Fluctuations in extracellular dopamine and DOPAC levels in nucleus accumbens septi (NAS) were monitored in 1-min microdialysis samples taken from rats engaged in intravenous cocaine self-administration. For four rats the dose per injection was fixed at 2.0 mg/kg; for four others the dose per injection was varied irregularly, from one response to the next, between three levels (0.5, 1.0 and 2.0 mg/kg). Regardless of the dosing regimen, extracellular dopamine levels were tonically elevated by 200-800% within the cocaine self-administration periods, fluctuating phasically within this range between responses. In the fixed dose condition, the phasic increases following each injection (and the phasic decreases preceding them) averaged approximately 50% of the mean tonic elevation. Phasic fluctuations in dopamine levels remained time-locked to lever-presses even when response rate was irregular, because of the variable dose condition. In the variable dose condition greater increases in dopamine and longer inter-response times followed injections of the higher doses; dopamine fluctuations were consistent with the multiple-infusion pharmacokinetics of cocaine. DOPAC levels showed a slow tonic depression during cocaine self-administration, but individual injections were not associated with discernible phasic fluctuations of DOPAC. These data are consistent with the hypothesis that falling dopamine levels trigger successive responses in the intravenous cocaine self-administration paradigm, but inconsistent with the notion that extracellular dopamine levels are depleted at the times within sessions when the animal initiates drug-seeking responses.

Single neurons (n = 76) were recorded in the nucleus accumbens septi (NAS) of rats self-stimulating the ipsilateral medial forebrain bundle (MFB) at the level of the ventral tegmental area (VTA). Responses evoked by rewarding trains of stimulus pulses fell into five categories. The first category (40% of the sample) was characterized by a single discharge at invariant latency in response to individual pulses of the train, and hence was termed "tightly time locked" (TTL). Two TTL neurons were collision tested, and both showed collision, suggesting that self-stimulation of the VTA may involve antidromic, and thus direct, activation of a substantial number of NAS axons. The second category (26%) was characterized by discharges that varied in latency from pulse to pulse and hence was termed "loosely time locked" (LTL). Responses of the remainder of the sample showed no coupling to individual pulses but were categorized based on general firing patterns during the train: excited (7%), inhibited (4%), and no change (23%). Irrespective of category, immediately after the self-stimulation session, the likelihood of evoked discharge at monosynaptic latency by single pulse stimulation of the ipsilateral fimbria was reduced (relative to pre-session level), concurrent with elevations in mean firing rate and motor activity. NAS neurons thus exhibit vigorous activation, apparently both antidromically and orthodromically, in response to VTA self-stimulation. The responses of certain LTL and TTL neurons increased as a function of pulse number in the train, suggestive of integrative mechanisms important for brain stimulation reward. Conduction velocities of directly activated (TTL) axons (0.41-0.65 m/sec) were slower than those previously reported for first-stage, reward-relevant axons. Nonetheless, an implication of direct activation of NAS (and other MFB) axons is that rewarding stimulation triggers action potentials that could invade all axonal branches, including those between the stimulation site and the soma, and send synaptic signals to target neurons. Such signals from NAS neurons could contribute to the increased motor behavior accompanying MFB self-stimulation, and/or could interact with dopamine-mediated signals projected to the NAS from reward circuitry.

No abstract