Joseph B. Justice

Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis

The extracellular dopamine (DA) concentration in the nucleus accumbens was measured following intravenous cocaine administration. The DA concentration increased in a dose-dependent manner following a single intravenous infusion of cocaine. The concentration of DA was observed to increase and stabilize in a schedule-dependent manner when cocaine was repeatedly administered 15-, 5- and 2.5-minute intervals. When cocaine was administered in regular intervals to animals by an experimenter or when animals self-administered cocaine. DA concentrations stabilized substantially above the basal level. These data support research that suggests that reinforcing properties of cocaine are primarily mediated by DA release in the nucleus accumbens. The data and pharmacokinetic calculations indicate that the DA concentration increases for a short period following each infusion. It then falls to a level until the animal again self-administers the drug. Animals may regulate self-administration responding for cocaine in order to maintain DA levels above a certain level, yet titrate responding so that aversive effects are not produced.

Effect of dose on cocaine self-administration behavior and dopamine levels in the nucleus accumbens

The reinforcing properties of cocaine are thought to be primarily mediated by the release of dopamine (DA) in the nucleus accumbens (N ACC). The extracellular concentration of DA in the N ACC was monitored with in vivo microdialysis procedures during ongoing cocaine self-administration to achieve a more detailed understanding of how DA mediates the reinforcing effects of cocaine. A dose-dependent decrease in lever pressing behavior occurred as the dose of cocaine was increased. The mean number of lever presses (in 20 min intervals) for 0.25, 0.50 and 0.75 mg/infusion doses was 5.6 +/- 0.7, 3.3 +/- 0.3 and 2.4 +/- 0.3, respectively. However, a simple inverse relationship did not occur between lever pressing behavior and the total amount of cocaine injected. Lever pressing behavior significantly increased cocaine intake as the dose of cocaine was increased. The total amount of cocaine intake that occurred during the 3 h self-administration period of the 0.25, 0.50 and 0.75 mg/infusion doses was 12.0 +/- 1.8 mg, 14.6 +/- 0.37 mg and 16.6 +/- 1.2 mg. Correspondingly, the extracellular concentration of DA in the N ACC was increased and maintained at significantly higher levels as the dose of cocaine was increased. The average concentration of DA that occurred during the self-administration of 0.25, 0.50 and 0.75 mg/infusion doses of cocaine was 269 +/- 26%, 381 +/- 21% and 464 +/- 49% of the basal DA concentration. As dose is increased, a corresponding increase occurs in both cocaine intake and in the extracellular concentration of DA in the N ACC.(ABSTRACT TRUNCATED AT 250 WORDS)

Extracellular dopamine in rat striatum following uptake inhibition by cocaine, nomifensine and benztropine.

A microdialysis/smallbore chromatographic system was used to monitor changes in extracellular dopamine concentration in the striatum of the rat following administration of drugs that block catecholamine uptake. Analysis of 0.5 microliter of dialysate every 5 min showed dose-dependent elevations in extracellular dopamine following systemic administration of nomifensine (1 and 10 mg/kg), benztropine (5 and 25 mg/kg) and cocaine (3, 10 and 30 mg/kg). The order of potency in vivo was nomifensine greater than cocaine greater than benztropine. The short sampling interval allows accurate temporal profiles following pharmacological manipulations to be acquired.

Individual differences in basal and cocaine-stimulated extracellular dopamine in the nucleus accumbens using quantitative microdialysis

The current experiment examined the role of nucleus accumbens (NACC) dopamine in individual differences. Subjects were divided into high responders (HR) and low responders (LR) based on their locomotor response to a novel environment. HR rats were subjects which had a locomotor response to novelty in the upper third of the population screened and LR rats in the bottom third of the population. A new method of microdialysis was then used that allowed determination of the extracellular dopamine concentration. This was accomplished by adding various dopamine concentrations (0.0, 5.0 and 20.0 nM) to the perfusate. The concentration of dopamine in the dialysate was subsequently determined. The difference in the dialysate and perfusate dopamine was regressed on the perfusate dopamine. The regression yielded the in vivo recovery and the extracellular concentration. HR rats exhibit a 250% higher basal dopamine concentration (6.45 +/- 1.01 nM, n = 6) than LR rats (2.58 +/- 0.16 nM, n = 7). The in vivo microdialysis recovery was used to estimate the extracellular dopamine following cocaine challenge (15 mg/kg) in the two groups. Following i.p. cocaine administration, HR rats had both a greater locomotor response and increase in absolute dopamine concentration compared to LR rats. The maximum dopamine concentration in the HR group was 23 +/- 2.9 nM, while that in the LR group was only 8.6 +/- 1.1 nM. The maximum in the LR group is comparable to the basal level in the HR group. However, there were no difference in percent change in dopamine following cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Detecting behaviorally relevant changes in extracellular dopamine with microdialysis

A method is described for monitoring extracellular levels of striatal dopamine in the rat during behavior. The extracellular fluid is sampled using a microdialysis probe modified for use in behaving animals. Dopamine concentration in the perfusate is determined every 5 min using an automated smallbore chromatographic system with electrochemical detection. The system is capable of detecting behaviorally related changes of 5 nM, in extracellular dopamine.

