Circadian variations of serotonin in plasma and different brain regions of rats

Most of the physiological processes that take place in the organism follow a circadian rhythm. Serotonin is one of the most important neurotransmitters in our nervous system, and has been strongly implicated in the regulation on the mammalian circadian clock, located in the suprachiasmatic nuclei (SCN). The present study analysed the levels of serotonin over a period of 24 h in the plasma and in different brain regions. The model used was of male Wistar rats, 14 +/- 2 weeks of age (n = 120), maintained under conditions of 12 h light and 12 h dark, and food and water ad libitum. The serotonin levels were measured by ELISA every hour at night (20:00-08:00 h) and every 4 h during the daytime (08:00-20:00 h). Ours results show that the maximum levels of serotonin in plasma were obtained at 09:00 and 22:00 and a minor peak at 01:00 h. In hypothalamus there was a significant peak at 22:00 and two minor peaks at 17:00 and 02:00 h; the same occurred in hippocampus with a significant peak at 21:00, and two secondary peaks at 24:00 and 05:00 h; in cerebellum there were two peaks at 21:00 and 02:00 h, while in striatum and pineal there were peaks at 21:00 h and 23:00, respectively. In conclusion, the higher levels of serotonin were during the phase of darkness, which varies depending on the region in which it is measured.     

Comparison of the efficacy of morning versus evening administration of olmesartan in uncomplicated essential hypertension

A total of 18 diurnally active subjects with uncomplicated, mild to moderate, essential hypertension were studied to compare the efficacy of the morning versus evening administration of an oral olmesartan medication. After a two-week, wash-out/placebo run-in period, subjects with clinic diastolic blood pressure (DBP) > or = 90 mm Hg and <110 mm Hg began 12 weeks of 20 mg olmesartan medoxomil tablet therapy at 08:00 h daily. Four of the 18 subjects required dose escalation to 40 mg at eight weeks because of clinic DBP > or = 90 mm Hg. After the 12-week period of once-a-day 08:00 h treatment, subjects were immediately switched to an evening (20:00 h) drug-ingestion schedule for another 12-week period without change in dose. Subjects underwent 24 h ambulatory blood pressure monitoring (ABPM) before the initiation of morning treatment and at the end of both the 12-week morning and evening treatment arms. Dosing time did not exert statistically significant differences on the efficacy of olmesartan: the reduction from baseline in the 24 h mean systolic (SBP) and DBP was, respectively, 18.8 and 14.6 mm Hg with morning dosing and 16.1 and 13.2 mm Hg with evening dosing (p>0.152 between groups). The amplitude of the BP 24 h pattern did not vary with dosing time, indicating full 24 h BP reduction no matter the clock hour of treatment. Although, the BP-lowering effect was somewhat better with morning dosing, the results of this study suggest that the studied olmesartan medoxomil preparation efficiently reduces BP when ingested in the morning (08:00 h) or evening (20:00 h) in equivalent manner, based on statistical testing, throughout the 24 h.     

Comparison of the Efficacy of Morning versus Evening Administration of Olmesartan in Uncomplicated Essential Hypertension

A total of 18 diurnally active subjects with uncomplicated, mild to moderate, essential hypertension were studied to compare the efficacy of the morning versus evening administration of an oral olmesartan medication. After a two‐week, wash‐out/placebo run‐in period, subjects with clinic diastolic blood pressure (DBP) ≥90 mm Hg and <110 mm Hg began 12 weeks of 20 mg olmesartan medoxomil tablet therapy at 08:00 h daily. Four of the 18 subjects required dose escalation to 40 mg at eight weeks because of clinic DBP≥90 mm Hg. After the 12‐week period of once‐a‐day 08:00 h treatment, subjects were immediately switched to an evening (20:00 h) drug‐ingestion schedule for another 12‐week period without change in dose. Subjects underwent 24 h ambulatory blood pressure monitoring (ABPM) before the initiation of morning treatment and at the end of both the 12‐week morning and evening treatment arms. Dosing time did not exert statistically significant differences on the efficacy of olmesartan: the reduction from baseline in the 24 h mean systolic (SBP) and DBP was, respectively, 18.8 and 14.6 mm Hg with morning dosing and 16.1 and 13.2 mm Hg with evening dosing (p>0.152 between groups). The amplitude of the BP 24 h pattern did not vary with dosing time, indicating full 24 h BP reduction no matter the clock hour of treatment. Although, the BP‐lowering effect was somewhat better with morning dosing, the results of this study suggest that the studied olmesartan medoxomil preparation efficiently reduces BP when ingested in the morning (08:00 h) or evening (20:00 h) in equivalent manner, based on statistical testing, throughout the 24 h.     

