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NEUROPHARMACOLOGY
Departments of Anesthesiology (K.-Y.L., C.X., M.X., E.D., J.-H.Y.) and Physiology and Pharmacology (J.-H.Y.), University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey
Received for publication
October 2, 2007
Accepted
January 22, 2008.
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Abstract |
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-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. We observed that propofol increased the amplitude but decreased the paired-pulse ratio of EPSCs evoked by stimulation in the absence and the presence of gabazine (SR 95531), a GABAA receptor antagonist. Moreover, the propofol-induced facilitation of EPSCs was mimicked by 6-phenyl-4-azabicyclo[5.4.0]undeca-7,9,11-triene-9,10-diol (SKF38393), an agonist of dopamine D1 receptor, and by 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12935), a dopamine reuptake inhibitor, but blocked by (±)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SKF83566), a D1 antagonist, or by depleting dopamine stores with reserpine. Finally, 1 nM propofol increased the spontaneous discharge rate of dopamine neurons. These findings suggest that propofol at minute concentrations enhances presynaptic D1 receptor-mediated facilitation of glutamatergic synaptic transmission and the excitability of VTA dopamine neurons, probably by increasing extracellular dopamine levels. These changes in synaptic plasticity in the VTA, an addiction-related brain area might contribute to the development of propofol abuse and the increased susceptibility to addiction of other drugs.
). A recently proposed hypothesis on second-hand exposure might explain this trend (McAuliffe et al., 2006). Chronic exposure to low levels of aerosolized i.v.-administered drugs, such as propofol, can potentially lead to a sensitization and later abuse of drugs (McAuliffe et al., 2006). However, it is not clear how this exposure induces addiction.
Propofol is the most widely used i.v. drug for induction of general anesthesia. Although propofol has not traditionally been considered as a drug of abuse, growing evidence suggests that it may have an abuse potential. Patients anesthetized with propofol report experienced euphoria during recovery (Gepts et al., 1985). Besides medical use, propofol is abused for recreational purpose. Nine human cases of abuse and dependence in anesthesiologists, nurses, and laypersons have been reported since 1992. Death occurred in four among these nine cases. Note that this number is certainly not representative of propofol abuse, as only serious cases have been reported (Roussin et al., 2007). According to a recent survey, propofol abuse in academic anesthesiology has probably increased over the past 10 years. Eighteen percent of the anesthesiology programs in the United States have experienced one or more cases of propofol abuse or diversion in the past 10 years, and this percentage is possibly an underestimate because the challenges of detecting propofol abuse, as propofol is not a drug routinely tested for on urine (Wischmeyer et al., 2007). Propofol abuse potential has also been supported by studies in human volunteers. Under blind conditions, 50% of the volunteers (6 or 12) chose propofol over placebo, and four of those six subjects chose propofol exclusively across three repeated trials (Zacny et al., 1993a,b). Propofol abuse potential has also been supported by animal studies. Propofol is self-administered by baboons (Weerts et al., 1999) and rats (LeSage et al., 2000). Conditioned-place preference for propofol has been established in rats (Pain et al., 1996).
The mesolimbic dopamine system is a critically important component of the neuronal circuits mediating addiction. This system originates in the ventral tegmental area (VTA) and terminates in the nucleus accumbens (NAcc). All drugs of abuse enhance the activity of this dopamine circuit of reward (Nestler, 2005). In previous rat studies, propofol has been found to alter dopamine levels in the NAcc (Pain et al., 2002), suggesting that propofol may modify the activity of VTA dopamine neurons. However, the cellular mechanisms of the effects of propofol remain to be determined. Glutamatergic inputs to the VTA are the primary excitatory control of dopamine neurons. The purpose of current investigation was to determine whether minute concentrations of propofol can alter glutamatergic transmission and dopamine neuronal activity.
