Coupled effects of mass transfer and uptake kinetics on in vivo microdialysis of dopamine

Voltammetric microelectrodes and microdialysis probes were used simultaneously to monitor extracellular dopamine in rat striatum during electrical stimulation of the medial forebrain bundle. Microelectrodes were placed far away (1 mm) from, immediately adjacent to, and at the outlet of microdialysis probes. In drug-naive rats, electrical stimulation (45 Hz, 25 s) evoked a robust response at microelectrodes far away from the probes, but there was no response at microelectrodes adjacent to and at the outlet of the probes. After nomifensine administration (20 mg/kg i.p.), stimulation evoked robust responses at all three microelectrode placements. These results demonstrate first that evoked release in tissue adjacent to microdialysis probes is suppressed in comparison with evoked release in tissue far away from the probes and second that equilibration of the dopamine concentration in the extracellular fluid adjacent to and far away from the probes is prevented by the high-affinity dopamine transporter. Hence, models of microdialysis, which assume the properties of tissue to be spatially uniform, require modification to account for the distance that separates viable sites of evoked dopamine release from the probe. We introduce new mass transfer resistance parameters that qualitatively explain the observed effects of uptake inhibition on stimulation responses recorded with microdialysis and voltammetry.     

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In a recent paper [R.R. Holson, J.F. Bowyer, P. Clausing, B. Gough, Methamphetamine-stimulated striatal dopamine release declines rapidly over time following microdialysis probe insertion, Brain Res. 739 (1996) 301-307] we reported that methamphetamine-stimulated striatal dopamine release declined rapidly over the first eight hours following microdialysis probe insertion. This decline was strictly a function of time post-probe implantation, and not due to tolerance or desensitization. To further examine this phenomenon, we subjected rats to three brief pulses of several DA-releasing compounds at 2, 4 and 6 h post-probe insertion, and compared these results to those caused by a single pulse 6 h post-insertion, or in some cases to pulses given more than 24 h post-insertion. We found that when buproprion, a dopamine reuptake blocker, was infused briefly into the striatum via the microdialysis probe, there was a pronounced drop in the amount of dopamine released at 6 h vs. 2 h post-insertion; this drop was not due to repeated exposure, since dopamine release at 6 h post-insertion was the same for a single pulse, or when preceded by two earlier pulses. Twenty-four hours later, buproprion-stimulated dopamine release was still lower, but did not appear to drop further thereafter. Potassium-stimulated dopamine release, on the other hand, dropped rapidly over the first 8 h post-insertion, and this decline continued throughout the 24-32 h interval post-insertion. Similarly, a single i.p. injection of 0.5 mg/kg haloperidol released three times as much dopamine when given two compared to six hours post-implantation. Both bupropion- and potassium-stimulated dopamine release were accompanied by declines in extracellular DOPAC concentrations, and these declines were the same 2 or 26 h post-insertion. In contrast, haloperidol exposure increased extracellular DOPAC, and this haloperidol-stimulated DOPAC increase was also greatly attenuated at 6 compared to 2 h post-insertion. We conclude that there is a general decline over time post-probe implantation in the ability of the striatal dopamine system to release dopamine, and perhaps to increase dopamine synthesis, in response to pharmacological challenges.     

Medicine, the media, and bioethics

The striatum of rats was lesioned by unilateral administration of MPP+. Two weeks later, a suspension of fetal mesencephalic cells (FMC), obtained from 14-day rat embryos, was injected into the lesioned striatum. Two weeks after grafting, the success of implantation and recovery of dopamine function were assessed by tyrosine hydroxylase immunocytochemistry (TH) and the measurement of striatal dopamine content. In addition, the extracellular concentrations of dopamine and dopamine metabolites were studied by microdialysis in vivo before and after perfusion of MPP+ to induce dopamine release from vesicular stores. TH+ cell bodies were seen in the lesioned grafted striata, indicating that fetal cells survived in these striata. In addition, there was a marked increase in TH-immunoreactivity in the neuronal fibers and terminals in the area surrounding the cell implant, suggesting a compensatory response of the host tissue which may involve fiber sprouting. Grafting induced a recovery in indices of dopamine function, including recovery in dopamine content, and basal and MPP+-induced dopamine release. Thus, grafts of FMC may provide a significant recovery of dopamine function in MPP+-lesioned striata.     