Circadian Variation in the Intracortical Accumulation Kinetics of Tobramycin in Conscious Rats

The time-dependent variation in the renal accumulation of aminoglycosides has not been extensively investigated. The aim of the present study was to better characterize the temporal variation in the intracortical accumulation kinetics of tobramycin. Female Sprague-Dawley rats weighing 210–254 g were maintained in a 14 h light/10 h dark cycle (light on 06h00–20h00). They were infused for 6 h with tobramycin to achieve individual steady-state serum levels of 0.5–15 μg/ml over four different periods of the day (02h00–08h00; 08h00–14h00; 14h00–20h00; and 20h00–02h00). As previously reported, the steady-state elevation of serum tobramycin concentrations was associated with a linear increase of the cortical concentration in all groups. The tobramycin accumulation rate was significantly lower in animals infused at 20h00–02h00 compared to rats infused at 08h00–14h00 (p < 0.001). The data suggest that the lower rate of tobramycin accumulation during the dark period might be responsible for the lower toxicity observed during this time.     

Differences in Dopamine Clearance and Diffusion in Rat Striatum and Nucleus Accumbens Following Systemic Cocaine Administration

Acute cocaine administration preferentially increases extracellular dopamine levels in nucleus accumbens as compared with striatum. To investigate whether a differential effect of cocaine on dopamine uptake could explain this observation, we used in vivo electrochemical recordings in anesthetized rats in conjunction with a paradigm that measures dopamine clearance and diffusion without the confounding effects of release. When a finite amount of dopamine was pressure-ejected at 5-min intervals from a micropipette adjacent to the electrode, transient and reproducible increases in dopamine levels were detected. In response to 15 mg/kg of cocaine-HCl (i.p.), these signals increased in nucleus accumbens, indicating significant inhibition of the dopamine transporter. The time course of the dopamine signal increase paralleled that of behavioral changes in unanesthetized rats receiving the same dose of cocaine. In contrast, no change in the dopamine signal was detected in dorsal striatum; however, when the dose of cocaine was increased to 20 mg/kg, enhancement of the dopamine signal occurred in both brain areas. Quantitative autoradiography with [3H]mazindol revealed that the affinity of the dopamine transporter for cocaine was similar in both brain areas but that the density of [3H]mazindol binding sites in nucleus accumbens was 60% lower than in dorsal striatum. Tissue dopamine levels in nucleus accumbens were 44% lower. Our results suggest that a difference in dopamine uptake may explain the greater sensitivity of nucleus accumbens to cocaine as compared with dorsal striatum. Furthermore, this difference may be due to fewer dopamine transporter molecules in nucleus accumbens for cocaine to inhibit, rather than to a higher affinity of the transporter for cocaine.     

Post-mortem changes of neurotransmitter concentrations in the rat brain regions

Using High Performance Liquid Chromatography coupled with electrochemical detection the post-mortem stability of noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxy indole acetic acid (5-HIAA) were examined in the rat hypothalamus, amygdala, cerebral cortex, cerebellum and corpus striatum over an 8 hour time period. Changes in concentrations of the different neurotransmitters were less than it might be expected. The significant changes were: a. A fall in NA levels in the cerebral cortex by 4 hours and in the hypothalamus at 8 hours. b. A reduction in DA concentrations in the corpus striatum at 8 hours but a two fold rise of levels in the hypothalamus at 1 and 2 hours. c. A four-fold increase in 5-HT concentrations in the amygdala throughout the 8 hours studied. The results indicate that for comparative studies on post-mortem brain tissue correction factors should be employed to take into account differential changes in the concentrations of the various neurotransmitters.     