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Materials and Methods |
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Slice Preparation. The midbrain slices were prepared as described previously (Ye et al., 2004). In brief, rats were anesthetized and then sacrificed by decapitation. Coronal midbrain slices (300 µm in thickness) were cut using a VF-200 Slicer (Precisionary Instruments, Greenville, NC). Slices were prepared in ice-cold glycerol-based artificial cerebrospinal fluid containing 250 mM glycerol, 2.5 mM KCl, 1.2 mM NaH2PO4, 1.2 mM MgCl2, 2.4 mM CaCl2, 26 mM NaHCO3, and 11 mM glucose, and they were saturated with 95% O2, 5% CO2 (carbogen). Slices (two/animal) were allowed to recover for at least 1 h in a holding chamber at 32°C in carbogen-saturated regular ACSF, which has the same composition as glycerol-based artificial cerebrospinal fluid, except that glycerol was replaced by 125 mM NaCl.
Electrophysiological Recording. Electrical signals were obtained in whole-cell patch-clamp configurations with MultiClamp 700A amplifiers (Molecular Devices, Union City, CA), a Digidata 1322A A/D converter (Molecular Devices), and pCLAMP 9.2 software (Molecular Devices). Data were filtered at 1 kHz, and they were sampled at 5 kHz. Neurons were voltage clamped at–70 mV to record -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs). Current-clamp mode was used to record spontaneous firing. The patch electrodes had a resistance of 4 to 6M
when filled with a pipette solution containing 135 mM potassium gluconate, 5 mM KCl, 2 mM MgCl2, 10 mM HEPES, 2 mM Mg ATP, and 0.2 mM GTP. The pH of the pipette solution was adjusted to 7.2 with Tris-base. The experiments presented on Fig. 9 were done with a CsF-based pipette solution, which has the same composition as the potassium gluconate-based solution, except that potassium gluconate was replaced by 135 mM CsF. A single slice was transferred into a 0.4-ml recording chamber, and it was stabilized by a round platinum ring. Throughout the experiments, the bath was continually perfused with carbogenated ACSF (1.5–2.0 ml/min). Cells were visualized with an upright microscope (E600FN; Nikon, Tokyo, Japan) and near-infrared illumination. To evoke monosynaptic EPSCs (eEPSCs), the tip of a glass-stimulating pipette filled with 1 M NaCl was placed 50 to 100 µm from the recorded neuron. Electrical stimuli (100–200 µs in duration) were applied at the rate of 0.05 Hz. Near the start of recording, an input/output curve was obtained. The stimulation was set to 20 to 30% of maximum, an intensity that evoked stable responses with no failures. Paired eEPSCs were elicited with a pair of identical stimuli separated by an interval of 20 ms. The series resistance (15–30 M) or input resistance (300–500 M) was monitored throughout the whole-cell recording, and data were discarded if the resistance changed by more than 20%. All recordings were made at 32°C, maintained by an automatic temperature controller (Warner Instruments, Hamden, CT). In some experiments, brain slices were pretreated with 10 µM reserpine for 90 min at 32°C to deplete endogenous monoamines (including dopamine).
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-opioid receptor (Fig. 1, A and B). A previous study has showed that U69593
[GenBank]
induced postsynaptic hyperpolarization in a subset of tyrosine hydroxylase-staining positive neurons (Margolis et al., 2003). Moreover, a prominent voltage-sag (equivalent to the hyperpolarization current, Ih, recorded in voltage-clamp mode) recorded in response to a hyperpolarizing current pulse (–130 pA) (Fig. 1C) confirmed the identity of dopamine neurons. Prominent Ih is present in 
60% of VTA dopamine neurons, whereas VTA GABAergic neurons have no prominent Ih (Lacey et al., 1990; Johnson and North, 1992).