A microdialysis study of nucleus accumbens core and shell dopamine during operant responding in the rat

This investigation examined dopamine release and metabolism in nucleus accumbens core and shell during three operant tasks in the rat. Rats were trained to lever press on a fixed-ratio 5, variable-interval 30 s, or a tandem variable interval 30/fixed-ratio 5 schedules; these three schedules were chosen because they generate a wide range of response and reinforcement rates. After several weeks of training, dialysis probes were implanted into nucleus accumbens core or shell subregions. A single 30 min behavioural session was conducted during the dialysis test session. Rats lever pressing on each of the three operant schedules showed a significant increase in extracellular dopamine relative to the food-deprived control group during the behavioural session. In addition, increases in dopamine in nucleus accumbens shell were found to be significantly greater than in the core during the lever pressing period. Across all three schedules, extracellular dopamine in the nucleus accumbens was significantly correlated with the number of lever presses performed, but was not correlated with the number of food pellets delivered. Analysis of covariance, which used amount of food consumed as the covariate, showed an overall group difference, indicating that dopamine levels increased in lever pressing animals even if one corrected for the amount of food consumed. These results indicate that dopamine release was more responsive in the nucleus accumbens shell than in the core during operant responding, and that increases in extracellular dopamine in nucleus accumbens are related to response rate rather than reinforcement magnitude.     

Electrical stimulation of the medial prefrontal cortex increases dopamine release in the striatum

Exogenous and endogenous glutamate has been shown to evoke dopamine (DA) release in the striatum using both in vitro and in vivo techniques. We hypothesized that stimulation of the prefrontal cortex (PFC) would phasically enhance striatal DA release via the glutamatergic corticostriatal pathway. To test this hypothesis, in vivo brain microdialysis was employed to measure extracellular concentrations of DA in the striatum during electrical stimulation of the PFC. Five rats were implanted with bilateral electrodes located in the medial PFC and dialysis probes in the dorsal striatum. Two days later the PFC of these awake, freely moving rats was stimulated first at 50 microA and then at 100 microA for 20 minutes at 2-hour intervals. Both currents significantly increased DA release. Extracellular DA rose rapidly during stimulation, peaked immediately afterward, and then slowly returned to baseline values. Dopamine reached 118% of baseline values with 50 microA stimulation and 138% with 100 microA stimulation. Histologic analysis using the fluorescent retrograde dye Fluoro Gold confirmed that cells projecting to the vicinity of the striatal dialysis probe originated in the vicinity of the PFC electrodes. These results provide direct evidence for phasic, excitatory modulation of striatal DA release by the PFC.     

Considerations in the determination by microdialysis of resting extracellular amino acid concentrations and release upon spinal cord injury

The following issues are further addressed: (1) Is there considerable leakage of amino acids from the circulation into the space around microdialysis probes, or are amino acid concentrations naturally much higher in the interstitial space than is generally thought? (2) Do observed high interstitial concentrations or depletion of substances in the intracellular space by microdialysis affect release measurements upon spinal cord injury? Amino acid concentrations around microdialysis fibres in the spinal cord of rats were found to approach those in the circulation and to be much higher than interstitial concentrations previously estimated in the CNS. However, much lower concentrations of amino acids were derived in the hippocampus by analogous experiments. Considerable Evans Blue/albumin leaked from the circulation into the interstitial space in the spinal cord immediately after fibre insertion. However, this movement diminished considerably by 4 h later, demonstrating substantial resealing of the blood-brain barrier, at least to large molecules. There is either substantial damage-induced movement of amino acids from the circulation into the dialysis zone after insertion of a microdialysis probe, or there is much less impediment to movement of amino acids across the blood-brain barrier in the spinal cord than in the brain. At low flow rates through the fibre, adding concentrations of amino acids to the inside of the fibre equal to the concentrations around the fibre to prevent their depletion by removal through the microdialysis fibre did not affect increases in concentrations of amino acids in microdialysates following injury. Thus the high concentrations of amino acids present around microdialysis fibres following their insertion do not seem to disturb measurements of amino acid release upon spinal cord injury.     

Repeated isolation in the neonatal rat produces alterations in behavior and ventral striatal dopamine release in the juvenile after amphetamine challenge.

