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Anesth Analg 2002;95:915-919 © 2002 International Anesthesia Research Society
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Abstract |
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There is growing evidence that propofol acts on affective and reward processes. We designed this study to assess the effect of propofol on the concentration of dopamine in the nucleus accumbens, a main component of the mesolimbic system. The concentration of dopamine in the nucleus accumbens was assessed by using in vivo brain microdialysis in freely moving rats. A microdialysis probe was placed within guide cannulae previously placed during stereotaxic surgery. Fluid was perfused through the probe, and samples were collected every 20 min for measuring concentrations by high-pressure liquid chromatography. All rats served as their own controls and were randomized to four different doses of propofol, injected intraperitoneally: 0, 9, 60, or 100 mg/kg, according to a within design. Compared with the baseline value, dopamine concentration was decreased at the smallest dose of 9 mg/kg, whereas concentration was largely increased at the subanesthetic (60 mg/kg) and anesthetic (100 mg/kg) doses. This increase was of the same magnitude (+90%) for subanesthetic and anesthetic doses but was more prolonged at the anesthetic dose. Data show that only subanesthetic and anesthetic doses of propofol increase the concentration of dopamine in the nucleus accumbens, as previously described with drugs of potential abuse.
IMPLICATIONS: Depending on the dose, propofol either increased or decreased the concentration of dopamine in the nucleus accumbens, as assessed during microdialysis in freely moving rats. Only large doses which display a pharmacological profile, such as propofol, may show promise.
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Introduction |
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There is growing evidence that propofol may interact with mood states. Patients report pleasant effects on awakening from propofol anesthesia, including elation and euphoria (1). Under blinded conditions, some volunteers have associated subanesthetic doses of propofol with a general sensation of well-being (2,3). One article described the case of an anesthesiologist who initially self-administered propofol to relieve stress but later on became psychologically dependent on it (4). In rats, propofol induces a pleasant affective state in the place-conditioning paradigm, at subanesthetic doses as well as at recovery from propofol anesthesia (5,6). It is important to note that propofol was found to be self-administered by rats at subanesthetic doses (7). Taken together, these results largely emphasize that propofol may have potential for abuse. However, the mechanisms by which propofol acts on reward-related processes remain unclear (8).
Drugs of abuse displaying both affective and rewarding properties have supposedly produced their effects by a common action on the mesolimbic system (9,10). Actually, opiates, cocaine, and amphetamines act directly on the mesolimbic system, leading to the release of dopamine in one of its main components, the nucleus accumbens, which receives a large dopaminergic input from the ventral tegmental area. Whatever their pharmacological profile, the common final mechanism of all these drugs appears to be an increase of the concentration of dopamine in the nucleus accumbens (11).
The aim of this study was to determine to what extent the administration of propofol could modify the concentration of dopamine in the nucleus accumbens. The putative effect of nonanesthetic and anesthetic doses of propofol was assessed by using in vivo microdialysis in freely moving rats.
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Methods |
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All procedures involving animals and their care conformed to institutional guidelines, which comply with the European Communities Council Directive of November 24, 1986 (86/609/EEC), and the National Council Directive of October 19, 1987 (87848, Ministère de l’Agriculture et de la Forêt, Service Vétérinaire de la Santé et de la Protection Animales). All efforts were made to minimize animal suffering and reduce the number of animals used.
Male Long-Evans rats (Center d’Elevage Janvier, Le Genest-St.-Isle, France) that weighed 320–380 g were housed one per cage in a colony room maintained on a 12:12-h light/dark cycle (lights on at 7:00 AM) with food and water provided ad libitum. Propofol (10 mg/mL; Diprivan; Zeneca, Paris, France) was prepared immediately before use and injected intraperitoneally (IP). The IP administration was chosen because of easy administration and reliability. Propofol IP produces behavioral effects within approximatively 5–10 min after administration that last 60–90 min (5,12). The effects of propofol were determined at 3 different doses administered IP: 9, 60, and 100 mg/kg. Intralipids (10 mg/mL; Braun Medical, Paris, France) were used as control and called 0 mg/mL.
The study was performed according to a within design. The effects of propofol (0, 9, 60, and 100 mg/kg) on the extracellular concentrations of dopamine were studied in four randomized experiments (at 1-day intervals) in three animals previously implanted with a guide cannulae 2 mm above the nucleus accumbens. On the samples obtained from microdialysis, we assessed the concentration of two major metabolites of dopamine—3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (4-hydroxy-3-methyphenylacetic acid; HVA)—but only for the doses 9 and 100 mg/kg. After the experiment, each animal was killed with an overdose of pentobarbitone, and the brain was dissected to verify probe placement.