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Chemicals and Applications. The chemicals, including 2,6-diisopropylphenol (propofol), gabazine (SR 95531), 2,3-dihydroxy-6,7-dinitroquinoxaline (DNQX), tetrodotoxin (TTX), U69593
[GenBank]
, methyl-11,17-dimethoxy-18β-[(3,4,5-trimethoxybenzoyl) oxy]-3β, 20-yohimban-16β-carboxylate (reserpine), and CdCl2 were obtained from Sigma-Aldrich (St. Louis, MO). (±)-SKF 83566, SKF 38393, and GBR 12935 were from Tocris Cookson Inc. (Ellisville, MO). Drugs were added to the superfusate.
Data Analysis. sEPSCs and spontaneous firing were counted and analyzed using the MiniAnalysis program (Synaptosoft, Leonia, NJ). Spontaneous events (sEPSCs and mEPSCs) were screened automatically (5-pA amplitude threshold), checked visually, and accepted or rejected according to their rise and decay times. The frequency and amplitude of all events, during and after drug applications, were normalized to the mean of the values observed during the initial control period. Cumulative probability plots of the incidence of various interevent intervals and amplitudes, recorded in control conditions and during pharmacological manipulations from the same neuron, were analyzed with the Kolmogorov-Smirnov (K-S) test. For other plots, data obtained over a 1-to 2-min period at the peak of a drug response were normalized to the average values of sEPSC (or mEPSC) frequency and amplitude during the initial control period (1–2 min). Data were expressed as means ± S.E.M. The statistical significance of drug effects was assessed by a paired two-tailed t test. Values of p < 0.05 were considered significant.
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Propofol Facilitation of Spontaneous EPSCs Depends on Sodium and Calcium Channels. We next tested the effect of propofol on spontaneous EPSCs recorded in the presence of 10 µM gabazine and 1 µM TTX, a blocker of sodium channels. Application of 1 µM tetrodotoxin only slightly, albeit significantly, reduced the frequency of the spontaneous events (1.3 ± 0.3 Hz in control, 1.0 ± 0.5 Hz in 1 µM tetrodotoxin; n = 4, p < 0.05 by paired t test), but not their amplitude (18.1 ± 1.8 pA in control, 17.0 ± 1.9 pA in tetrodotoxin; n = 5, p = 0.22 by paired t test). In the presence of tetrodotoxin, 1 nM propofol did not significantly increase the frequency of the miniature EPSCs (by 9 ± 7%, n = 5, p = 0.27; Fig. 4C1). We also tested the effect of 100 µM cadmium, a nonselective blocker of voltage-gated calcium channels. The application of cadmium significantly reduced sEPSC frequency, by 58 ± 8% (2.0 ± 0.4 Hz in control, 0.8 ± 0.2 Hz in cadmium; n = 4; p = 0.02 by paired t test), but not their amplitude (23.3 ± 4.0 pA in control, 24.2 ± 4.8 pA in cadmium; n = 4, p = 0.46 by paired t test). In the presence of cadmium, 1 nM propofol had no significant effect on sEPSC frequency (by 8.1 ± 20.6%, n = 4, p = 0.63; Fig. 4C2). These data indicate that propofol action depends on both tetrodotoxin-sensitive sodium channels and voltage-gated calcium channels.
Propofol Facilitation of sEPSCs Is Eliminated by Dopamine D1R Antagonist. Dopamine D1Rs are expressed on VTA glutamatergic axons (Lu et al., 1997). Previous in vivo study has shown that activation of D1Rs increases glutamate levels in the VTA (Kalivas and Duffy, 1995). To test a possible involvement of D1Rs in propofol-induced facilitation of glutamatergic transmission, we compared the effects of propofol on sEPSC frequency in the absence and the presence of 10 µM SKF 83566, a D1R antagonist. All sEPSCs were recorded in the presence of 10 µM gabazine. As illustrated in Fig. 5, although ineffective when applied alone, 10 µM SKF 83566 suppressed the effects of 1 nM propofol. On five cells, 1 nM propofol slightly decreased sEPSC frequency by 0.3 ± 4.0% (p = 0.95; Fig. 5C1) and amplitude by 12 ± 5% (p = 0.06; Fig. 5C2) in the presence of 10 µM SKF 83566. These results strongly suggest that D1Rs are an essential element in the mechanism of propofol-induced facilitation of glutamatergic transmission.