Rat pups were isolated from the mother and nest for 1 hr per day from Postnatal Day (PN) 2 to 9. At PN 27, rats were tested for behavioral responsiveness to 2.0 or 7.5 mg/kg amphetamine. Only isolated rats receiving the 7.5 mg/kg dose displayed increased activity scores, compared with nonisolated and nonhandled controls. Their increased activity is attributed to a slower latency to enter into stereotypy. In a second experiment, similarly treated groups were challenged by the 7.5 mg/kg dose during a session in which a microdialysis probe implanted in the ventral striatum was being perfused. The challenge drug elicited a much greater increase in dialysate dopamine in isolated vs nonisolated groups. Results are discussed with regard to dissociation between sensitized and subsensitized responses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Transitional cell bladder carcinoma with presentation mimicking ovarian carcinoma

Rats were implanted with dual dialysis probes, one in the ventral tegmental area, and another one ipsilateral in the nucleus accumbens. Infusion of cocaine (10, 100, 1000 mM) into the ventral tegmental area gradually increased extracellular dopamine to 164, 329 and 991% of baseline in the ventral tegmental area, but reduced dopamine to 76, 47 and 38% of baseline in the nucleus acumbens. These results are consistent with cocaine-induced feedback regulation of dopamine cell activity involving somatodendritic impulse regulating dopamine D2 autoreceptors.     

Increased resting and exercise-induced oxidative stress in young IDDM men

The effects of local application of the 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (CPBG), and i.p. administration of ethanol on the extracellular levels of dopamine (DA) in the ventral tegmental area (VTA) were studied using in vivo microdialysis. Adult female Wistar rats were implanted with microdialysis probes in the VTA at least 24 h before each experiment. Stable extracellular levels of DA (101 +/- 9 fmol/20 min) were established before initiating the experiments. Application of 10-250 microM CPBG through the microdialysis probe dose-dependently enhanced the extracellular concentrations of DA but did not alter the levels of either 3,4-dihydroxyphenylacetic acid or homovanillic acid in the dialysate. The effects of CPBG were reversible and dependent upon Ca2+. Co-perfusion with the 5-HT3 receptor antagonist, 3-tropanyl-indole-3-carboxylate (ICS 205-930), inhibited the effects of CPBG on enhancing extracellular DA levels. The i.p. administration of 2 g/kg ethanol significantly (p < 0.005) enhanced the levels of DA to 150% of baseline values; this ethanol-induced increase was prevented by local perfusion with 100 microM ICS 205-930. These results suggest that 5-HT3 receptors in the VTA are involved in regulating the somatodendritic release of DA and in mediating the stimulatory effects of ethanol on this neuronal system.     

Vitamin D metabolism is altered in Asian Indians in the southern United States: a clinical research center study

In order to define precisely the relation between descending monoaminergic systems and the motor system, we measured in the ventral horn of spinal cord of adult rats the variations of extracellular concentrations of 5-HT, 5-HIAA, DA and MHPG. Measurements were performed during rest, endurance running on a treadmill, and a post-exercise period, with microdialysis probes implanted permanently for 45 days. We found a slight decrease in both 5-HT and 5-HIAA during locomotion with a more marked decrease during the post-exercise period compared to the mean of rest values. In contrast, the concentration of DA and MHPG increased slightly during the exercise and decreased thereafter. These results, when compared with those of a previous study, which measured monoamines in the spinal cord white matter [C. Gerin, D. Bécquet, A. Privat, Direct evidence for the link between monoaminergic descending pathways and motor activity: I. A study with microdialysis probes implanted in the ventral funiculus of the spinal cord, Brain Res. 704 (1995) 191-201], highlight the complex regulation of the release of monoamines that occurs in the ventral horn.     