Brain mast cells and therapeutic potential of vasoactive intestinal peptide in a Parkinson's disease model in rats: brain microdialysis, behavior, and microscopy

In the present study, the effect of systemically administered vasoactive intestinal peptide (VIP) (25 ng/kg i.p.) was investigated on drug-induced rotational behavior, extra-cellular dopamine levels and histology of corpus striatum in a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. After 15 days of 6-OHDA lesion, apomorphine-induced (0.05 mg/kg s.c.) rotational behavior of the animals significantly increased and extra-cellular dopamine levels of corpus striatum were significantly reduced. VIP reversed the rotational deficits but did not alter the decrease in striatal dopamine levels. On the other hand, histological data indicate that VIP significantly reduced neuronal death and demyelination. Electron microscopic appearance of mast cells showed ultra-structural variety between VIP-treated and 6-OHDA lesioned groups. VIP activates mast cells without any evidence of typical exocytosis, and possibly mast cells could participate in neuroprotection. Our results suggest that systemically administered VIP can attenuate the motor response changes, neuronal cell death, and myelin sheet loss characteristically associated with 12 microg 6-OHDA administration into the rat striatum. Brain mast cells seem to participate in neuronal protection. Possibly, protective cues could be produced by brain mast cells.     

Chronopharmacokinetic study of gentamicin in dogs

The purpose of this experiment was to determine whether the time of day of single intravenous doses of gentamicin affects the drug's pharmacokinetics in dogs maintained under a 12 h light (08:00 to 20:00 h), 12 h dark (20:00 to 08:00 h) cycle. Using a crossover design, 6 mixed-breed male dogs received a single dose of 2 mg/kg of gentamicin at 8:00 or 20:00 h. Serial blood samples were collected and pharmacokinetic parameters were calculated following each timed dose. The concentration of the antibiotic was lower following the 08:00 h compared to the 20:00 h administration. When gentamicin was administered at 20:00 h, the initial concentration, mean residence time, and area under the disposition curve were significantly higher (p < 0.05) and the apparent volume of distribution of the central compartment, apparent volume of distribution, apparent volume of distribution at steady-state, and total body clearance (1.73+/-0.55 at 20:00 h versus 3.31+/-0.67 L/min/kg at 08:00 h) were significantly lower than for the 08:00 h administration (p < 0.05). Our results show that the pharmacokinetics of gentamicin exhibits significant temporal variation when administered to dogs at different times of day.     

Diurnal variations of serum GM-CSF levels

We aimed to investigate the daily variations of serum granulocyte-macrophage colony-stimulating factor (GM-CSF) levels and to correlate them with peripheral blood cells counts. Venous blood samples from eleven healthy volunteers were taken four times a day, being at 08:00, 14:00, 20:00 and 02:00h and serum GM-CSF levels measured by ELISA. We could not find a significant overall difference among GM-CSF levels at four different times of the day using the Friedman test. On the other hand, serum GM-CSF levels at night (20:00h) were found to be significantly increased when compared to the morning levels (08:00h) using the Wilcoxon test (P=0. 022). The levels of lymphocytes and white blood cells (WBCs) at 20:00h were also higher than the morning levels (08:00h) as expected. While there was a strong relationship between the morning levels of GM-CSF (08:00h) and all measurements of peripheral blood cells during the day, the levels of GM-CSF measured at 02:00, 14:00 and 20:00h were found to be significantly correlated with only the WBC levels. It was concluded that there may be a significant difference between morning and night levels of GM-CSF and morning levels of GM-CSF may be more important in the regulation of WBC counts during the day. These variations warrant further studies about diurnal rhythms of haematopoiesis chronotherapy with CSFs.     

Circadian rhythm in circulating CD16-positive natural killer (NK) cells in macaque monkeys,implication of plasma cortisol levels

The daily change in both percentage and absolute number of circulating major lymphocyte subset was determined with young Japanese monkeys and rhesus monkeys. The blood sample was collected at four hour-intervals beginning at 16:00 for 24 hours under the condition of applying tethering system by which blood samples could be collected without restraint. During the dark period (from 20:00 to 08:00), the number of peripheral lymphocytes increased and that of granulocytes decreased, resulting in no significant change in the number of total peripheral white blood cells. The absolute number of CD4 + T, CD8 + T, and CD20 + B cells showed the significant daily change similar to that in number of peripheral lymphocytes, indicating no proportional change in these subsets. The typical proportional change was observed in CD16 + natural killer (NK) cells and the percentage of CD16 + cells decreased during dark period (from 20:00 to 04:00) and increased in the morning (from 08:00 to 12:00). The NK activity determined by killing K562 target cells showed the same changing pattern as that of percentage in CD16+ NK cells. The changing pattern of both percentage and activity of NK cells was consistent with that of plasma cortisol levels. In addition, the intravenous injection of 300 μg/kg of cortisol induced increase in plasma cortisol levels and decrease in percentage of CD16 + NK cells during the first 60 min after cortisol injection. These results strongly suggest that the levels of peripheral functional CD16 + NK cells might be directly regulated by plasma cortisol level in macaque monkeys.     

