Stanisław Chrapusta - Academia.edu (original) (raw)

Papers by Stanisław Chrapusta

Folia Neuropathologica, 2014

(Sub)chronic local drug application is clearly superior to systemic administration, but may be as... more (Sub)chronic local drug application is clearly superior to systemic administration, but may be associated with substantial obstacles, particularly regarding the applications to highly sensitive central nervous system (CNS) structures that are shielded from the outer environment by the blood-brain barrier. Violation of the integrity of the barrier and CNS tissues by a permanently implanted probe or cannula meant for prolonged administration of drugs into specific CNS structures can be a severe confounding factor because of the resulting inflammatory reactions. In this study, we tested the utility of a novel way for (sub)chronic local delivery of highly active (i.e., used in very low amounts) drugs to the rat spinal cord employing a non-woven nanofiber mat dressing. To this end, we compared the morphology and motoneuron (a + g) counts in spinal cord cervical and lumbar segments between rats with glutamate-loaded nanofiber mats applied to the lumbar enlargement and rats with analogical implants carrying no glutamate. Half of the rats with glutamate-loaded implants were given daily valproate treatment to test its potential for counteracting the detrimental effects of glutamate excess. The mats were prepared in-house by electrospinning of an emulsion made of a solution of the biocompatible and biodegradable poly(L-lactide-co-caprolactone) polymer in a mixture of organic solvents, an aqueous phase with or without monosodium glutamate, and sodium dodecyl sulfate as an emulsifier; the final glutamate content was 1.4 µg/mg of the mat. Three weeks after mat implantation there was no inflammation or considerable damage of the spinal cord motoneuron population in the rats with the subarachnoid dressing of a glutamate-free mat, whereas the spinal cords of the rats with glutamate-loaded nanofiber mats showed clear symptoms of excitotoxic damage and a substantial increase in dying/damaged motoneuron numbers in both segments studied. The rats given systemic valproate treatment showed significantly lower percentages of damaged/dying motoneurons in their lumbar enlargements. These results demonstrate the capacity of nanofiber mats for generation of neurotoxic glutamate in the rat CNS. However, the tested nanofiber mats need further improvements aimed at extending the period of effective drug release and rendering the release more steady.

Anti-Cancer Drugs, 2007

a 2-Chloro-2 0-deoxyadenosine (cladribine) and chlorambucil are two drugs used in the treatment o... more a 2-Chloro-2 0-deoxyadenosine (cladribine) and chlorambucil are two drugs used in the treatment of lymphoid malignancies. We have synthesized 5 0-O-esters of cladribine and its parental nucleoside 2 0-deoxyadenosine with chlorambucil (2-chloro-2 0-deoxyadenosinechlorambucil and 2 0-deoxyadenosine-chlorambucil, respectively) and compared some properties of the esters with regard to their potential use as antileukemic prodrugs. The 5 0-O-ester bond showed no spontaneous hydrolysis at pH 7.4, but was susceptible to hydrolysis by porcine liver esterase and enzymes present in human lymphocyte lysate and blood plasma. Both 2-chloro-2 0-deoxyadenosinechlorambucil and 2 0-deoxyadenosine-chlorambucil were taken up more avidly than their parental nucleosides by normal and malignant human lymphoid cells. 2-Chloro-2 0-deoxyadenosine-chlorambucil was by an order of magnitude more toxic than 2 0-deoxyadenosinechlorambucil to human leukemic MOLT4 cells in culture. On the other hand, 2-chloro-2 0-deoxyadenosinechlorambucil cytotoxicity did not exceed that of its parental 2-chloro-2 0-deoxyadenosine in MOLT4 cells, whereas 2 0-deoxyadenosine-chlorambucil was considerably more cytotoxic than free chlorambucil in a variety of myeloid and lymphoid human malignant cell lines. Moreover, acute toxicity of 2 0-deoxyadenosine-chlorambucil was lower than that of chlorambucil in mice. In summary, 2 0-deoxyadenosine-chlorambucil, but not 2-chloro-2 0-deoxyadenosine-chlorambucil, shows promise for clinical utility as a chlorambucil prodrug and thus warrants a more detailed study in vivo. Anti-Cancer Drugs

Medical science monitor : international medical journal of experimental and clinical research, 2004