Dopamine agonist-induced inhibition of neurotransmitter release from the awake squirrel monkey putamen as measured by microdialysis

Male squirrel monkeys (Saimiri sciureus) were surgically prepared with cranial guide cannulae for acute microdialysis sampling of the putamen nucleus, a dopamine (DA)-rich brain region. On the day of an experiment an animal was placed in a Plexiglas restraining chair and a microdialysis probe was inserted through the guide into the putamen. Perfusates of artificial cerebrospinal fluid were collected every 20 min over several hours and analyzed via HPLC with electrochemical detection. DA D2/ D3 agonist drugs were administered either orally (p.o.) or subcutaneously (s.c.), and changes in levels of DA in the dialysates were measured. All of the drugs tested, i.e., quinpirole (0.5 mg/kg p.o.), talipexole (0.75 mg/kg p.o. or s.c.), and PD 135222 (7 mg/kg p.o.), decreased spontaneous DA overflow by approximately 40-50% during the first 2 h following dosing. In animals that routinely underwent the microdialysis procedure up to 23 times over a 2-year period, there was neither an appreciable change in basal DA overflow nor a significant change in the magnitude of drug response. These data suggest that DA D2/D3 agonists attenuate DA neuronal overflow in the primate brain, similar to effects seen in rodents. Furthermore, these results also demonstrate the utility of repeated intracerebral microdialysis as a tool to monitor dynamic changes in neurochemical activity in monkeys over a prolonged period of time.     

Stability of the input-output properties of chronically implanted multiple contact nerve cuff stimulating electrodes

The objective of this investigation was to measure the input-output (I-O) properties of chronically implanted nerve cuff electrodes. Silicone rubber spiral nerve cuff electrodes, containing 12 individual platinum electrode contacts, were implanted on the sciatic nerve of seven adult cats for 28-34 weeks. Measurements of the torque generated at the ankle joint by electrical stimulation of the sciatic nerve were made every 1-2 weeks for the first 6 weeks post-implant and every 3-5 weeks between 6 weeks and 32 weeks post-implant. In three implants the percutaneous lead cable was irreparably damaged by the animal within 4 weeks after implant and further testing was not possible. One additional lead cable was irreparably damaged by the animal at 17 weeks post-implant. The three remaining implants functioned for 28, 31, and 32 weeks. Input-output curves of ankle joint torque as a function of stimulus current amplitude were repeatable within an experimental session, but there were changes in I-O curves between sessions. The degree of variability in I-O properties differed between implants and between different contacts within the same implant. After 8 weeks, the session to session changes in the stimulus amplitude required to generate 50% of the maximum torque (I50) were smaller (15+/-19%, mean +/- s.d.) than the changes in I50 measured between 1 week and 8 weeks post-implant (34+/-42%). Furthermore, the I-O properties were more stable across changes in limb position in the late post-implant period than in acutely implanted cuff electrodes. These results suggest that tissue encapsulation acted to stabilize chronically implanted cuff electrodes. Electrode movement relative to the nerve, de- and regeneration of nerve fibers, and the inability to precisely reproduce limb position in the measurement apparatus all may have contributed to the variability in I-O properties.     

Identification and characterization of CDS2, a mammalian homolog of the Drosophila CDP-diacylglycerol synthase gene

The technique of intracranial microdialysis was used to investigate the effects of aging on the striatal dopaminergic system of the anesthetized Fischer 344 rat. Microdialysis probes were implanted into the striatum of young (2-8 months) and aged (24-28 months) urethane anesthetized rats. Striatal dialysate levels were analyzed for dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and serotonin (5-HT) by high performance liquid chromatography with electrochemical detection. As compared to the young animals, basal extracellular levels of DA and DOPAC were significantly decreased in two groups of aged animals. Stimulation with excess potassium added through the microdialysis probe produced a robust overflow of DA in the young and aged rat striatum, but the evoked overflow of DA was not diminished in the aged rat striatum as compared to young animals. In contrast, d-amphetamine-evoked overflow of DA was again robust in young and aged animals, but was greatly decreased in the aged rat striatum as compared to the signals recorded in the young rats. Taken together with previous reports, these data support the hypothesis that a major change in the regulation of DA release that occurs in aging involves changes in the function of the neuronal uptake of DA, which may be a compensatory property of DA neurons in senescence.     