Animals were anesthetized with 150 mg/kg of ketamine, and a siliconized guide cannula was randomly (left/right) stereotaxically implanted into the nucleus accumbens shell region at the following coordinates with regard to the bregma (flat skull position; incisor bar, -3.3): 1.8 mm anterior, 1.3 mm lateral, and 5.4 mm ventral to the cortical surface (13), at least 2 days before the microdialysis experiment.
The microdialysis probe (CMA12; Carnegie Medicine, Stockholm, Sweden) was positioned within the guide cannulae into the nucleus accumbens (7.4 mm ventral to the cortical surface). A solution (147 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 4.0 mM KCl) was perfused through the probe by using a microinfusion pump at a flow rate of 1 µL/min. Samples were collected every 20 min (CMA140). A minimum of seven samples were collected to establish baseline neurotransmitter activity before drug administration.
The dialysates were assayed for dopamine, DOPAC, and HVA by high-pressure liquid chromatography with electrochemical detection according to the method of Kontur et al. (14) with several modifications previously described (15). The high-pressure liquid chromatography system consisted of a Hypersil C18-ODS column (length, 25 cm; diameter, 4.6 cm; particle size, 5 µm; Biochrom, France) and an electrochemical transducer with a glassy carbon electrode set at 650 mV. The mobile phase (flow rate, 1.2 mL/min) consisted of 0.1 M NaH2PO4 and 0.1 mM disodium EDTA (pH 4.85) in double-distilled water with methanol added to a final concentration of 6%. The system was calibrated by injection of various amounts (0.2 nmol to 20 fmol) of standard solutions containing dopamine, DOPAC, HVA, and 5 pmol of internal standard. The whole dialysate (20 µL) of each sample was injected onto the column, and the peak identification was performed by comparison of retention times with regard to calibration solutions.
The measurements of the concentration of DOPAC and HVA may vary largely with time after a few days of microdialysis experiments (16). This is why the data obtained on these metabolites were analyzed only if the 7 samples used to determine the baseline neurotransmitter activity did not vary more than ±15%.
The seven samples obtained before any treatment provided basal dopamine, DOPAC, and HVA values. Results are expressed as the mean (SEM) percentage of basal value. At each dose, the significance of differences between mean values was determined by analysis of variance with repeated measures, followed by the Newman-Keuls test to locate significant differences from the basal value. The significance of differences between the peak values of dopamine obtained 60 min after the administration of propofol 0, 9, 60, and 100 mg/kg was determined with analysis of variance for the repeated measure, followed by a Scheffé F test for multiple comparisons (three comparisons). The 
level was set at 0.05 to achieve statistical significance.
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Results |
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Basal values (mean = 100% ± SEM) of dopamine concentration (mean of 7 samples obtained before treatment) were 659 ± 42, 775 ± 100, 585 ± 63, and 870 ± 84 fmol/20-µL sample for 0, 9, 60, and 100 mg/kg, respectively ( Fig. 1). Propofol modulated the dopamine concentrations. At the 9 mg/kg dosage, it caused a significant decrease of dopamine concentration that reached statistical significance 60 min after propofol injection when compared with the basal value (P < 0.05) and when compared with the percentage change obtained with intralipids (P < 0.05). Conversely, larger doses of propofol (60 and 100 mg/kg) significantly increased the dopamine concentration. At the dosage 60 mg/kg, the percentage change of dopamine concentration was significantly increased in the 20- to 80-min period after the injection (all P < 0.05). At the dosage 100 mg/kg, the change of dopamine concentration was significantly increased in the 20- to 120-min period after the injection (all P < 0.05). The peak values obtained 60 min after the injection of propofol 60 or 100 mg/kg were significantly increased compared with the percentage change obtained with intralipids (all P < 0.05).
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The basal values (mean = 100% ± SEM) of DOPAC concentration (mean of 7 samples obtained before treatment) were 15.80 ± 0.68 and 9.01 ± 0.80 pmol/20-µL sample for 9 and 100 mg/kg, respectively (Fig. 2). We observed no significant effect of propofol (9 or 100 mg/kg) on the concentration of DOPAC. The basal values (mean = 100% ± SEM) of HVA concentration (mean of 7 samples obtained before treatment) were 25.21 ± 1.62 and 7.78 ± 0.93 pmol/20-µL sample for 9 and 100 mg/kg, respectively. Propofol 9 mg/kg had no significant effect, whereas propofol 100 mg/kg significantly modulated the concentration of HVA. At the dosage 100 mg/kg, the change of HVA concentration was statistically increased 100 min after the injection (P < 0.05). The histological assessment of probe placement in each of the three animals confirmed the position of the probe in the shell part of the nucleus accumbens.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We found that the administration of propofol dose-dependently modulated the concentration of dopamine in the nucleus accumbens. The extracellular dopamine measurement was actually reduced (approximately 40%) at a nonanesthetic dose (9 mg/kg), whereas larger subanesthetic (60 mg/kg) and anesthetic (100 mg/kg) doses produced an increase comparable in magnitude (approximately 90%) but more prolonged in the case of the anesthetic dose. Thus it appears that the effects of propofol on the dopaminergic neurotransmission in the nucleus accumbens differ according to the dose.