BACKGROUND The presence of sex steroid receptors in breast cancer tissue is of considerable diagn... more BACKGROUND The presence of sex steroid receptors in breast cancer tissue is of considerable diagnostic/prognostic value. However, the relative utility of the diverse assays used for receptor detection/quantitation is disputed. We compared the utility of a monoclonal antibody-based semiquantitative immunohistochemical assay of estrogen receptor alpha (irERalpha) and of quantitative single-point radioligand assays of "cytosolic" estrogen (ERc) and progesterone receptors (PRc). MATERIAL/METHODS Correlations were studied between the receptor levels in 235 breast cancers in patients treated between 1987 and 1990. Relationships were then analyzed between tumor receptor status, overall survival (OS; end-point: 10 years postmastectomy), age, axillary nodal status, and adjuvant tamoxifen in primary breast cancer patients for whom the respective data were accessible (N < or =121). RESULTS Univariate analysis showed no correlation between OS and the ERc status, whereas positive ir...

The Society for Neuroscience Abstracts, 1994

Acta neurobiologiae experimentalis, 2006

Respiratory effects of an intra-common carotid artery injection of N-methyl-D-aspartic acid (NMDA... more Respiratory effects of an intra-common carotid artery injection of N-methyl-D-aspartic acid (NMDA) were investigated in anesthetized spontaneously breathing rats, using three experimental paradigms: (1) midcervical vagotomy followed by supranodosal vagotomy, (2) midcervical vagotomy followed by section of the carotid sinus nerves (CSNs), and (3) midcervical vagotomy followed by pharmacological blockade of NMDA receptors. The intra-common carotid artery injection of NMDA (4 mg/kg) induced transient expiratory apnea followed by a brief and variably occurring period of breathing at reduced tidal volume. There were no consistent changes in respiratory rate in rats subjected to midcervical vagotomy alone. Supranodose vagotomy exerted no effect on NMDA-induced respiratory arrest, whereas CSNs' section or blockade of NMDA receptors with AP-7 abolished the apnea. These results indicate that the apnea induced by intra-arterial NMDA challenge is due to activation of peripheral NMDA recept...

Neurosurgical procedures often involve, as a result of the surgeon approaching the diseased regio... more Neurosurgical procedures often involve, as a result of the surgeon approaching the diseased region, unavoidable trauma to the adjacent, non-diseased brain structures. Because of the priority of removing the immediate threats to health or life that underlie such interventions, side effects of surgical brain injuries were not given much attention until recently. The cause-and-effect association of the eventual delayed cognitive and/or neurological deficits is often obscure due to substantial potential of the brain for compensatory changes, long life span in man, and aging-related phenomena. However, animal and human studies have demonstrated that physical insults to the brain can initiate a cascade of changes that results, in the long run, in massive neurodegeneration and brain atrophy. Here we present a review of morphological and ultrastructural findings obtained mostly in a rat model of surgical neocortex injury, with consideration of the current view of this region as a network of...

A colony of transgenic rats expressing the human mutant Cu,Zn superoxide dismutase gene (hSOD1G93... more A colony of transgenic rats expressing the human mutant Cu,Zn superoxide dismutase gene (hSOD1G93A) that is associated with some cases of familial form of amyotrophic lateral sclerosis (ALS) has been maintained in the Animal House of the Polish Academy of Sciences Medical Research Centre since 2003. This transgenic model, generated by Howland et al. (Proc Natl Acad Sci USA 2002; 99: 1604-1609), has been obtained under the material transfer agreement from Wyeth Corporation. The transgenic SOD1G93A (or 'Howland') rats develop neurological and neuropathological symptoms reminiscent of human ALS, i.e. progressive loss of motoneurons leading to paralysis and death. This paper describes maintenance of the transgenic rat colony, and general procedures used in experiments with these animals (i.e. genotyping, neurological observations, anaesthesia, etc.). At the beginning of the colony, up to the 3rd generation of the rats, symptoms of the model disease appeared at 95-125 days of age...

