Fluctuations in nucleus accumbens dopamine during cocaine self-administration behavior: an in vivo electrochemical study.
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.(ABSTRACT TRUNCATED AT 400 WORDS)
Kiyatkin
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Department of Psychiatry, Medical College of Wisconsin, Milwaukee 53226, USA.
Stein
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EA
D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage; D017660:Autoreceptors / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology / Q000379:methods; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011343:Procaine / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D017661:Receptors, Presynaptic / Q000378:metabolism; D012646:Self Administration; D019966:Substance-Related Disorders / Q000503:physiopathology; D013997:Time Factors
D017660:Autoreceptors; D017661:Receptors, Presynaptic; D011343:Procaine; D003042:Cocaine; D001058:Apomorphine; D004298:Dopamine