Dopamine Uptake In Nucleus Accumbens Research Articles

Effects of cocaine on monoamine uptake as measured ex vivo

The increase in extracellular dopamine (DA) following cocaine administration plays a major role in cocaine abuse. In vitro, cocaine binds to DA transporters (DAT) and blocks DA uptake. Moreover, cocaine can increase extracellular DA concentration as measured by in vivo neurochemical methods. The present study examined the effects of cocaine and other drugs on DA, NE and 5-HT uptake using an ex vivo assay. Rats were injected i.v. with saline or drug and sacrificed at various time points after injections. Brains were dissected for regional monoamine uptake studies ex vivo. In most brain regions, cocaine given in vivo blocked monoamine uptake as expected. [ 3H]DA uptake in nucleus accumbens was inhibited with an ED 50 = 22.3 μmol/kg. Cocaine fully inhibited [ 3H]NE uptake (ED 50 = 4.58 μmol/kg) in the occipital cortex and partially inhibited [ 3H]5-HT uptake (33% at 30 μmol/kg) in the midbrain. However, under the same conditions [ 3H]DA uptake in the striatum was not inhibited after injections of cocaine up to 56 μmol/kg. Although the mechanism for this discrepancy is unclear, DA binding and uptake sites may be distinct and/or there may be regional differences in DA transporters.

Phasic inhibition of dopamine uptake in nucleus accumbens induced by intravenous cocaine in freely behaving rats

A new approach combining fast-scan cyclic voltammetry with iontophoretic dopamine delivery was used in freely behaving rats to evaluate the time-course of dopamine uptake inhibition in nucleus accumbens induced by intravenous cocaine at a dose (1.0 mg/kg) known to maintain self-administration behavior. Cocaine significantly increased the decay time of the dopamine response without altering its magnitude or time to peak. An increase in decay time was evident at 2 min, peaked at 6 min (+87%), and decreased to baseline at 18 min after a single cocaine injection. The change in decay time was similar in all rats and remained essentially the same, albeit slightly larger, for subsequent cocaine injections both within a session and over repeated sessions. The change in dopamine decay time did not correlate with cocaine-induced motor activation, which was maximal during the first minute after injection and decreased slowly over the next 20 min. Our data provide direct evidence for a phasic change in dopamine uptake induced by intravenous cocaine under behaviorally relevant conditions. The relatively slow and gradual development of dopamine uptake inhibition, which peaks at times when behaving rats self-inject cocaine, is inconsistent with the suggested role of this mechanism in the acute rewarding (euphoric) effects of self-injected cocaine, but supports its role in the activational and motivational aspects of drug-seeking and drug-taking behavior. Because intravenous cocaine enters the brain rapidly and peaks in neural tissue (1–2 min) long before it effectively inhibits dopamine uptake (6 min), it appears that some of the acute psychoemotional (“rush”), behavioral, autonomic, and neuronal effects of this drug, which are apparently resistant to dopamine receptor blockade, are mediated via rapid central or peripheral mechanisms independent of monoamine uptake.

Methodology for coupling local application of dopamine and other chemicals with rapid in vivo electrochemical recordings in freely-moving rats

Methodology is presented for constructing and using an electrode/microcannulae assembly that allows in vivo electrochemical measurements coupled with local application of dopamine (DA) and other chemicals in the unanesthetized freely-moving rat. Rats were implanted with a voltammetric electrode constructed of a carbon fiber sealed in fused silica tubing attached to a pair of stainless steel guide cannulae, into which fused silica injection cannulae were inserted for local application of DA and other chemicals. Precise delivery of nanoliter volumes was accomplished using a syringe drive combined with a fluid swivel to deliver the solutions to the injection cannulae. A newly-designed miniature potentiostat connected to a commutator via a modular telephone jack assembly allowed for high-speed chronoamperometric electrochemical recordings in freely-moving rats. Initial experiments characterized the in vitro electrochemical recording characteristics of the voltammetric electrode. In vivo studies were also carried out to study clearance of locally-applied DA and of potassium-evoked endogenous DA in the striatum and nucleus accumbens of freely-moving rats. In addition, the effects of chloral hydrate anesthesia on DA clearance signals in the nucleus accumbens were investigated. Moreover, the stability and reproducibility of this recording technique for measuring exogenous DA clearance was verified over a period of 5 days. Finally, the concurrent effects of systemic cocaine injection on DA uptake in nucleus accumbens and locomotor activity were examined. These studies support the conclusion that the methodology described herein allows for rapid chronoamperometric electrochemical recordings in freely-moving rats with precise microapplications of DA and other chemicals combined with concurrent measures of animal behavior.