Glutamate (mGluR-5) gene expression in brain regions of streptozotocin induced diabetic rats as a function of age: role in regulation of calcium release from the pancreatic islets in vitro

Metabotrophic glutamate receptors (mGluRs) modulate cellular activities involved in the processes of differentiation and degeneration. In this study, we have analysed the expression pattern of group-I metabotropic glutamate receptor (mGlu-5) in cerebral cortex, corpus striatum, brainstem and hippocampus of streptozotocin induced and insulin treated diabetic rats (D+I) as a function of age. Also, the functional role of glutamate receptors in intra cellular calcium release from the pancreatic islets was studied in vitro. The gene expression studies showed that mGlu-5 mRNA in the cerebral cortex increased siginficantly in 7 weeks old diabetic rats whereas decreased expression was observed in brainstem, corpus striatum and hippocampus when compared to control. 90 weeks old diabetic rats showed decreased expression in cerebral cortex, corpus striatum and hippocampus whereas in brainstem the expression increased significantly compared to their respective controls. In 7 weeks old D+I group, mGlu-5 mRNA expression was significantly decreased in cerebral cortex and corpus striatum whereas the expression increased significantly in brainstem and hippocampus. 90 weeks old D+I group showed an increased expression in cerebral cortex, while it was decreased significantly in corpus striatum, brainstem and hippocampus compared to their respective controls. In vitro studies showed that glutamate at lower concentration (10^-7 M) stimulated calcium release from the pancreatic islets. Our results suggest that mGlu-5 receptors have differential expression in brain regions of diabetes and D+I groups as a function of age. This will have clinical significance in management of degeneration in brain function and memory enhancement through glutamate receptors. Also, the regulatory role of glutamate receptors in calcium release has immense therapeutic application in insulin secretion and function.     

Chronopharmacokinetic Study of Gentamicin in Dogs

The purpose of this experiment was to determine whether the time of day of single intravenous doses of gentamicin affects the drug's pharmacokinetics in dogs maintained under a 12 h light (08:00 to 20:00 h), 12 h dark (20:00 to 08:00 h) cycle. Using a crossover design, 6 mixed‐breed male dogs received a single dose of 2 mg/kg of gentamicin at 8:00 or 20:00 h. Serial blood samples were collected and pharmacokinetic parameters were calculated following each timed dose. The concentration of the antibiotic was lower following the 08:00 h compared to the 20:00 h administration. When gentamicin was administered at 20:00 h, the initial concentration, mean residence time, and area under the disposition curve were significantly higher (p<0.05) and the apparent volume of distribution of the central compartment, apparent volume of distribution, apparent volume of distribution at steady‐state, and total body clearance (1.73±0.55 at 20:00 h versus 3.31±0.67 L/min/kg at 08:00 h) were significantly lower than for the 08:00 h administration (p<0.05). Our results show that the pharmacokinetics of gentamicin exhibits significant temporal variation when administered to dogs at different times of day.     

Effects of Cannabinoids on Dopamine Release in the Corpus Striatum and the Nucleus Accumbens In Vitro

Cannabinoid receptors are widely distributed in the nuclei of the extrapyramidal motor and mesolimbic reward systems; their exact functions are, however, not known. The aim of the present study was to characterize the effects of cannabinoids on the electrically evoked release of endogenous dopamine in the corpus striatum and the nucleus accumbens. In rat brain slices dopamine release elicited by single electrical pulses was determined by fast cyclic voltammetry. Dopamine release was markedly inhibited by the OP2 opioid receptor agonist U-50488 and the D2/D3 dopamine receptor agonist quinpirole, indicating that our method is suitable for studying presynaptic modulation of dopamine release. In contrast, the CB1/CB2 cannabinoid receptor agonists WIN55212-2 (10(-6) M) and CP55940 (10(-6)-10(-5) M) and the CB1 cannabinoid receptor antagonist SR141716A (10(-6) M) had no effect on the electrically evoked dopamine release in the corpus striatum and the nucleus accumbens. The lack of a presynaptic effect on terminals of nigrostriatal and mesolimbic dopaminergic neurons is in accord with the anatomical distribution of cannabinoid receptors: The perikarya of these neurons in the substantia nigra and the ventral tegmental area do not synthesize mRNA, and hence protein, for CB1 and CB2 cannabinoid receptors. It is therefore unlikely that presynaptic modulation of dopamine release in the corpus striatum and the nucleus accumbens plays a role in the extrapyramidal motor and rewarding effects of cannabinoids.     

