Concurrent pharmacological MRI and in situ microdialysis of cocaine reveal a complex relationship between the central hemodynamic response and local dopamine concentration (original) (raw)
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The mechanisms underlying the signal changes observed with pharmacological magnetic resonance imaging (phMRI) remain to be fully elucidated. In this study, we obtained microdialysis samples in situ at 5-min intervals during phMRI experiments using a blood pool contrast agent to correlate relative cerebral blood volume (rCBV) changes with changes in dopamine and cocaine concentrations following acute cocaine challenge (0.5 mg/kg iv) in the rat over a duration of 30 min. Three brain areas were investigated: the dorsal striatum (n = 8), the medial prefrontal cortex (mPFC; n = 5), and the primary motor cortex (n = 8). In the striatum and mPFC groups, cocaine and dopamine temporal profiles were tightly correlated, peaking during the first 5-min period postinjection, then rapidly decreasing. However, the local rCBV changes were uncorrelated and exhibited broader temporal profiles than those of cocaine and dopamine, attaining maximal response 5 -10 min later. This demonstrates that direct vasoactivity of dopamine is not the dominant component of the hemodynamic response in these regions. In the motor cortex group, microdialysis revealed no local change in dopamine in any of the animals, despite large local cocaine increase and strong rCBV response, indicating that the central hemodynamic response following acute iv cocaine challenge is not driven directly by local dopamine changes in the motor cortex. The combination of phMRI and in situ microdialysis promises to be of great value in elucidating the relationship between the phMRI response to psychoactive drugs and underlying neurochemical changes. D 2004 Elsevier Inc. All rights reserved.
Journal of Neurochemistry, 1988
A sensitive and rapid HPLC-UV method for in vivo determinations of cocaine levels in extracellular fluid of specific brain regions and plasma is described. Free drug levels resulting from intravenous administration of cocaine were sampled using in vivo microdialysis probes simultaneously located in the jugular vein, nucleus accumbens, and anteromedial caudate-putamen of halothane-anesthetized rats. In a separate group of animals, the influence of cocaine on extracellular dopamine concentrations in the anteromedial caudate-putamen was also assessed. The time dependences of changes in cocaine concentration in each of the above regions were congruent, and peak concentrations were reached 10 min after the drug was administered. The half-lives of cocaine in the blood, nucleus accumbens, and anteromedial caudate-putamen were estimated to be 3 1.5, 29.1, and 21.4 min, respectively. A repeated injection of cocaine, given 90 min later, produced a maximal cocaine level and pharmacokinetic profile that were indistinguishable from those of the initial infusion. Cocaine was concentrated to a greater extent in brain than in blood, a feature consistent with the action of a lipophilic drug. In addition, extracellular dopamine levels measured in the anteromedial caudate-putamen following cocaine infusions closely mirrored those of cocaine itself. The ability to measure the free concentration of drugs by microdialysis should be applicable to a wide range of in vivo pharmacological studies.
Psychopharmacology, 2000
Rationale: The behavioral effects of cocaine have been linked to brain dopamine systems. Extending the findings to neurochemical studies in the squirrel monkey would enhance our understanding of the behavioral pharmacology of cocaine in nonhuman primates. Objectives: The present studies characterized the effects of cocaine and the selective dopamine uptake inhibitor GBR 12909 on extracellular dopamine in the caudate nucleus of awake squirrel monkeys through microdialysis experiments. Methods: Guide cannulae were implanted in the caudate nucleus of four monkeys using a stereotaxic apparatus and coordinates obtained from a standard squirrel monkey brain atlas. Accurate probe placement was confirmed in all subjects with magnetic resonance imaging. Results: Collectively, the results support the feasibility of a repeated-measures design. Stability of tissue integrity after repeated probe insertion was supported by measurement of consistent basal levels of dopamine and its metabolites across several experiments, observation of potassium-induced dopamine release and absence of significant glial proliferation as assessed by GFAP (glial fibrillary acidic protein) immunochemistry. Moreover, peak drug effects and time-course of action were similar when multiple probes were positioned in the same anatomical site over several experiments. Cocaine (1.0 mg/kg i.m.) and GBR 12909 (3.0 mg/kg i.m.) elevated extracellular dopamine to approximately 300% of basal levels, but GBR 12909 produced a slower, more sustained elevation than cocaine. Conclusions: The results validate the use of microdialysis in awake primates using repeated sampling of the same anatomical site and demonstrate orderly changes in extracellular dopamine following administration of dopamine uptake inhibitors.