D1R Agonist Mimics Propofol-Induced Facilitation of sEPSCs. To further test the involvement of D1Rs, we applied D1R agonist SKF 38393 to the VTA in slices. As illustrated in Fig. 6, 10 nM SKF 38393 significantly increased sEPSC frequency, thus shortening intervals between successive sEPSCs (K-S test, p < 0.01; Fig. 6B). The effect of SKF 38393 was reversible. The sEPSC frequency soon returned to its control level after washout (Fig. 6C). As illustrated in Fig. 6D, the effects of SKF 38393 on sEPSC frequency were dose-dependent: 10, 100, 1000, and 3000 nM SKF 38393 increased sEPSC frequency by 45 ± 8% (n = 10, p < 0.01), 57 ± 19% (n = 5, p = 0.01), 101 ± 22% (n = 6, p < 0.007), and 96 ± 16% (n = 5, p = 0.004), respectively. No corresponding changes in sEPSC amplitude were produced by 10, 100, 1000, and 3000 nM SKF 38393: –2 ± 7% (n = 10, p = 0.44), 6 ± 12% (n = 5, p = 0.88), –0.1 ± 10% (n = 6, p = 0.5), and –3 ± 8% (n = 5, p = 0.74), respectively. These results, which closely parallel the effects of propofol, provide additional evidence for the presence of functional D1Rs on glutamatergic terminals.
Dopamine Release Is Essential for Propofol-Induced Facilitation of eEPSCs. To determine whether dopamine release is necessary for propofol-induced facilitation of glutamatergic transmission, we applied propofol to slices in which dopamine was depleted by reserpine. As illustrated in Fig. 7, 1 nM propofol was ineffective when applied to slices pretreated for 90 min with 10 µM reserpine (Fig. 7A), and propofol influenced neither the amplitudes of eEPSCs (by –7 ± 15%; n = 5, p = 0.67) nor their paired-pulse ratio (by 10 ± 15%, from 1.4 ± 0.1 to 1.5 ± 0.1; n = 5, p = 0.7).
Propofol-Induced Facilitation of sEPSCs Is Mimicked by a Dopamine Reuptake Blocker. Another, perhaps more important mechanism is suggested by previous evidence that acute administration of propofol (i.p. injection) elevates extracellular dopamine levels (Pain et al., 2002). To elicit a rise in local dopamine levels in slices, we applied GBR 12935, a selective blocker of dopamine transporter. As illustrated in Fig. 8, A to C, 20 nM GBR 12935 significantly and reversibly increased the frequency of sEPSCs recorded in VTA dopamine neurons (by 55 ± 10%; n = 12, p = 0.002). Like propofol, GBR 12935 was ineffective in the presence of the D1R antagonist SKF 83566 at 10 µM (the sEPSC frequency changed by –7 ± 6%; n = 5, p = 0.16; Fig. 8, D–F). This finding shows that a rise in local dopamine levels also mimics the action of propofol.
