Modulation of drug-conditioned responses by NMDA receptor antagonists

Abstract

High-speed chronoamperometry with Nafion-coated monoamine-sensitive carbon fiber electrodes was used to estimate changes in extracellular dopamine concentration in the nucleus accumbens during cocaine self-administration behavior in rats. In trained animals, time-locked biphasic fluctuations in dopamine-dependent electrochemical signal were found to accompany cocaine self-injections (0.8−0.9 mg/kg/inj). The mean signal gradually increased by the equivalent of 20–30 nM of dopamine during the 60 s preceding the injection, reached a peak value at the lever-press and decreased abruptly by about 20–30 nM for 40–60 s after the injection. This cyclic pattern was repeated with the next lever-press. The post-cocaine signal decreases were most pronounced during the first 30 min of each session, when self-administration behavior was highest (eight to 16 injections), and gradually diminished during the session. In contrast, the pre-injection signal increases became enhanced over time. Lever-presses reinforced by a double cocaine dose were followed by significantly larger and longer lasting signal decreases. These biphasic fluctuations quickly disappeared after several non-reinforced lever-presses. Although experimenter-delivered cocaine injections paced to mimic the pattern of self-administration also induced biphasic signal fluctuations, both the post-drug signal decreases and subsequent pre-injection increases were significantly smaller.It is hypothesized that the increases in signal seen in trained animals are a consequence of cocaine-induced dopamine uptake inhibition following behavior-associated dopamine cell activation. In contrast, the post-cocaine abrupt transient signal depression may be related to a decrease in mesolimbic dopamine release due to inhibition of dopamine cell activity. Signal decreases seen after self-administered procaine suggest that cocaine's local anesthetic action may contribute to this decrease in dopamine release. Additionally, while the latency of response differed somewhat, since apomorphine administration also led to a reduction in signal, autoreceptor activation may also have contributed to the cocaine-induced signal depression. That learning and behavioral mechanisms are also important determinants of the observed cocaine-induced signal changes is suggested by the signal decreases after the first non-reinforced responses, signal differences between self- and passively-administered cocaine and signal increases caused by cocaine-related cues.In light of numerous neuropharmacological studies implicating the significance of the mesolimbic dopamine system in the organization and regulation of goal-directed behaviors, these data suggest that mesolimbic dopamine system activation may mediate motivational and activational components of drug-seeking and drug-taking behavior, while the transient, reward-associated inhibition of the system may be involved in regulating these behaviors. The co-existence of two functionally antagonistic actions of cocaine on mesolimbic dopamine release and accumulation may be important in mediating the drug's unique psychogenic properties, including the ability to drive and maintain compulsive drug-taking behavior.