) receptor antagonists were injected systemically prior to or during self-administration sessions to assess the effects of dopamine receptor blockade on anticipatory and postcocaine responses. Each antagonist, given separately, often produced extinction of lever pressing. Both antagonists blocked the post-cocaine inhibitory response of neurons that had anticipatory responses. Neither antagonist modified anticipatory unit responses, nor did they affect postcocaine inhibitory responses in neurons that did not exhibit anticipatory responses. Taken together, these results suggest that the role of the NAS in cocaine self-administration may consist of two different mechanisms: (1) An initiation or trigger mechanism, as represented by the anticipatory neuronal responses, in which the NAS participates in triggering or mediating the goal-directed behaviors (e.g., lever pressing) that lead to the acquisition of the reinforcing agent (e.g., cocaine).(ABSTRACT TRUNCATED AT 400 WORDS)

To compare neuronal activity within the mesocorticolimbic circuit during the self-administration of cocaine and heroin, multiple-channel single-unit recordings of spike activity within the rat medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) were obtained during the consecutive selfadministration of cocaine and heroin within the same session. The variety of neuronal responses observed before the lever press are termed anticipatory responses, and those observed after the lever press are called post-drug infusion responses. For the total of the 110 mPFC and 111 NAc neurons recorded, 30-50% of neurons, depending on the individual sessions, had no alteration in spike activity in relation to either cocaine or heroin self-administration. Among the neurons exhibiting significant neuronal responses during a self-administration session, only a small portion (16-25%) of neurons responded similarly under both reinforcement conditions; the majority of neurons (75-84%) responded differently to cocaine and heroin self-administration as revealed by variations in both anticipatory and/or post-drug infusion responses. A detailed video analysis of specific movements to obtain the selfadministration of both drugs provided evidence against the possibility that locomotive differences contributed to the observed differences in anticipatory responses. The overall mean activity of neurons recorded in mPFC and NAc measured across the duration of the session segment for either cocaine or heroin self-administration also was different for some neurons under the two reinforcement conditions. This study provides direct evidence that, in mPFC and NAc, heterogeneous neuronal circuits mediate cocaine and heroin self-administration and that distinct, but overlapping, subpopulations of neurons in these areas become active during operant responding for different reinforcers.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease (PD). In spite of proven therapeutic success, the mechanism underlying the benefits of DBS has not been resolved. A multiple-channel single-unit recording technique was used in the present study to investigate basal ganglia (BG) neural responses during behaviorally effective DBS of the STN in a rat model of PD. Rats underwent unilateral dopamine (DA) depletion by injection of 6-hydroxyDA (6-OHDA) into one side of the medial forebrain bundle and subsequently developed a partial akinesia, which was assessed during the treadmill locomotion task. High frequency stimulation (HFS) of the STN restored normal treadmill locomotion behavior. Simultaneous recording of single unit activity in the striatum (STR), globus pallidus (GP), substantia nigra pars reticulata (SNr), and STN revealed a variety of neural responses during behaviorally effective HFS of the STN. Predominant inhibitory responses appeared in the STN stimulation site. Nearly equal numbers of excitatory and inhibitory responses were found in the GP and SNr, whereas more rebound excitatory responses were found in the STR. Mean firing rate did not change significantly in the STR, GP, and SNr, but significantly decreased in both sides of STN during DBS. A decrease in firing rate in the contralateral side of STN provides neural substrate for the clinical observation that unilateral DBS produces bilateral benefits in patients with PD. In addition to the firing rate changes, a decrease in burst firing was observed in the GP and STN. The present study indicates that DBS induces complex modulations of the BG circuit and further suggests that BG network reorganization, rather than a simple excitation or inhibition, may underlie the therapeutic effects of DBS in patients with PD.

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