PeerJ

In some countries, anabolic-androgenic steroid abuse is rampant among adolescent boys and young m... more In some countries, anabolic-androgenic steroid abuse is rampant among adolescent boys and young men, including some of those seeking physical fitness and/or pleasing appearance through various exercise types. This tactic carries the risk of severe harmful health effects, including liver injury. Most anabolic-androgenic steroid stacking protocols employed are based on the use of the ‘prototypic’ anabolic-androgenic steroid testosterone and/or its esters. There is a vast body of data on the effects of anabolic-androgenic steroids’ abuse combined with physical exercise training on the liver antioxidant barrier in adult subjects, whereas those concerning adolescents are scant. This study aimed to assess, in adolescent male Wistar rats undergoing a 6-week moderate-intensity endurance training (treadmill running), the influence of concurrent weekly supplementation with intramuscular testosterone enanthate (TE, 8 or 80 mg/kg body weight/week) on selected indices of liver status and oxidati...

Behavioural Brain Research

Measuring ultrasonic vocalizations (USVs) allows studying psychoactive drug use-related affective... more Measuring ultrasonic vocalizations (USVs) allows studying psychoactive drug use-related affective states in laboratory rats and may help understand changes underlying the progress of addictions. We aimed at finding an effective scheme for amphetamine self-administration training in rats, identifying factors affecting their anticipatory and drug-evoked, frequency-modulated 50-kHz USV responses, and verifying whether the rewarding action of amphetamine promotes current drug intake during the training. Therefore, we monitored amphetamine intake and anticipatory and drug-evoked USVs in two rat cohorts trained using two different training schemes. Then we retrospectively divided these cohorts into low-amphetamine and high-amphetamine intake subsets and analyzed their frequency-modulated 50-kHz USV responses accordingly. Anticipatory (i.e., drug-context-related) USVs as well as USVs induced by self-administration training-related non-pharmacological manipulations (tested in an additional rat group) showed surprisingly high call rates but faded spontaneously relatively quickly. Only the scheme employing short cycles of training sessions (two instead of six) and intermittent instead of continuous intra-session drug availability yielded long-lasting escalation of amphetamine intake in a sizable subset. This subset showed high initial amphetamine-evoked USV call rate, which suggests that a strong rewarding action of the drug early in the SA training favors intake escalation. A major decrease in the drug-evoked USVs during advanced training indicated the emergence of tolerance to the rewarding action in these rats, a phenomenon that is characteristic of addiction. Frequency-modulated 50-kHz rat USVs are a good index of the rewarding action of amphetamine at the absence of USVs induced by drug context and other training-related factors.

Folia Neuropathologica

Lower motoneurons (MNs) show varied vulnerability in amyotrophic lateral sclerosis (ALS): those o... more Lower motoneurons (MNs) show varied vulnerability in amyotrophic lateral sclerosis (ALS): those of non-ocular brainstem nuclei and most of those of the spinal cord are highly vulnerable, while those of extraocular brainstem nuclei are quite resistant. Results of our former study on the immunoexpression of the survival of motor neuron protein (SMN) and Gemins 2-4 in cervical spinal cord anterior horn α-MNs of sporadic ALS patients suggested that a relative deficit in Gemin2 may play some role in the pathomechanism of the disease. Here, we tested this idea further by comparing immunoexpression patterns of SMN and Gemins 2-8 between MNs of the oculomotor nucleus and α-MNs of the cervical spinal cord anterior horns in autopsy material from sALS patients and controls. In the latter, no considerable difference in any studied protein was found between these structures except that SMN expression was slightly but significantly lower (p < 0.01) in the oculomotor MNs. In the sporadic ALS patients, the expression of SMN, Gemin4 and Gemin7 was significantly weaker (p < 0.05, p < 0.05 and p < 0.01, respectively), while that of Gemin8 was stronger (p < 0.001) in the MNs of the oculomotor nucleus than in the examined cervical spinal cord anterior horn α-MNs. The immunoexpression of Gemin3 and Gemin6 in the spinal cord correlated strongly negatively with ALS duration (Spearman's correlation coefficient: R S =-0.84, p < 0.001, and R S =-0.86, p = 0.002, respectively). In the oculomotor nucleus MNs, no studied protein immunoexpression correlated significantly with ALS duration, but there was a tendency for such negative correlation for Gemin2 (R S =-0.56, p = 0.07). There was an apparent relative deficit of Gemin2 and Gemin8 in the spinal cord α-MNs and of Gemins 2, 4 and 7 in the oculomotor nucleus MNs. These data do not support the hypothesis that the diverse ALS vulnerability of the two MN subsets is related to their disparate expression patterns of SMN and Gemins 2-8. The differences in these patterns may result from ALS-related epiphenomena, or from intrinsic differences in the structure and function between the MN subsets, or both.