Data obtained on dopamine concentrations in the nucleus accumbens appear to parallel the behavioral effects of propofol on affective states. The effects of propofol were determined at three doses for which we have shown different effects on affect in the same strain of rats. Indeed, we previously showed that propofol at the subanesthetic dose (60 mg/kg) or at recovery from an anesthetic dose (100 mg/kg) induced a pleasant affective state (5) in the place-conditioning paradigm (i.e., animals exhibit a large preference for a distinctive cage in which they received the drug) (17). Similarly, LeSage et al. (7) found in rats that propofol had strong reinforcing properties at a subanesthetic dose. In this study, we observed that only large doses of propofol, responsible for either a subanesthetic or an anesthetic state, increased the concentration of dopamine in the nucleus accumbens. Conversely, we previously demonstrated that the smallest dose (9 mg/kg), devoid of locomotor impairment, exhibited an anxiolytic effect on an anxiogenic situation (18) but did not induce a modification of affective state in the place-conditioning paradigm in rats (i.e., animals exhibited no preference for a distinctive cage in which they received a small dose of propofol) (5). At this small dose, we observed a decrease in dopamine concentration in the nucleus accumbens. Our results suggest that large doses of propofol increasing the dopamine concentration in the nucleus accumbens could sustain their behavioral effects on both affect and reward. However, one could argue that the propofol effects on dopamine concentration could be a non-region-specific effect at a large dose. This is unlikely, because an in vivo microdialysis experiment in rats showed that an anesthetic dose of propofol decreased the concentration of dopamine in another brain structure, the striatum (19).
Propofol is chemically unrelated to other anesthetics but has a potent agonistic effect on 
-aminobutyric acid (GABA)ergic neurotransmission, although it is different from those caused by barbiturates or benzodiazepines (20,21). GABA-releasing neurons exert an inhibitory control on dopaminergic neurons originating in the ventral tegmental area and projecting to the nucleus accumbens (22). GABA-releasing neurons in the nucleus accumbens also modulate the dopamine-releasing neurons in the ventral tegmental area (23). However, propofol had no effect on the nucleus accumbens concentration of GABA assessed by microdialysis in vivo (24). In the nucleus accumbens, local applications of a large dose of propofol modulated the electrically stimulated dopamine release from nucleus accumbens rat slices, but this effect was independent of any effect on dopamine D2, GABA, and N-methyl-D-aspartate receptors (8). Our results obtained in vivo emphasize and extend these previous results, because large doses of propofol increased the extracellular concentration of dopamine. The largest dose of propofol (100 mg/kg) induced limited changes in the concentration of the metabolites DOPAC and HVA. We suggest that propofol might inhibit the reuptake of dopamine. Such a hypothesis is in agreement with previous findings on brain synaptosomes from rats. Indeed, propofol inhibited the uptake of [H3]-dopamine on this in vitro preparation (25). However, our results cannot distinguish clearly whether propofol presynaptically stimulated the release of dopamine or whether it inhibited the reuptake of dopamine from the synaptic space, thus leading to an increase of the concentration of extracellular dopamine.
The affective and reinforcing properties of drugs of abuse, such as opioids, psychostimulants, and cocaine, appear to derive from their ability to increase the concentration of dopamine in the nucleus accumbens (26). Because propofol exhibits both pleasant and reinforcing properties, it may have a potential for abuse. We here provide evidence that an in vivo administration of propofol results in a large change of the dopamine concentration in the nucleus accumbens. However, only subanesthetic/anesthetic doses of propofol increased the concentration of dopamine and therefore were exhibiting a pharmacological profile similar to that observed with drugs of abuse. This was not the case for the small anxiolytic dose of propofol. It appears that only large doses of propofol exhibit behavioral and neurochemical effects that might be compatible with a potential for abuse.
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Acknowledgments |
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Supported by the Ministère de l’Education Nationale et de la Recherche Technologique-Institut National Santé et de la Recherche Médicale (Soutien aux Sciences du Vivant au sein des IFR 1999) and by Université Louis Pasteur (Appel à Projets Exceptionnels 2001).
The authors thanks Jean Zwiller for his helpful comments with the preparation of the manuscript.
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Footnotes |
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Presented in part at the meeting of the European Society of Anesthesiologists, Nice, France, April 6, 2002.
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