Propofol at Minute Concentrations Enhances eEPSCs in the Absence of Gabazine. GABAA receptor is a major target of propofol (Krasowski et al., 1998; Orser et al., 1998). However, the above-mentioned experiments were conducted in the presence of gabazine, a GABAA receptor antagonist. To determine whether gabazine may alter the effect of propofol on EPSCs, we reexamined the effect of propofol on EPSCs in the absence of gabazine, using the CsF-based internal solution (see Materials and Methods) and at a VH of –60 mV. The postsynaptic responses to GABA or glycine were suppressed under these experimental conditions (Bormann et al., 1987), allowing us to monitor propofol effect on EPSC. As illustrated in Fig. 9A, the evoked postsynaptic currents recorded under these experimental conditions were completely blocked by 10 µM DNQX, indicating that they were the EPSCs mediated by AMPA receptors. Figure 9, B and C, illustrates that 1 nM propofol enhanced the amplitude of evoked EPSCs and reduced the PPR (EPSC2/EPSC1). These effects depend on the concentrations of propofol: 0.1, 0.3, 1, 3, and 1000 nM propofol increased the amplitude of evoked EPSCs (Fig. 9D1) by: 15 ± 7% (n = 4, p = 0.12), 30 ± 9% (n = 6, p = 0.02), 41 ± 6% (n = 5, p = 0.002), 27 ± 4% (n = 5, p = 0.003), and –16 ± 2% (n = 7, p < 0.001), respectively, and reduced the PPR (Fig. 9D2) by: 5 ± 2% (n = 4, p = 0.046), 19 ± 6% (n = 6, p = 0.03), 31 ± 7% (n = 5, p < 0.01), 21 ± 6% (n = 5, p = 0.02), and –15 ± 6% (n = 7, p = 0.05), respectively. Thus, propofol induces similar changes in EPSCs in the absence and the presence of gabazine.
Propofol (1 nM) Increases the Frequency of Spontaneous Firing of VTA Dopamine Neurons. Having established that minute concentrations of propofol facilitate glutamatergic transmission, we next assessed the physiological consequences of this action of propofol by examining the spontaneous firing of VTA dopamine neurons. As shown in Fig. 10, 1 nM propofol reversibly increased the frequency of spontaneous firing of VTA dopamine neurons in brain slices by 33 ± 7% (from 1.5 ± 0.3 Hz in control to 1.9 ± 0.4 Hz in propofol; n = 7, p = 0.005 by paired t test).
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; Orser et al., 1998), and it has generally inhibitory effects on the brain. Furthermore, this intriguing action of propofol is mediated by D1Rs in glutamate-releasing terminals on VTA dopamine neurons.
Although a recent study found propofol concentration in the expired breath of patients is close to that in the plasma (Takita et al., 2007), propofol concentration in the air of operating rooms has not been quantified. We speculate that it is very low and that the minute concentrations tested in current study coincide with the possibly very low concentrations of propofol in the air of operating rooms. Our finding may offer a plausible mechanism to the proposed hypothesis of second-hand exposure (McAuliffe et al., 2006). Because glutamatergic transmissions play a major role in mediating behavioral manifestations of drug abuse (Kalivas, 1993), propofol-induced enhancement of glutamatergic transmission in the VTA could be an important aspect underlying the development of propofol abuse.
Several lines of evidence indicate that propofol acts presynaptically to enhance glutamatergic transmission. Propofol increased sEPSC frequency, but it had no effect on the amplitude of sEPSCs and mEPSCs. Propofol enhanced the amplitude of stimulation-evoked EPSCs and decreased their paired-pulse ratio. All these effects point to a presynaptic mechanism of propofol action.
Dopamine receptors, including both the D2 family (in particular D2R) (Blum et al., 1990) and D1R are associated with drug dependence and abuse. For example, administration of D1R antagonist (Liu and Weiss, 2002) or disruption of D1R gene expression (El-Ghundi et al., 1998) prevents or attenuates alcohol-seeking behavior. Activation of D1R can increase glutamatergic transmission (Kalivas and Duffy, 1995). Consistent with this report, in the current investigation, SKF 38393, a D1R agonist, dose-dependently increased the frequencies of sEPSCs without affecting their amplitudes. A similar effect was produced by an endogenous dopamine, induced by GBR 12935, a dopamine reuptake blocker. All these changes were abolished by SKF 83566, a D1R antagonist, which also eliminated the effects induced by propofol: increases the amplitude but decreases the paired-pulse ratio of evoked EPSCs. In keeping with a crucial involvement of dopamine was the suppression of the action of propofol when endogenous monoamines (including dopamine) were depleted by reserpine. All these findings support the notion that propofol increases glutamate transmission via the activation of D1Rs.