Psychopharmacology, 1991
Cocaine and two other local anesthetics were applied directly into the nucleus accumbens for 20 min by diffusion from a 4 mm microdialysis probe in freely moving rats. Cocaine (7.3 mM) increased the extracellular concentration of dopamine (DA). Equimolar procaine did also, but was not as potent as cocaine. Equimolar lidocaine had no effect. The concentration of these drugs outside the probe as measured by capillary electrophoresis in vitro was about 28% of that inside the probe, i.e. 72% remained inside. However, an in vivo test showed that about 53% cocaine and procaine, and 37% lidocaine remained in the perfusion fluid after passing through a probe inserted in the brain. This suggests that in vivo about 68 nmol cocaine diffused into the nucleus accumbens (NAC) during the 20 min. Five conclusions are drawn: (1) this confirms our earlier finding that local injection of cocaine increases extracellular DA, but in this case the cocaine was infused via the probe without disturbing the animal; (2) the action of cocaine on dopamine terminals in the accumbens is independent of local anesthesia; (3) procaine may enhance mood by a cocaine-like effect; (4) capillary electrophoresis has potential for measuring cocaine levels in small samples and (5) in vitro calibrations are of limited value to evaluate in vivo performance of microdialysis probes.
Journal of Pharmacological and Toxicological Methods, 2015
Dopamine Heroin Microdialysis Ultra high performance liquid chromatography tandem mass spectrometry UHPLC-MS/MS Introduction: An increase in striatal dopamine is considered essential for the rewarding and reinforcing effects of drugs of abuse. We have developed and validated an ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for the analysis of dopamine in rat brain extracellular fluid (ECF) sampled with microdialysis. The method was applied to monitor changes in dopamine concentrations over time after an intravenous bolus injection of heroin. Methods: Dopamine and dopamine-d3 were analyzed using a 2.1 × 100 mm Aquity T3 column, 1.7 μm particle size, with a formic acid and methanol gradient. The run time of the method was 2.5 min including equilibration time. Results: The method had an LOQ of 0.15 ng/mL, which equals 0.55 pg on column. The calibration curves were linear in the tested area of 0.15 to 16 ng/mL. Inter-assay coefficients of variation varied between 5-17%, with an accuracy expressed as bias of − 10 to 5%. The intra-assay coefficients of variation varied between 9-15%, with an accuracy of −3-7%. Discussion: Heroin metabolism is very rapid. Sampling intervals of only 2 min were thus required to obtain an adequate number of samples of dopamine analysis accompanying the concentration-time profile of opioids in the brain. Applying a flow of 2 μL/min, 4 μL of dialysate were sampled at 2 min intervals, in 7 μL internal standard. The injection volume onto the UPLC column was 10 μL. Analyses of microdialysate samples from a rat given heroin i.v. showed that it was possible to measure baseline levels and rapid changes in dopamine concentrations with very short sampling periods.
Synapse, 1989
The effects of cocaine on dopamine (DA) neurotransmission were evaluated by in vivo microdialysis in the striatum of halothane-anesthetized rats. Intravenous cocaine produced a dose-dependent, transient increase of the extracellular concentration of DA, with a peak response within 10 min and a return to control level by 30 min. The sharp DA response pattern was abolished in a calcium-free environment, indicating that DA release enhanced by cocaine originates from a vesicular storage pool. Continuous administration of cocaine (via the perfusion medium) directly into the nigrostriatal terminal region also produced a dose-dependent increase in DA release. Low concentrations M) of cocaine maintained DA at a constant stable level, consistent with the effects observed after potent DA uptake inhibitory agents (e.g., nomifensine and Lu19005). However, continuous exposure to high concentrations (2 lop4 M) induced a transient elevation of DA within 20 min, following which DA decreased to a stable but high level; this decrease might reflect tolerance to the effect of cocaine. Administration of cocaine (lop3 M) into the substantia nigra did not change striatal DA release. The local striatal action of cocaine was less potent than amphetamine in elevating DA overflow and in its effect on DA metabolism. These findings suggest that the fast transient enhancement of DA by intravenous cocaine is most likely a consequence of the transient presence of cocaine in the terminal region, correlating with the well-known rapid pharmacokinetic and behavioral aspects of the drug.