Pharmacological reports : PR, Jan 11, 2017

Anabolic-androgenic steroids abuse is on the rise among adolescent boys and young men, mostly in ... more Anabolic-androgenic steroids abuse is on the rise among adolescent boys and young men, mostly in those seeking a 'shortcut' to an improved body image. This approach is associated with the risk of severe adverse health effects, some of which involve the liver and are linked to hepatic oxidative stress. Testosterone and its esters is a cornerstone of most anabolic-androgenic steroid stacking protocols. We assessed and compared several hepatotoxicity and liver oxidative stress indices, as well as the contents of some components of the hepatic antioxidant barrier between sedentary adolescent male rats given a 6-week course of weekly im testosterone enanthate (TE, 8 or 80mg/kgBW/week) or vehicle (sesame oil) injections. Blood and livers for the assessments were harvested seven days after the last injection. TE supplementation dose-dependently elevated blood testosterone and significantly increased the liver content of thiobarbituric acid-reactive substances. Only the high-dose TE...

Folia Neuropathologica, 2016

An excessive glutamate level can result in excitotoxic damage and death of central nervous system... more An excessive glutamate level can result in excitotoxic damage and death of central nervous system (CNS) cells, and is involved in the pathogenesis of many CNS diseases. It may also be related to a failure of the blood-spinal cord barrier (BSCB). This study was aimed at examining the effects of extended administration of monosodium glutamate on the BSCB and spinal cord cells in adult male Wistar rats. The glutamate was delivered by subarachnoidal application of glutamate-carrying electrospun nanofiber mat dressing at the lumbar enlargement level. Half of the rats with the glutamate-loaded mat application were treated systemically with the histone deacetylase inhibitor valproic acid. A group of intact rats and a rat group with subarachnoidal application of an 'empty' (i.e., carrying no glutamate) nanofiber mat dressing served as controls. All the rats were euthanized three weeks later and lumbar fragments of their spinal cords were harvested for histological, immunohistochemical and ultrastructural studies. The samples from controls revealed normal parenchyma and BSCB morphology, whereas those from rats with the glutamate-loaded nanofiber mat dressing showed many intraparenchymal microhemorrhages of variable sizes. The capillaries in the vicinity of the glutamate-carrying dressing (in the meninges and white matter alike) were edematous and leaky, and their endothelial cells showed degenerative changes: extensive swelling, enhanced vacuolization and the presence of vascular intraluminal projections. However, endothelial tight junctions were generally well preserved. Some endothelial cells were dying by necrosis or apoptosis. The adjacent parenchyma showed astrogliosis with astrocytic hypertrophy and swelling of perivascular astrocytic feet. Neurons in the parenchyma revealed multiple symptoms of degeneration, including, inter alia, perikaryal, dendritic and axonal swelling, and destruction of organelles. All the damage symptoms were slightly less severe in the rats given valproic acid treatment, and were absent from both the intact rats and the rats with 'empty' nanofiber mat dressing. These results demonstrate that glutamate-loaded nanofiber mat dressing can locally create glutamate levels capable of damaging BSCB and that the resulting damage can be mitigated with concurrent systemic valproate treatment.