How does propofol activate presynaptic D1Rs? In the midbrain, dopamine is released from the somatodendritic region of dopamine neurons (Björklund and Lindvall, 1975). Dopamine molecules travel retrogradely across the synapse to bind to the D1Rs in the glutamate-releasing terminals. In reserpine-treated slices, in which dopamine was depleted, propofol failed to alter the amplitude and paired-pulse ratio of evoked EPSCs. This excludes the possibility that propofol directly activates presynaptic D1Rs. Propofol may raise local dopamine level. This possibility is supported by the similar effects of propofol and of dopamine reuptake blocker.
A rise in local dopamine levels is also suggested by the bell-shaped dose dependence of propofol action. The diminishing potency of concentrations >1 nM cannot be explained by saturation of D1Rs at the site of action on glutamatergic terminals, because the selective D1R agonist was effective over a wide range of concentrations. One possible explanation is suggested by opposite effects of dopamine (the nonselective endogenous agonist) acting on different dopamine receptor subtypes. At low concentrations, dopamine seems to bind predominantly to D1Rs, and at higher concentrations it binds to D2Rs. For example, Trantham-Davidson et al. (2004) found that low concentrations of dopamine (<0.5 µM) enhance inhibitory postsynaptic currents by activating mainly D1Rs, whereas higher concentrations of dopamine (>1 µM) have the opposite effect of reducing inhibitory postsynaptic currents by predominantly activating D2Rs. In comparable experiments on EPSCs, Koga and Momiyama (2000) found that dopamine inhibits non-N-methyl-D-aspartate receptor-mediated evoked EPSCs in VTA dopamine neurons through presynaptic D2Rs, with a high IC50 value of 16 µM. The bell-shaped concentration dependence of propofol action in our slices is thus consistent with potentiation of dopamine release and opposite presynaptic actions via D1Rs and then D2Rs as the local dopamine rises. Our assumption that with minute concentrations of propofol local dopamine concentrations remain below the micromolar level, which predominantly activates D1Rs, is supported by previous evidence that electrical stimulation in the VTA does not raise extracellular dopamine levels above the submicromolar range (Kalivas and Duffy, 1991; Adell and Artigas, 2004).
Propofol increases excitation of VTA dopamine neurons. VTA dopamine neurons receive numerous inputs that can modulate their eventual output. Integration of the synaptic inputs and the intrinsic properties sets the frequency and pattern of firing (Alberto et al., 2006). As mentioned, glutamatergic afferents are the major excitatory inputs. Thus, the increase in glutamatergic transmission may contribute to the excitatory effect of minute concentrations of propofol on the dopamine neurons in the VTA.
Although many factors modulate glutamate release onto VTA dopamine neurons, the current study focused on the mechanism operating via presynaptic D1Rs because these receptors are involved in the rewarding action of abused drugs such as ethanol, and D1R activation enhances glutamate releases in the VTA. Furthermore, that a selective D1R antagonist eliminated propofol-induced elevation of glutamate transmission demonstrated the predominant role of D1Rs in propofol-induced increase in glutamate transmission in the VTA.
Although the main action of propofol is to potentiate GABAergic transmission (Krasowski et al., 1998; Orser et al., 1998), the effect of minute concentrations of propofol on the EPSCs in the VTA seems independent of GABAergic action, because the effects of propofol on EPSCs were similar in presence and absence of gabazine, the GABAA receptor antagonist. Although the underlying mechanisms warrant further study, we propose that propofol at nanomolar concentrations may not be able to activate GABAA receptors, as a previous study in brain slices indicates that propofol activates GABAA receptors at concentrations 
1 µM (Shirasaka et al., 2004). Nevertheless, our finding is in general agreement with a previous report that propofol effect on dopamine release in the NAcc is independent of GABAA receptors (Schulte et al., 2000).