Quantitative microdialysis of ethanol in rat striatum

We have applied a steady-state theory of microdialysis to characterize the diffusion of ethanol through a microdialysis membrane and through rat striatum. Quantitative characterization required measurement of in vitro and in vivo extraction fractions for ethanol and determination of the clearance of ethanol from brain tissue during steady-state perfusion through a microdialysis probe. Extraction fraction of ethanol was determined in vitro by perfusing a known concentration of ethanol through probes immersed in water at 37 degrees C with stirring. The in vitro extraction fraction yielded a probe permeability value of 0.046 +/- 0.004 cm/min that is comparable with an estimate from published measurements for similar dialysis membranes. The in vivo extraction fraction was determined for probes placed in the striatum. Clearance of ethanol and a brain slice concentration profile of ethanol were determined by measurement of the amount of ethanol remaining in the brain tissue during steady-state perfusion of the probe. Steady state was achieved within 10 min after beginning the ethanol perfusion in vivo, and the extraction fraction was not altered by sedation of the rat with pentobarbital. The tissue concentration profile was symmetrical around the probe track, and ethanol was detected 1 mm from the probe. The experimental clearance rate constant value obtained for ethanol (2.0 +/- 0.3 min(-1)) was higher than that expected for removal solely by loss to the blood. The tissue diffusivity for ethanol, Dt, derived from the experimental measurements was 1.2 +/- 0.2 x 10(-5) cm2/sec. This value is greater than expected for interstitial diffusion, suggesting a substantial contribution by transcellular diffusion of ethanol as well. The predicted tissue concentration profile had a higher peak value and did not extend into the tissue (0.5 mm) as much as the experimental profile (1 mm), although there was reasonable agreement between experiment and theory. Our quantitative characterization of the microdialysis behavior of ethanol in brain provides a framework for interpretation of brain microdialysis experiments using ethanol by supplying, inter alia, a means for estimating the ethanol concentration achieved in the tissue volume being sampled by the probe.     

Dopamine transporter is required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter

The neurotoxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was tested on mice lacking the dopamine (DA) transporter (DAT-/- mice). Striatal tissue DA content and glial fibrillary acidic protein (GFAP) mRNA expression were assessed as markers of MPTP neurotoxicity. MPTP (30 mg/kg, s.c., b.i.d.) produced an 87% decrease in tissue DA levels and a 29-fold increase in the level of GFAP mRNA in the striatum of wild-type animals 48 h after administration. Conversely, there were no significant changes in either parameter in DAT-/- mice. Heterozygotes demonstrated partial sensitivity to MPTP administration as shown by an intermediate value (48%) of tissue DA loss. Direct intrastriatal infusion of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+; 10 mM), via a microdialysis probe produced a massive efflux of DA in wild-type mice (>320-fold). In the DAT-/- mice the same treatment produced a much smaller increase in extracellular DA (sixfold), which is likely secondary to tissue damage due to the implantation of the dialysis probe. These observations show that the DAT is a mandatory component for expression of MPTP toxicity in vivo.     

Brain parenchyma/pO2 catheter interface: a histopathological study in the rat

Local cerebral oxygenation can be monitored continuously using an intraparenchymal Clark-type pO2 sensitive catheter. Measured values of brain tissue pO2 (PbrO2) not only depend on the clinically interesting balance between oxygen offer and demand, but also on catheter properties and characteristics of the probe tissue interface. Microdamage surrounding pO2-sensitive needles, inserted into various tissues, has been reported; we evaluated histologic changes at the probe tissue interface after insertion of pO2 probes, suitable for clinical use, in the rat brain. The effect of insertion of the probe itself (mechanical damage), the application of micropotential during the measurements, and the effect of time was evaluated using digital image analysis of H&E-stained histological slices. Surrounding the probe tract, a zone of edema with an average radius of 126.8 microm was seen; microhemorrhages with an average surface area of 56.2 x 10(3) microm2 were observed in nearly all cases. The area of edema and the presence of microhemorrhages were not influenced by performed measurements or by time. Intraventricular blood was observed in 10 of 19 rats studied. Measured low PbrO2 values were related to the presence of a microhemorrhage in either probe tract or ventricles. Tissue damage due to the measurements is negligible, and the amount of edema itself does not influence the accuracy or response time of the pO2 probe. Low PbrO2 readings, however, could be caused by local microhemorrhages, undetectable on CT or MRI.     