Effect of aging on 24-hour changes in dopamine and serotonin turnover and amino acid and somatostatin contents of rat corpus striatum

This study examined the 24-hour changes in a number of transmitters in the corpus striatum of young and middle-aged male Wistar rats. The contents of excitatory amino acids (glutamate, aspartate) and inhibitory amino acids (gamma-aminobutyric acid, GABA; taurine, glycine) and of somatostatin were measured in 2-month- and 18- to 20-month-old rats killed at six different time points along the 24-hour cycle. The striatal serotonin and dopamine turnover was also measured. Both young and middle-aged rats showed significant 24-hour variations in striatal glutamate and aspartate contents; only in young rats these variations fitted a cosine function, with acrophase during the first part of rest span. Mesor values of striatal excitatory amino acid contents were lowest in middle-aged rats. Significant 24-hour variations in striatal contents of GABA, taurine, and glycine occurred in young rats, while only striatal GABA exhibited 24-hour changes in middle- aged rats (acrophases during the first part of rest span). For every inhibitory transmitter, the mesor values in middle-aged rats were significantly lower than in young rats. The 24-hour variation of the striatal somatostatin content showed acrophase during the first part of rest span, mesor values and amplitude being lowest in middle-aged rats. Aging rats exhibited significantly higher mesor values of striatal serotonin turnover (34% increase) and lower mesor values of dopamine turnover (69% decrease) than their younger counterparts. Some of the circadian modifications of motor function seen in aging rats could be related to the striatal transmitter changes reported herein.     

The development of dopamine overflow from foetal nigral grafts in the intact rat striatum and their influence on contralateral striatal dopamine overflow.

In this study, cell suspensions of foetal rat ventral mesencephalic dopaminergic tissue were grafted to the intact (non-lesioned) striatum of adult rats. Differential pulse voltammetry at carbon-fibre micro electrodes (12 microm diameter) was employed to first, monitor the development of dopamine overflow over a 20 week period within the grafts and secondly, their influence on contralateral striatal dopamine overflow. At 8 and 20 weeks, animals were pre-treated with pargyline and both striata were monitored for dopamine overflow for 90 min following d-amphetamine administration. Amphetamine led to a significant increase in dopamine overflow in both the grafted striatum and the contralateral striatum. The time course of dopamine overflow in both the grafted striatum and the striatum contralateral to the graft was similar in all groups of animals. Although the actual concentration of dopamine measured in 20 week old grafts was more (approximately 21%) than that measured in 8 week old grafts, there was no significant difference between the two time points. The concentration of dopamine measured in the striatum contralateral to 8 week old grafts was significantly lower (approximately 43%) than that measured in the striatum of a normal control rats. There was no significant difference between the concentration of dopamine measured in the striatum contralateral to 20 week old grafts and normal control rats. In conclusion, dopamine overflow from a ventral mesencephalic graft does not change significantly between 8 and 20 weeks following grafting. However, the grafted tissue causes a decrease of d-amphetamine-induced dopamine overflow in the contralateral side 8 weeks following grafting, which is restored 12 weeks later.     

Dopamine Uptake is Differentially Regulated in Rat Striatum and Nucleus Accumbens

Active uptake of 3,4-dihydroxyphenylethylamine (dopamine) is sodium- and temperature-dependent, strongly inhibited by benztropine and nomifensine, and present in corpus striatum and nucleus accumbens. In rat striatum dopamine uptake is related to a receptor that is specifically labelled by [3H]cocaine in the presence of Na+ and is located on dopaminergic terminals. The dopamine uptake is differentially affected in the two areas by single or repeated injections of cocaine. Cocaine inhibits dopamine uptake in slices of corpus striatum. Moreover Na+-dependent [3H]cocaine binding is not detectable in nucleus accumbens. Nomifensine inhibits [3H]dopamine uptake by interacting with low- and high-affinity sites in corpus striatum, but shows only low affinity for dopamine uptake in nucleus accumbens. The present data indicate that different mechanisms are involved in the regulation of dopamine uptake in corpus striatum and nucleus accumbens.     