As mentioned, previous clinical trials performed by Zacny et al. (1993a,b) on healthy human volunteers have shown that the rewarding effect of propofol was observed only in a subgroup of treated people (half). In these studies, a discretetrial procedure was used. This procedure has been used with well known drugs of abuse, such as alcohol, amphetamines, 
-9-tetrahydrocannabinol, or methylphenidate. As observed with propofol, although to a different extent, these other drugs were not clearly served as a reinforcer in a good number of volunteers tested (Uhlenhuth et al., 1981; de Wit et al., 1986; Stern et al., 1989; Chait and Zacny, 1992).
Our in vitro data are in general agreement with a previous in vivo study regarding propofol alters the activity of the mesolimbic dopamine system. Nevertheless, in that in vivo microdialysis study, propofol increases extracellular dopamine levels in the NAcc only in subanesthetic and anesthetic doses (Pain et al., 2002), which are in apparent conflict with our in vitro electrophysiological data in the VTA, where only minute concentrations of propofol increase EPSCs. We have no firm answer about the difference. Note that whereas electrophysiology measures synaptic release with high temporal and spatial resolution, microdialysis measures extrasynaptic outflow and reuptake. As suggested, propofol-increased dopamine in the NAcc might be the result of inhibition of dopamine reuptake (Pain et al., 2002). Furthermore, several brain-imaging mappings of human and primate functioning found no activity in any midbrain area or limbic structures after the use of threshold, submaximal, or maximal doses of anesthetics (Heinke and Schwarzbauer, 2002). Note that in these imaging studies, the effect of minute concentrations of propofol has not been tested.
The high sensitivity to propofol of the D1R-glutamatergic pathway unveiled in the current investigation may have particular significance in that anesthesiologists are exposure to trace amounts of general anesthetics in the air of the operating room. Furthermore, the changes in synaptic plasticity in the VTA, an addiction-related brain area, shown in the current investigation may not only contribute to the mechanism of the development of propofol abuse but also to the mechanism of the higher rate of drug abuse among anesthesiologists, because a history of exposure to one drug (such as propofol) can facilitate self-administration of another drug (such as cocaine) (Young, 1986).
In conclusion, the present study shows that propofol at minute concentrations enhances presynaptic D1 receptor-mediated facilitation of glutamatergic synaptic transmission and the excitability of VTA dopamine neurons, probably by increasing extracellular dopamine levels. The stimulating effect of minute concentrations of propofol on VTA dopamine neurons may contribute to the mechanisms underlying the development of propofol abuse. Furthermore, the proposed mechanism supports the hypothesis that physicians may become addicted to drugs through second-hand exposure. Through further study, preventive measures can be adopted to protect physicians and healthcare professionals.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: VTA, ventral tegmental area; NAcc, nucleus accumbens; ACSF, artificial cerebrospinal fluid; AMPA, -amino-3-hydroxy-5-methylisoxazole-4-propionic acid; sEPSC, spontaneous excitatory postsynaptic current; mESPC, miniature excitatory postsynaptic current; eEPSC, evoked excitatory postsynaptic current; U69593
[GenBank]
, (+)-(5,7,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; Ih, hyperpolarization current; DNQX, 6,7-dinitroquinoxaline-2, 3-dione; DNQX, 2,3-dihydroxy-6,7-dinitroquinoxaline; TTX, tetrodotoxin; SKF38393, 6-phenyl-4-azabicyclo[5.4.0]undeca-7,9,11-triene-9,10-diol; GBR 12935, 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride; SKF83566, (±)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride; K-S, Kolmogorov-Smirnov; VH, holding potential; PPR, paired-pulse ratio; D1R, dopamine D1 receptor; SR 95531, 6-imino-3-(4-methoxyphenyl)-1(6H)-pyridazinebutanoic acid hydrobromide.
Address correspondence to: Dr. Jiang-Hong Ye, Department of Anesthesiology, New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103-2714. E-mail: ye{at}umdnj.edu
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