Brain microdialysis studies on the control of dopamine release and metabolism in vivo
Journal of Neuroscience Methods, 1990
This paper studies the actions of drugs known to release dopamine from brain tissue. Most of the theoretical background to this work has been developed in experiments on shces of brain in vitro but using in vivo microdialysis we have elaborated and extended the ideas from the in vitro experiments and been able to make a direct comparison of the mechanism of action and source of dopamine released by 5 different manipulations. The mode of action of tyramine, amphetamine, veratrine, ouabain and potassium is discussed in the light of the computer model of the nerve terminal published by Justice et al. (1988). The data may lend themselves to such an interpretation, but they could be compatible with several other models.
Real-time measurement of dopamine fluctuations after cocaine in the brain of behaving rats
Proceedings of the National Academy of Sciences of the United States of America, 2005
Electrodes. Glass-encased carbon-fiber microelectrodes were constructed as described . Individual 5-m-diameter carbon fibers (T-650 Thornell, Amoco Corp., Greenville, SC) were aspirated into glass capillaries (A-M Systems, Carlsborg, WA) and then pulled in a vertical micropipette puller (Narishige, Tokyo). The microelectrode was then inspected under an optical microscope. Electrodes having a good seal between the glass and the carbon fiber were cut with a scalpel to a length of 50-100 m. All others were discarded. Before use, electrodes were soaked in 2-propanol purified with Norit A-activated carbon (ICN, Costa Mesa, CA) for at least 10 min (20). The reference electrodes were chloridized silver wires (0.5 mm diameter; Sigma-Aldrich) in 0.1 M HCl. All potentials reported are versus Ag͞AgCl. Data Acquisition. Voltammetric recordings were made with a triangular waveform (Ϫ0.4 to 1.3 V versus Ag͞AgCl, 400 V͞s) repeated every 100 ms. The electrode was held at Ϫ0.4 V between scans. The waveform was generated and the voltam-
Journal of Neurochemistry, 1993
Cocaethylene is a pharmacologically active metabolite resulting from concurrent cocaine and ethanol consumption. The effects of cocaine and cocaethylene on extracellular levels of dopamine in the nucleus accumbens, and serotonin in the striatum were characterized in vivo in the anesthetized rat. Both intravenous (3 pmollkg) and intraperitoneal (44 pmol/kg) routes of administration were used. In addition to monitoring neurotransmitter levels, microdialysate levels of cocaine and cocaethylene were determined at 4-min intervals after intravenous administration, and at 20-min intervals after intraperitoneal administration. Extracellular levels of dopamine in the nucleus accumbens were increased to -400% ofpreinjection value by both cocaine and cocaethylene when administered intravenously. Cocaine caused a significant increase of striatal serotonin to 200% preinjection value, whereas cocaethylene had no effect. Brain levels of cocaine and cocaethylene after intravenous administration did not differ. After intraperitoneal administration, extracellular levels of dopamine in the nucleus accumbens were increased to 400% of preinjection levels by cocaine, but were only increased to 200% of preinjection levels by cocaethylene, the difference being statistically significant. Serotonin levels were increased to 360% of preinjection levels by cocaine, but only to 175% of preinjection value by cocaethylene. Levels of cocaine attained in brain were significantly higher than those for cocaethylene, suggesting pharmacokinetic differences with the intraperitoneal route. These results confirm in vivo that cocaethylene is more selective in its actions than cocaine with respect to dopamine and serotonin uptake. In addition, route-dependent differences in attainment of brain drug levels have been observed that may impact on interpretations of the relative potency of the reinforcement value of these compounds. Key Words: Cocaine-Cocaethylene-Dopamine -Serotonin-Microdialysis-Pharmacokinetics.