The effects of feeding and housing on the behaviour of the laboratory rabbit

The effects of housing, feeding time and diet composition on the behaviour of the laboratory rabbit were examined. The animals were caged individually in single or double metal cages with perforated metal floors, metal walls, and bars in the front, or kept as a group in floor pens. The light/dark cycle was 12/12 h with light from 04:00 to 16:00 h and 30 min twilight. One experiment compared feeding equal energy levels of a high energy diet (10.1 MJ/kg) and with a low energy diet (7.0 MJ/kg) at 08:00 h. The second experiment compared feeding the high energy diet at 08:00 h and at 14:00 h. In both studies the behaviour of the rabbits was recorded between 08:00 and 14:00 h and between 16:00 and 22:00 h. Feeding the animals at 14:00 h reduced abnormal behaviour during the dark period compared to feeding at 08:00 h, whereas no difference in behaviour could be detected between feeding a high-energy and a low-energy diet at 08:00 h. Animals in floor pens generally showed less abnormal behaviour than caged animals. The results indicate that the welfare for caged rabbits can be improved by feeding the animals in the afternoon rather than in the morning.     

Regional Specificity in Alterations of Rat Brain Copper and Catecholamines Following Perinatal Copper Deficiency

Abstract: Perinatal copper deficiency was studied in 1-month-old female and male Sprague-Dawley rat offspring to investigate regional changes in brain copper and catecholamine levels. Offspring of dams given the low copper treatment beginning at day 7 of gestation exhibited signs characteristic of deficiency such as impaired growth and 10-fold lower liver copper levels compared with copper-adequate controls. Regional analysis of brain copper by graphite furnace atomic absorption spectroscopy revealed uniform and severe reduction of copper to levels 20 ± 3% of controls in all regions, except the hypothalamus, where reductions to 56 and 28% of those in copper-adequate females and males, respectively, were measured. HPLC analysis revealed significant reductions in norepinephrine levels in cerebrum, midbrain, corpus striatum, cerebellum, and medulla-pons of copper-deficient offspring ranging between 39 and 67% of control values. There were no significant differences in norepinephrine concentration in the hypothalamus. There was a significant, one-third reduction of dopamine in the corpus striatum of copper-deficient male rats. Consistent with altered in vivo dopamine β-monooxygenase activity, there were five-, three-, and twofold elevations of dopamine in cerebellum, medulla-pons, and hypothalamus of copper-deficient rats. Spectrophotometric measurement of in vitro dopamine β-monooxygenase activity of brain and adrenal homogenates was higher in copper-deficient rats, confirming prior work. An explanation for the in vitro data is unclear. Changes in copper and catecholamine levels were influenced by diet and were regionally selective, especially in the hypothalamus.     

Effects of long-term recovery from transient cerebral ischemia in rat brain: Tissue levels of acetylcholine,monoamines, and their metabolites

Concentrations of acetylcholine and the monoaminergic neurotransmitters dopamine, serotonin and their respective metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxyphenylacetic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and choline were simultaneously determined in the corpus striatum of rats after 15 min. complete cerebral ischemia (CCI) and in different intervals (1, 24, 48, 72, 96 hours) of postischemic cerebral reperfusion. Results were compared to respective sham-operated control animals. After 15 min. CCI acetylcholine concentration decreased to 15%, and dopamine concentration to 56% of the control values. The metabolite levels of DOPAC decreased to 40% and HVA to 64% of the control values. Acetylcholine, dopamine, serotonin and choline concentrations were not changed significantly after reperfusion. The metabolites HVA and 5-HIAA showed their maximum increases after 1 and 24 hours of reperfusion, additionally HVA was decreased both, after 72 and 96 hours of reperfusion. The data indicate that surprisingly little permanent damage could be caused by a 15 min. ischemia in the striatum. Tissue levels of the neurotransmitters appeared differentially altered but similarly regulated during ischemia and subsequent recirculation. Acetylcholine and dopamin levels decreased profoundly during ischemia. However, acetylcholine levels could be compensated rapidly during reperfusion, whereas the dopaminergic system showed a long-lasting change in its turnover rate. Although serotonin levels were unaffected by CCI, there was an increase of its presumed turnover rate during reperfusion.