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.

Moment-to-moment fluctuations of nucleus accumbens dopamine (DA) were determined in rats self-administering or passively receiving "yoked" intravenous infusions of D-amphetamine. The initial lever presses of each session caused elevations in DA concentration, usually to an initial peak that was not maintained throughout the rest of the session. As the initial ("loading") injections were metabolized, DA levels dropped toward baseline but were sustained at elevated plateaus by subsequent lever pressing that was spaced throughout the remainder of the 3 hr sessions. During this period, DA levels fluctuated phasically, time-locked to the cycle of periodic lever pressing. Consistent with the known pharmacological actions and dynamics of amphetamine, peak DA elevations were seen approximately 10-15 min after each injection, and the mean DA level was at a low point in the phasic cycle at the time of each new lever press. During extinction periods when saline was substituted for amphetamine, DA levels dropped steadily toward baseline levels despite a dramatic increase in (now-unrewarded) lever pressing. Noncontingent injections during extinction reinstated lever-pressing behavior and increased nucleus accumbens DA concentrations. These data are consistent with the hypothesis that under the conditions of this experiment-during periods of amphetamine intoxication in well-trained animals-the timing of amphetamine self-administration comes primarily under the control of extracellular DA concentrations. The probability of lever pressing during the maintenance phase is highest when DA concentrations fall near a characteristic trigger point, a trigger point that is significantly elevated above baseline, and falls as DA concentrations fall below or increase above that trigger point.

No abstract

Male rats were fed 100 nM dichlorodiphenyltrichloroethane‐14C in oil by gastric tube. Recovery of dichlorodiphenyltrichloroethane‐14C in thoracic duct lymph was 60% in 12 hr. Lymph dichlorodiphenyltrichloroethane‐14C (97%) occurred in lipoproteins of d<1.006, designated chylomicrons. Mechanical separation of chylomicron triglyceride core (labeled with triglyceride‐3H) from chylomicron membrane (labeled with phospholipid‐32P) showed that 97% dichlorodiphenyltrichloroethane‐14C was present in triglyceride core. To investigate possible association of plasma clearance of the two core lipids, rats were pulse injected with chylomicrons, doubly labeled with triglyceride‐3H and dichlorodiphenyltrichloroethane‐14C. The decay of dichlorodiphenyltrichloroethane‐14C in sequential serum samples was rapid (T1/2=2 min) and was independent of triglyceride‐3H decay. In tissues removed 14 min after injection of chylomicrons, 30% administered dichlorodiphenyltrichloroethane‐14C was found in liver but only 1% in adipose tissue. In hepatectomized (eviscerated) rats, the decay of serum dichlorodiphenyltrichloroethane‐14C (T1/2=10 min) was also independent of and more rapid than triglyceride‐3H decay. With sucrose density gradients, it was shown that chylomicron dichlorodiphenyltrichloroethane‐14C transferred to higher density serum proteins in vitro and in vivo and to bovine albumin in vitro. Thus, dichlorodiphenyltrichloroethane was transported from intestine largely in the triglyderide phase of chylomicrons; disappearance of chylomicron‐dichlorodiphenyltrichloroethane from the systemic circulation was rapid and partly independent of the presence of the liver and of triglyceride hydrolysis; some dichlorodiphenyltrichloroethane was transported from serum chylomicrons to albumin or other plasma proteins before tissue uptake.