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PubMed1992

The effect of peripheral loading with kynurenine and probenecid on extracellular striatal kynurenic acid concentrations.

Kynurenic acid (KYA) is the only known endogenous excitatory amino acid antagonist in mammalian brain. In the present study we examined the effects of precursor loading with kynurenine (KYN) and blockade of organic acid transport with probenecid, either alone or in combination, on extracellular striatal KYA concentrations in unanesthetized rats. Baseline KYA concentrations were 1.61 +/- 0.29 pmol/ml. Following administration of KYN 150 mg/kg with increasing doses of probenecid a maximal increase in KYA to 946 +/- 210 pmol/ml was seen with probenecid 200 mg/kg. Probenecid 200 mg/kg alone increased KYA levels to 16.0 +/- 5.2 pmol/ml. The combination of probenecid 200 mg/kg with KYN 450 mg/kg produced a maximal increase of KYA to 2085 +/- 391 pmol/ml, a 1300-fold increase indicating marked potentiation. These results show that pharmacologic manipulation can markedly increase extracellular fluid concentrations of KYA into a range which may be useful in attempts to block NMDA receptor-mediated neurotoxicity.

Animals↗
PubMed1992

Kynurenine and probenecid inhibit pentylenetetrazol- and NMDLA-induced seizures and increase kynurenic acid concentrations in the brain.

Kynurenine is a direct precursor of kynurenic acid, the only known endogenous antagonist of excitatory amino acid receptors in the brain. Kynurenine administered intraperitoneally (150, 450, 900 mg/kg) 2 h before pentylenetetrazol injection dose-dependently increased the time to seizures, the time to death and the survivorship of mice. Kynurenine dose-dependently increased the time to seizures and the time to death in mice with NMDLA-induced seizures. Kynurenine, 900 mg/kg, was equally efficacious to diazepam, 2 mg/kg. Probenecid dose-dependently increased the time to seizures, the time to death and the survivorship of mice with pentylenetetrazol-induced seizures. Probenecid had no significant effects on NMDLA-induced seizures, although the time to death was prolonged in the NMDLA 500 mg/kg group. Probenecid potentiated the effects of kynurenine in these tests. Both probenecid and kynurenine significantly increased kynurenine and kynurenic acid concentrations in mouse cerebral cortex and striatum. These findings suggest that kynurenine (metabolized to kynurenic acid) has anticonvulsant effects, and probenecid potentiates these effects in mice.

Analysis of Variance↗
PubMed2000

Probenecid-inhibitable efflux transport of valproic acid in the brain parenchymal cells of rabbits: a microdialysis study.

Delivery of valproic acid (VPA) to the human brain is relatively inefficient as reflected by a low brain-to-unbound plasma concentration ratio (< or =0.5) at steady state. Previous pharmacokinetic studies suggested that the unfavorable brain-to-plasma gradient is maintained by coupled efflux transport processes at both the brain parenchymal cells and blood-brain barrier (BBB); one or both of the efflux transporters are inhibitable by probenecid. The present study in rabbits utilized microdialysis to measure drug concentration in the brain extracellular fluid (ECF) of the cerebral cortex during steady-state i.v. infusion with VPA alone or with VPA plus probenecid. Probenecid co-infusion elevated VPA concentration in the brain tissue surrounding the tip of the microdialysis probe to a greater extent than in the ECF (230% versus 47%). Brain intracellular compartment (ICC) concentration was estimated. In control rabbits, the ICC concentration was 2.8+/-0.28 times higher than the ECF concentration. Probenecid co-infusion elevated the ICC-to-ECF concentration ratio to 4.2+/-0.44, which confirms the existence of an efflux transport system in brain parenchymal cells. The ECF-to-unbound plasma concentration ratio was well below unity (0.029), indicating an uphill efflux transport of VPA across the BBB. Co-infusion of probenecid did not have a significant effect on VPA efflux at the BBB as evidenced by a minimal change in the ECF-to-unbound plasma concentration ratio. This study suggests the presence of distinctly different organic anion transporters for the efflux of VPA at the parenchymal cells and capillary endothelium in the brain.

Animals↗
PubMed1991

Sulfate homeostasis. IV. Probenecid-induced alterations of inorganic sulfate in rats.