Neuroscience Research, 1997

Brain Research, 2016

Individuals predisposed to addiction constitute a minority of drug users, in both humans and anim... more Individuals predisposed to addiction constitute a minority of drug users, in both humans and animal models of the disorder, but there are no established characteristics that would allow identifying them beforehand. Our studies demonstrate that sensitization of rat 50-kHz ultrasonic vocalization (USV) response to amphetamine shows marked inter-individual diversity but substantial intra-individual stability. Low sensitization of the response shows relevance to the acquisition of self-administration of this drug and hence might be of predictive value regarding the risk of addiction. We compared amphetamine-induced Fos expression in 16 brain regions considered important for the development of addiction between rats preselected for low and high sensitization of the response and next given nine daily amphetamine doses followed by a 2-week withdrawal and final amphetamine challenge. Ventral tegmental area and nucleus accumbens shell Fos-positive nuclei counts correlated positively with 50-kHz USV response to the challenge in high-sensitized rats. Compared to those in amphetamine-untreated controls, Fos-positive nuclei counts were significantly and markedly (2-6 times) higher in 12 regions in high-sensitized rats, whereas in low-sensitized rats they were significantly higher in the cingulate cortex and dorsomedial striatum only. The difference in the counts between the latter two subsets reached statistical significance in dorsomedial and dorsolateral striatum and three out of four cortical regions studied. The fact that the diversification was most distinct in dorsal striatum that plays a critical role in the transition from controlled to compulsive drug intake suggests that the USV-based categorization may be related to divergent vulnerability of rats to AMPH addiction.

Acta neurobiologiae experimentalis, 2016

Adult mammalian brain contains a number of specialized neurovascular structures termed "nich... more Adult mammalian brain contains a number of specialized neurovascular structures termed "niches" that act as sources of neuronal cells throughout the individual's life. Some of the niches generate neurons to satisfy the need for 'replacement' neurons within the same or closely located brain structures, whereas the other can provide such cells for more distant destinations in the brain. A common characteristic of known neurovascular niches is the presence of a complex 3-dimensional network of basal lamina processes, called fractones. It apparently plays a major role in communication between the various niche-populating cell types as well as in niche activity and output. We hypothesized that similar niches may form ad hoc after a mechanical brain trauma, and tested this possibility in a rat model of surgical brain injury. Four days after removing a small fragment of sensorimotor cortex, the peri-wound region showed numerous symptoms of active repair and remodeling...

Psychopharmacology, 2016

Rationale Our previous studies showed promise for using sensitization of the frequency-modulated ... more Rationale Our previous studies showed promise for using sensitization of the frequency-modulated 50-kHz vocalization response to amphetamine (AMPH) as an index of rat vulnerability to AMPH addiction. Objective This study aimed to test the utility of sensitizing frequency-modulated (FM) 50-kHz vocalization in the AMPH self-administration paradigm as well as the ability of N-acetylcysteine to prevent self-administration relapse. Methods Rats were subjected to the so-called two-injection protocol of sensitization (TIPS) using AMPH and were categorized as low-sensitized callers (LC TIPS) or high-sensitized callers (HC TIPS) based on the individual outcomes. Then, they were given 44 sessions of AMPH self-administration followed by a 17-session N-acetylcysteine-aided extinction course and a single session of AMPH-primed self-administration reinstatement. Results LC TIPS compared to HC TIPS rats showed no considerable difference in the FM 50-kHz vocalization rate during the self-administration training or extinction course, but they were considerably more likely to acquire AMPH selfadministration and experience drug-induced reinstatement of this trait. Moreover, the LC TIPS rats were more likely than HC TIPS rats to have a markedly higher FM 50-kHz vocalization rate after AMPH reinstatement. N-acetylcysteine did not affect the course of self-administration extinction or the instrumental or FM 50-kHz vocalization responses to AMPH reinstatement. Conclusions There is no link between the FM 50-kHz vocalization and key characteristics of AMPH self-administration. Additionally, N-acetylcysteine does not help prevent AMPH self-administration relapse. However, there is a high predictive value for poor sensitization of the FM 50-kHz vocalization response to AMPH with respect to the acquisition and maintenance of self-administration of this psychostimulant.

Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences, 2015

Amyotrophic lateral sclerosis (ALS) is a fatal incurable neurodegenerative disease whose etiology... more Amyotrophic lateral sclerosis (ALS) is a fatal incurable neurodegenerative disease whose etiology is unknown and pathogenesis is still not fully understood. A great majority of its cases are sporadic. Clinical ALS signs are caused by damage and dying-out of the lower and upper motor neurons. This study was aimed at identifying possible sporadic ALS-associated aberrations in the spinal cord expression of the transcription nuclear factor κ light-chain-enhancer of activated B cells (NF-κB). NF-κB is widely distributed among various cell types, including those specific for the central nervous system (CNS), and is involved in the control of many physiological and pathological processes, including, inter alia, inflammatory response, proliferation, angiogenesis, and cell survival and death. It is constitutively expressed and its inactive form resides in the cytoplasm. After activation, it enters the cell nucleus and promotes the transcription of target genes. NF-κB is a dimer and its most ...

