Behavioral significance of phasic changes in mesolimbic dopamine-dependent electrochemical signal associated with heroin self-injections.

Abstract

High-speed chronoamperometry with monoamine-selective carbon fiber electrodes was used in rats to monitor, during 5-6 consecutive daily sessions, changes in DA-dependent electrochemical signal in the nucleus accumbens (NAcc) during intravenous heroin (0.1 mg/kg) self-administration (SA) behavior and passive repeated drug injections performed with a temporal scheme similar to that in the SA experiment. In trained animals, biphasic signal fluctuations time-locked to the individual lever-presses were found to accompany all but the first daily SAs. The signal gradually increased by 30-40 nM for the 10 minutes preceding the SA, reached a peak at the moment of lever-press and decreased abruptly by approximately 40 nM for 3-4 min after heroin SA. The cycle then repeated, reaching a new peak at the moment of the next lever-press. Rapid bi-directional fluctuations in signal associated with individual heroin SAs were superimposed on substantial tonic increase in signal baseline (400-500 nM). This increase quickly developed after presentation of heroin-related light cue and the first SA, was relatively stable during all subsequent SAs and decreased towards the baseline after the last SA of a session. Changes in signal baseline induced by repeated heroin SAs depended strongly upon the signal's basal level (r = -0.787); that signal preferentially increased when its basal values were low (0-300 nM), and decreased when signal was tonically elevated (> 600 nM). Repeated passive heroin injections also induced biphasic signal fluctuations and a similar tonic increase in signal baseline. Although a transient signal decrease (25 nM for 2-4 minutes) followed by a prolonged signal increase occurred after each but not the first passive injection, the gradual pre-injection signal acceleration was absent. Although DOPAC, a principal DA metabolite, may significantly contribute to the tonic increase in electrochemical signal seen during SA session, the changes in extracellular DA may be the main contributor to both the rapid signal increases preceding drug-taking and the transient signal decreases following heroin SA. If so, the present findings suggest that activation of mesolimbic DA cells and increase in DA transmission may be involved in the mediation of motivational and/or activational components of drug-seeking and drug-taking behavior. An acute termination of previous drug- and behavior-associated DA activation with a transient inhibition of DA release, immediately following heroin SA may correlate with the drug's rewarding action, representing a part of a mechanism regulating drug-taking behavior.