Transient increase of blood histamine level induced by pentagastrin. Continuous monitoring by in vivo microdialysis

BACKGROUND: Since few studies of (penta)gastrin-induced histamine release from the gastric mucosa into blood has been performed, an effect of pentagastrin on histamine level of rat blood was examined by using the in vivo microdialysis method. METHODS: Pentagastrin was perfused through the microdialysis probe implanted into the jugular vein of urethane-anesthetized rats or in urethane-anesthetized, totally gastrectomized rats, and dialysis samples of blood were concurrently collected. Histidine decarboxylase (HDC) activities and histamine contents in the glandular stomach and gastric acid output after pentagastrin stimulation were also investigated. RESULTS: Pentagastrin induced a transient increase of blood histamine in a dose-dependent manner but failed to cause any increase of blood histamine in the totally gastrectomized rat. Pentagastrin also induced increases of the HDC activity in the glandular stomach and of the gastric acid output. The peak histamine level in blood occurred 40 min after pentagastrin perfusion, whereas the peak acid secretion occurred after 80-120 min and then leveled off. CONCLUSIONS: The transient increase of blood histamine induced by pentagastrin is attributable to the histamine released from enterochromaffin-like cells and could be monitored by using the in vivo microdialysis method.     

Characterisation of muscarinic autoreceptors in the septo-hippocampal system of the rat: a microdialysis study

The effects of local administration of cholinergic drugs on the release of acetylcholine in the septo-hippocampal system were investigated using intracerebral microdialysis. Dialysis probes were implanted in the cell-body area of septo-hippocampal neurones in the medial septal area, and in the terminal area of the same neurones in the ventral hippocampus. Drugs were administered locally via the dialysis probe. Administration of the mixed muscarinic/nicotinic receptor agonist carbachol caused a decrease, whereas administration of the muscarinic receptor antagonist methyl-atropine caused an increase in the output of acetylcholine in both the hippocampus and the medial septal area. In contrast, perfusion with the same drugs and the acetylcholine esterase inhibitor neostigmine bromide in the septal area had little or no effect on the output of acetylcholine in hippocampus. The results indicate that acetylcholine autoreceptors are localised on nerve terminals in medial septal area and hippocampus, and exert an inhibitory control over acetylcholine release. However, autoreceptors seem to be sparse or absent on dendrites and cell bodies of septo-hippocampal cholinergic neurones.     

Increase in dopamine release from the nucleus accumbens in response to feeding: a model to study interactions between drugs and naturally activated dopaminergic neurons in the rat brain

The aim of the present study was to investigate the interactions between the in vivo release of dopamine and certain drugs, during conditions of increased dopaminergic activity. Dopaminergic neurons in the nucleus accumbens were activated by feeding hungry rats. 48-96 h after implantation of a microdialysis probe 30 min food ingestion by hungry rats induced an immediate eating response that was accompanied with a reproducible and long-lasting increase in extracellular dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC). The effect of various drugs (infused into the nucleus accumbens via the microdialysis probe), on the extracellular levels of dopamine and DOPAC were recorded, and the effect of eating was determined. Infusion of 5 mumol/l nomifensine and 3.4 mmol/l calcium increased dopamine release respectively 5.4 and 2-fold but did not modify the eating related increase in dopamine and DOPAC release. Infusion (1 mumol/l) as well as intraperitoneal administration (20 mg/kg) of sulpiride induced an increase in basal dopamine release to 220 and 195% of controls, respectively. Both routes of sulpiride pretreatment enhanced the eating related increase in extracellular dopamine and DOPAC. The results of the sulpiride experiments indicate that a behaviorally induced stimulation of dopamine release is modified by autoinhibition.     

Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis

1. The effect of electroconvulsive shock (ECS) on the extracellular concentration of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) was examined in the frontal cortex of rats with the use of in vivo microdialysis. 2. The extracellular concentration of DOPAC, HVA and 5-HIAA was largely increased after the first ECS treatment. The increase after the eighth ECS treatment tended to be attenuated or was significantly attenuated as compared to that after the first ECS treatment. The baseline concentration of DOPAC and 5-HIAA was significantly increased after repeated ECS, though that of DA and HVA did not show any significant change after repeated ECS. 3. These results suggest that the activating effect of repeated ECT on 5-hydroxytryptaminergic (5-HT) and DA neurotransmission, (especially on 5-HT neurotransmission), is significant in improving depression both in patients with Parkinson's disease (PD) and in those who do not suffer from PD.