Cocaine-sensitive and -insensitive dopamine uptake in prefrontal cortex, nucleus accumbens and striatum.

Behavioral studies have indicated that the reinforcing effects of cocaine are dependent on inhibition of dopamine uptake in nucleus accumbens and prefrontal cortex. As it has been suggested that dopamine uptake and cocaine-inhibition of dopamine uptake may differ in nucleus accumbens, prefrontal cortex and striatum, we have further characterized dopamine uptake and its susceptibility to inhibition in these three regions. Dopamine uptake was resolved into two processes, which accounts for some of the apparent reported regional differences in sensitivity of dopamine to inhibition by cocaine. One, which is probably associated with uptake into dopaminergic terminals, was sensitive to 6-hydroxydopamine lesions, cocaine, GBR 12909 or ouabain and was dependent on temperature and sodium ion concentration; this was responsible for most of the observed uptake in tissue from striatum and nucleus accumbens, but not from prefrontal cortex. There appeared to be no regional difference in susceptibility of this mode of dopamine uptake to either cocaine or GBR 12909. The other type of dopamine uptake, which represented a significant proportion of the total in prefrontal cortex, but not in striatum or nucleus accumbens, was relatively insensitive to cocaine, GBR 12909 and ouabain and was dependent on temperature, but not sodium ion concentration. In addition, the cocaine-insensitive dopamine uptake was more sensitive to inhibition by dopamine than serotonin, but did not distinguish between dopamine and norepinephrine. The occurrence of cocaine-sensitive dopamine uptake in all examined regions and its equal sensitivity to cocaine and GBR 12909 is consistent with the involvement of nucleus accumbens and/or prefrontal cortex in the reinforcing effects of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Daily cocaine treatment produces a persistent reduction of [ 3H]dopamine uptake in vitro in rat nucleus accumbens but not in striatum

Daily administration of cocaine (15 mg/kg i.p. × 3 days) led to a decrease in the total amount of 15 nM [ 3H]dopamine uptake in rat nucleus accumbens with no changes in uptake in the striatum when tested 24 h after the last injection. There was an increase in the K m for dopamine uptake in the nucleus accumbens of cocaine-treated rats, with no change in the V max . Furthermore, cocaine was a more potent inhibitor of [ 3H]dopamine uptake in vitro in the nucleus accumbens of rats treated with cocaine than in those which had received saline.

Interaction of [ 3H]GBR 12935 and GBR 12909 with the dopamine uptake complex in nucleus accumbens

Although some behavioral effects of cocaine are hypothesized to be due to blockade of dopamine uptake in nucleus accumbens, it has been reported that in nucleus accumbens there are no specific cocaine binding sites and that cocaine is a weak inhibitor of dopamine uptake. [ 3H]GBR 12935 and an unlabelled analog, GBR 12909, are ligands that bind with great affinity and specificity to a site on dopamine uptake complex in striatum. We therefore investigated the interaction of these GBR compounds with the dopamine uptake complex in nucleus accumbens. We found specific high affinity [ 3H]GBR 12935 binding and a significant correlation between displacement of [ 3H]GBR 12935 binding by a series of compounds in striatum and nucleus accumbens. GBR 12909 inhibited dopamine uptake with equal potency in nucleus accumbens and striatum. Thus, there appear to be some aspects of the dopamine uptake complex in nucleus accumbens and striatum that are similar.