Homeostasis of inorganic sulfate is maintained by the capacity-limited renal reabsorption of sulfate in the proximal tubule. The purpose of the present investigation was to determine if probenecid, the classical inhibitor of renal organic anion secretion, may affect sulfate renal clearance. Two groups of rats were administered in a randomized crossover design, an i.v. bolus dose (20.6 or 92.4 mg/kg) and 4-hr infusion (0.28 or 0.59 mg/min/kg) of probenecid or vehicle, and blood and urine samples were collected. At a steady-state serum concentration of 0.45 mM, probenecid had no significant effect on the serum concentrations or renal clearance of inorganic sulfate, whereas at a serum concentration of 1.4 mM, probenecid treatment caused a significant decrease in serum sulfate concentrations (0.57 +/- 0.11 vs 0.96 +/- 0.19 mM in controls, mean +/- SD, n = 6, P less than 0.001) due to an increase in the renal clearance of sulfate (3.88 +/- 1.18 vs 2.13 +/- 0.84 ml/min/kg in controls, P less than 0.01). The fraction of the filtered sulfate that was reabsorbed was significantly decreased (0.38 +/- 0.23, vs 0.74 +/- 0.09 in controls, P less than 0.01). Therefore, probenecid treatment results in the inhibition of the renal reabsorption of inorganic sulfate in rats in vivo.

Animals↗
PubMed2002

Reduced gastrointestinal toxicity following inhibition of the biliary excretion of irinotecan and its metabolites by probenecid in rats.

PURPOSE: To ameliorate the late-onset of severe gastrointestinal toxicity provoked by irinotecan (CPT-11), which may be related to the biliary excretion of CPT-11 and/or its metabolites. METHODS: Effects of probenecid, an inhibitor of MRP2/ABCC2, on the biliary excretion and mucosal intestinal tissue concentration of CPT-11 and its metabolites were examined in rats. CPT-11-induced late-onset gastrointestinal toxicity was also evaluated. RESULTS: Coadministration of probenecid reduced the biliary excretion of CPT-11, an active metabolite (SN-38) and its glucuronide by half with a concomitant increase in their plasma concentration. When the dose of CPT-11, in the presence of probenecid, was set at half that in its absence, the plasma SN-38 concentration was maintained at the same level as the control, whereas the mucosal intestinal tissue concentration of SN-38 was reduced. Under this condition, CPT-11-induced watery diarrhea, changes in intestinal marker enzymes and body weight reduction were much less in the probenecid-treated group, although the degree of bone marrow suppression was almost the same as that in the control. CONCLUSIONS: Coadministration of probenecid with a reduced dose of CPT-11 potently reduces both SN-38 exposure and CPT-11-induced late-onset toxicity in gastrointestinal tissues, possibly by inhibiting the biliary excretion of CPT-11 and/or its metabolites.

Animals↗
PubMed2003

Impact of Mrp2 on the biliary excretion and intestinal absorption of furosemide, probenecid, and methotrexate using Eisai hyperbilirubinemic rats.

PURPOSE: This study assesses the impact of rat multidrug resistance-associated protein 2 (Mrp2) on the biliary excretion and oral absorption of furosemide, probenecid, and methotrexate using Eisai hyperbilirubinemic rats (EHBR). METHODS: To assess Mrp2-mediated biliary excretion, rats received a 2-h intravenous infusion of furosemide, probenecid, or methotrexate. Blood and bile samples were collected at specified intervals. To assess Mrp2's impact on oral absorption, rats received furosemide, probenecid, or methotrexate orally at 5 mg/kg. Jugular and portal blood samples were obtained at timed intervals. All samples were analyzed by LC-MS/MS. Pharmacokinetic parameters were estimated using WinNonlin and standard pharmacokinetic equations. RESULTS: Thirty seven- and 39-fold reductions in biliary clearance were observed in EHBR as compared to control rats for probenecid and methotrexate, respectively. Biliary clearance was comparable between EHBR and control rats for furosemide. In all cases, no significant difference in absorption was observed between EHBR and control rats. CONCLUSIONS: This study provides the first evidence that Mrp2 mediates the biliary excretion of probenecid but not furosemide. Additionally, Mrp2 apparently has a less profound impact on intestinal absorption than biliary excretion of its substrates. Furthermore, alteration in systemic clearance in EHBR indicates that a potential compensatory mechanism may occur in EHBR.

ATP-Binding Cassette Transporters↗
PubMed1981

Probenecid-clofibrate interaction.

