Effects of cocaine on release and uptake of dopamine in vivo: differentiation by mathematical modeling.

Although considerable effort has been invested trying to distinguish between the effects of cocaine on dopamine (DA) uptake and release in both in vitro and in vivo experiments, disagreement over the specific actions of cocaine remains. The results obtained by combining experimental extracellular DA data with a mathematical model of the dopaminergic neuron allow examination of the cocaine uptake inhibition/release question. The extracellular DA concentration profile observed following a 30 mg/kg IP cocaine injection can be modeled if both pre- and postsynaptic uptake are competitively inhibited by cocaine with or without an enhanced DA release effect. However, if cocaine elicits enhanced DA release, modeling predicts a 40% increase over basal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and a 30% increase in homovanillic acid (HVA) at 60 minutes following a 30 mg/kg IP cocaine injection. Reported DOPAC and HVA data for similar cocaine doses indicate little change in either DOPAC or HVA. These data agree best with modeled metabolite predictions for little or no cocaine-enhanced DA release.

Dopamine release at behaviorally relevant parameters of nigrostriatal stimulation: effects of current and frequency.

Released dopamine was monitored voltammetrically in the rat striatum in response to electrical stimulation of the nigrostriatal bundle. Stimulation parameters encompassed those typically used in behavioral studies. Dopamine released during intracranial self-stimulation (ICSS)-like stimulation reached a maximum within the first minute of stimulation, then rapidly decreased. The pattern of release obtained with continuous stimulation as a function of current and frequency supports the view that as the stimulation current is increased, a greater number of neurons are stimulated, while increasing the frequency of stimulation results in a fixed population of neurons being stimulated more intensely. Computer modeling of stimulated release from a population of dopaminergic nerve terminals was used to interpret effects of current and frequency and to predict ICSS release patterns as a function of schedule of reinforcement.

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.

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.