Conditioned place preference and locomotor activation produced by injection of psychostimulants into ventral pallidum

The ventral pallidum (VP) is often viewed as an output structure of the nucleus accumbens septi (NAS). However, VP, like NAS, receives a dopaminergic input from the ventral tegmental area. These experiments investigated some behavioral effects of microinjection into VP of drugs which enhance dopaminergic transmission. Injection of 25 micrograms dopamine or 5-10 micrograms amphetamine into VP produced hypermotility. In contrast, injection of 12.5-50 micrograms cocaine initially suppressed, then increased, activity. Injection of 100 micrograms cocaine only produced hypomotility in the 1-h period examined. The hypomotility following cocaine seemed to be a local anesthetic effect, because it was mimicked by 50-200 micrograms procaine. Procaine did not, however, produce subsequent hypermotility. Conditioned place preference (CPP) was produced by 10 micrograms amphetamine and 50 micrograms cocaine but not 100 micrograms procaine. We conclude that injection of cocaine into VP unlike similar injections into NAS, produces CPP. These results support the idea of an involvement of dopamine in VP in reward and locomotor activation, independent of dopamine in NAS. The use of intracerebral injections of cocaine is complicated, however, by an apparent local anesthetic effect of the drug.

Extracellular cocaine and dopamine concentrations are linearly related in rat striatum

Microdialysis and gas chromatography/mass spectrometry were used to determine temporal cocaine concentration profiles in the rat striatum following intraperitoneal (i.p.) cocaine injection. For a 30 mg/kg i.p. dose, cocaine reached a maximum in vivo concentration of 10.1 microM within 30 min, and then rapidly declined. A non-linear fit of a kinetic model to the experimental cocaine data gave a first-order rate constant for the appearance of cocaine in the extracellular fluid of the striatum after a 30 mg/kg dose of cocaine of 0.0304/min and a first-order rate constant of 0.0386/min for the disappearance of cocaine from the extracellular fluid. When combined with previous dopamine results for a 30 mg/kg i.p. cocaine dose, cocaine concentrations were found to be highly correlated (r = 0.963) with dopamine concentrations for the same point in time. The slope was 36.8 nM dopamine/microM cocaine and the y-intercept was 29.9 nM dopamine. Maximum dopamine and maximum cocaine concentrations were also found to be linearly related to i.p. dose of cocaine for doses of 3, 10, and 30 mg/kg.

Mechanisms contributing to the recovery of striatal releasable dopamine following MFB stimulation

In vivo voltammetry was used to monitor the concentration of dopamine released into striatal extracellular fluid during electrical stimulation of the medial forebrain bundle of anesthetized rats. During stimulation the dopamine concentration increases rapidly to micromolar levels. After cessation of the stimulus, uptake mechanisms rapidly clear the released dopamine. That dopamine is the compound detected during stimulation is confirmed by voltammetry and pharmacology. The interval between stimulations influences the amount of dopamine released. When 10 s stimulations are spaced by 30 s, only 50% of the amount of dopamine released by the first stimulation is released by the second stimulation. Twenty minutes are required for full recovery of the stimulation response. Full recovery requires dopamine synthesis but during the initial 2 min following stimulation the recovery exceeds synthesis rates. Possible mechanisms that contribute to the rapid initial recovery are the mobilization of intraneuronally stored dopamine and the recycling of the released dopamine via presynaptic uptake mechanisms. Dopaminergic receptors are able to modulate the rapid recovery.

Modeling the dopaminergic nerve terminal

A method is described for developing and evaluating models of neurochemical processes. Computer simulation and simplex optimization are used to examine a model of the dopaminergic nerve terminal of the rat striatum. In the model, synthesis, storage, release, uptake, and metabolism are described by a set of non-linear differential equations. Parameters of the model are optimized with respect to diverse experimental data. These data include steady state passage of radioactivity, decline in total dopamine after synthesis inhibition, and change in extracellular dopamine concentration during electrical stimulation.

Locomotor response to novelty does not predict cocaine place preference conditioning in rats

Previous studies have demonstrated that rats showing a strong locomotor response to a novel environment have a greater locomotor response to psycho-stimulant drugs and more rapidly acquire intravenous self-administration of amphetamine. In this report, we examined whether these high-responder (HR) rats would develop place-preference conditioning with cocaine more readily than low-responder (LR) rats. Neither group of rats developed conditioned place preference for cocaine, 2.5 mg/kg, intraperitoneally (IP). Both groups of rats developed conditioned place preference for cocaine, 5.0 and 15 mg/kg, IP. However, we could not find any evidence of enhanced conditioning in the HR rats. HR rats did show a greater locomotor response to cocaine, 15 mg/kg, IP, and the locomotor response of HR and LR rats to cocaine correlated with their response to a novel environment. We conclude that using the place-preference procedure, HR and LR rats do not differ in the rewarding effect of cocaine.