Clofibric acid disposition was studied in four healthy men after 1 wk of clofibrate ingestion (500 mg orally every 12 hr) with and without probenecid (500 mg orally every 6 hr). Mean (+/- SD) free clofibric acid plasma concentration in the four subjects over a dosage interval at steady state was 2.5 +/- 0.03 mg/1 before and 9.05 +/- 1.09 mg/1 after the probenecid. Probenecid reached an average plasma concentration of 71.3 mg/1. No clofibric acid glucuronide was detected in plasma during either treatment. The fractions of the dose recovered in urine as clofibric acid, clofibric acid glucuronide, and clofibric acid liberated after acid hydrolysis were not altered by probenecid. These data suggest that probenecid causes a reduction in renal and metabolic clearance of clofibric acid, probably as a result of inhibition of the conjugation of clofibric acid with glucuronide.

Adolescent↗
PubMed1982

Effects of probenecid on ketoprofen kinetics.

When six normal men took probenecid with ketoprofen in a two-treatment crossover study, steady-state plasma concentrations of ketoprofen and ketoprofen conjugates rose, but plasma protein binding of ketoprofen and urinary excretion of ketoprofen conjugates decreased. Probenecid decreased protein binding of ketoprofen by 28 +/- 7%, total ketoprofen clearance by 67 +/- 11%, clearance of unbound ketoprofen by 74 +/- 10%, clearance of unbound ketoprofen by conjugation by 91 +/- 5%, and renal clearance of ketoprofen conjugates by 93 +/- 4%. An apparent decrease (22 +/- 29%) in unbound ketoprofen clearance by mechanisms other than conjugation might have been established in a study of more than six subjects. Probenecid, which reaches plasma concentrations that approach 100 times those of ketoprofen or its conjugates, appears to inhibit both the conjugation of ketoprofen and the renal excretion of ketoprofen conjugates. An alternative explanation to inhibition of conjugation involves cumulation and subsequent hydrolysis of ketoprofen conjugates as a result of the renal action of probenecid. In addition to the advantages of obtaining simultaneous uricosuric and anti-inflammatory effects, there may be clinical kinetic advantages of administration of probenecid with ketoprofen, because the large interdose concentration swings of ketoprofen are then substantially reduced.

Adult↗
PubMed1985

Effect of probenecid on the formation and elimination of acyl glucuronides: studies with zomepirac.

When 100 mg oral zomepirac was taken with 500 mg b.i.d. oral probenecid by six healthy subjects, the disposition of zomepirac was markedly altered. Probenecid decreased total plasma clearance of zomepirac by 64%, which resulted in an increase in bioavailability from 0.55 without probenecid to 0.84 when given concurrently. The apparent metabolic clearance of zomepirac to form zomepirac acyl glucuronide was reduced 71% and zomepirac renal clearance, a minor elimination route, was reduced by 79%. When assayed by a method that prevents degradation of the labile acyl glucuronide, zomepirac glucuronide concentrations in plasma were comparable to those of zomepirac. Probenecid decreased the renal clearance of zomepirac glucuronide by 72%, which, together with the increased zomepirac levels, resulted in a 2.8-fold increase in the AUC of the conjugate. Urinary excretion of zomepirac glucuronide was reduced from 72% to 58% of the dose, but the excretion of free zomepirac was unchanged at 5% of the dose. The ratio of the total clearance/bioavailability of zomepirac in control subjects was 682 +/- 246 ml/min, which is double the value reported in previous studies of zomepirac disposition. We believe that this difference is due to degradation of the unstable zomepirac acyl glucuronide in the previous analytic methodologies used. Qualitatively, the effects of probenecid on zomepirac disposition are similar to those previously reported for other drugs of this class that are metabolized to acyl glucuronides. However, zomepirac appears unusual in that significant levels of its acyl glucuronide metabolite are found in vivo.

Adult↗
PubMed1989

The effect of probenecid on the renal elimination of cimetidine.

It is generally assumed that the systems involved in the transport of organic cations and organic anions in the renal proximal tubule are substrate selective (i.e., organic anions do not inhibit organic cation transport and vice versa). However, recent data obtained in vitro have suggested that the organic anion probenecid inhibits the renal transport of the organic cation cimetidine. We addressed the question of whether this interaction is biologically relevant in human beings. The study involved a two-treatment, randomized crossover design. Six healthy male subjects were given an intravenous infusion of 300 mg cimetidine alone as one treatment and, as the other treatment, received multiple oral doses of probenecid before receiving the cimetidine infusion. The renal clearance of cimetidine and inulin was determined in each period. There were no significant differences between treatments in cimetidine plasma concentrations, apparent volume of distribution, systemic clearance, half-life, amount of drug excreted unchanged in the urine, or nonrenal clearance. Probenecid significantly decreased the renal clearance of cimetidine by decreasing both the filtration clearance and the net secretory clearance. These effects were most evident in the first 1/2 to 1 hour after cimetidine administration, when probenecid levels in plasma and renal tissue would have been the highest. Because there was no effect of probenecid on cimetidine plasma concentrations, this interaction is not clinically relevant to the therapeutic use of these two compounds. However, the study demonstrates that renal interactions between organic cations and organic anions can occur in human beings. The mechanism of this interaction and the implications to other drug combinations are being explored.