Journal of Neurochemistry, 1994

3-Methoxytyramine (3-MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used,... more 3-Methoxytyramine (3-MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used, respectively, to assess the dynamics of dopamine (DA) release and turnover in the rat frontal cortex, nucleus accumbens, and striatum. Assuming total (re)uptake and metabolism of released DA are relatively uniform among the three brain regions, a simplified two pool model was used to assess the metabolic fate of released DA. Under basal conditions, 3-MT formation was found to comprise > 60% of total DA turnover (sum of 3-MT plus DOPAC rates of formation) in the frontal cortex, and not more than 15% in the nucleus accumbens and striatum. Haloperidol increased the 3-MT rate of formation to a greater extent in the frontal cortex than in the two other regions. Clozapine increased the 3-MT rate of formation in the frontal cortex and decreased it in the striatum. Both drugs increased DOPAC rate of formation in the frontal cortex and nucleus accumbens. It was elevated by haloperidol but not clozapine in the striatum. It is concluded that (1) O-methylation is a prominent step in the catabolism of DA in the frontal cortex under both physiological conditions and after acute treatment with antipsychotics, (2) 3-MT is the major metabolite of released DA in the frontal cortex and possibly also in the nucleus accumbens and striatum, (3) in contrast to the frontal cortex, most of the DOPAC in the nucleus accumbens and striatum appear to originate from intraneuronal deamination of DA that has not been released, (4) because presynaptic uptake and metabolism of DA give rise to DOPAC, whereas postsynaptic uptake and metabolism produced both DOPAC and 3-MT, the ratio of 3-MT to DOPAC rates of formation can be a useful index of reuptake inhibition.

Folia Histochemica Et Cytobiologica, Feb 1, 2002

A random finding of intracranial vascular Chlamydia sp. infection in Wistar rats and its associat... more A random finding of intracranial vascular Chlamydia sp. infection in Wistar rats and its associated damage of the component tissues of the basilar arterial wall are described as seen with transmission electron microscopy. The pathological changes observed showed no apparent specificity except for &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;striding&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; of the endothelial cells on the elastic lamina, the phenomenon observed in all five rats with basilar arterial Chlamydia infection, and in only two out of 13 rats with no proof of the infection. No atherosclerotic changes were found in the infected artery in rats sacrificed 8 or 26 weeks after the presumed infection.

J Neurochem, 2002

ABSTRACT 3-Methoxytyramine (3-MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation w... more ABSTRACT 3-Methoxytyramine (3-MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used, respectively, to assess the dynamics of dopamine (DA) release and turnover in the rat frontal cortex, nucleus accumbens, and striatum. Assuming total (re)uptake and metabolism of released DA are relatively uniform among the three brain regions, a simplified two pool model was used to assess the metabolic fate of released DA. Under basal conditions, 3-MT formation was found to comprise > 60% of total DA turnover (sum of 3-MT plus DOPAC rates of formation) in the frontal cortex, and not more than 15% in the nucleus accumbens and striatum. Haloperidol increased the 3-MT rate of formation to a greater extent in the frontal cortex than in the two other regions. Clozapine increased the 3-MT rate of formation in the frontal cortex and decreased it in the striatum. Both drugs increased DOPAC rate of formation in the frontal cortex and nucleus accumbens. It was elevated by haloperidol but not clozapine in the striatum. It is concluded that (1) O-methylation is a prominent step in the catabolism of DA in the frontal cortex under both physiological conditions and after acute treatment with antipsychotics, (2) 3-MT is the major metabolite of released DA in the frontal cortex and possibly also in the nucleus accumbens and striatum, (3) in contrast to the frontal cortex, most of the DOPAC in the nucleus accumbens and striatum appear to originate from intraneuronal deamination of DA that has not been released, (4) because presynaptic uptake and metabolism of DA give rise to DOPAC, whereas postsynaptic uptake and metabolism produced both DOPAC and 3-MT, the ratio of 3-MT to DOPAC rates of formation can be a useful index of reuptake inhibition.