Adult↗
PubMed2003

Effect of probenecid and quinidine on the transport of alovudine (3'-fluorothymidine) to the rat brain studied by microdialysis.

Microdialysis was used to sample extracellular unbound concentrations of alovudine in order to study the influence of well-known transport inhibitors (probenecid and quinidine) on the transport of alovudine between the blood and the brain extracellular fluid or whole brain tissue. The AUC (area under the time versus concentration curve) ratio brain extracellular fluid/serum was 0.17+/-0.036 after a subcutaneous injection of alovudine 25 mg/kg in rats treated with probenecid 25 mg/kg subcutaneous (n=5), which was not significantly different from the control group (AUC ratio 0.24+/-0.039). Perfusion through the microdialysis probe with probenecid 100 microM (n=4) also had no effect on the brain extracellular fluid/serum AUC ratio after alovudine 25 mg/kg subcutaneous. The AUC ratio brain extracellular fluid/serum was 0.085+/-0.009 after subcutaneous injection of alovudine 25 mg/kg in rats treated with quinidine 25 mg/kg intraperitoneally (n=8), which was significantly lower than the control group. However, the whole brain tissue concentration was not significantly different between control rats (n=5) and rats treated with quinidine (n=4) 1 hr after subcutaneous injection of alovudine 25 mg/kg (brain to serum ratios being 0.11+/-0.006 and 0.10+/-0.005 respectively). Finally, the microdialysis recovery of alovudine increased with increasing concentrations (10, 50, 250, 1250 microM) of alovudine in the perfusion fluid. The recovery of alovudine was increased in quinidine-treated rats but not in those given probenecid. Thus, probenecid does not significantly influence the concentration gradient of alovudine over the blood-brain barrier in the rat after systemic or after local administration, while quinidine lowered brain extracellular fluid concentration of alovudine, but not total brain tissue concentration. The mechanism behind this phenomenon is not yet known.

Animals↗
PubMed2002

Once-daily intravenous cefazolin plus oral probenecid is equivalent to once-daily intravenous ceftriaxone plus oral placebo for the treatment of moderate-to-severe cellulitis in adults.

A once-daily regimen of cefazolin (2 g intravenously [iv]) plus probenecid (1 g by mouth) was compared with a once-daily regimen of ceftriaxone (1 g iv) plus oral placebo in a randomized, double-blind equivalence trial of home-based therapy for moderate-to-severe cellulitis in adults. For the assessable recipients of cefazolin-probenecid (n=59) and ceftriaxone-placebo (n=57), clinical cure occurred at the end of treatment in 86% and 96% (P=.11), respectively, and was maintained at 1 month of follow-up in 96% and 91% (P=.55), respectively. The mean number of treatment doses (+/-standard deviation) given was similar in the 2 treatment arms (6.97+/-2.6 for cefazolin-probenecid and 6.12+/-2.1 for ceftriaxone-placebo; P=.06). The median antibiotic trough concentrations were 2.35 microgram/mL for cefazolin and 15.45 microgram/mL for ceftriaxone. Patients in the 2 treatment arms were similar with regard to overall rates of adverse reaction (P=.15), but nausea was more common among those in the cefazolin-probenecid arm (P=.048). The once-daily regimen of cefazolin-probenecid is a cheap, practical, and effective treatment option for moderate-to-severe cellulitis, and it avoids the need to use third-generation cephalosporins in most patients.

Administration, Oral↗
PubMed1979

Probenecid: an unexplained effect on cephalosporin pharmacology.

1 The influence of probenecid on serum levels and urinary excretion of orally administered cephradine and cefaclor has been investigated. 2 Probenecid caused serum levels of both antibiotics to be increased and also prolonged. Urinary excretion of antibiotic activity was slightly but not significantly decreased by probenecid during the initial 6 h postdosing. It was significantly increased in 6-12 h urine, but only a small percentage of the doses were excreted during that period. 3 The increased serum levels of antibiotic were greater than could be accounted for by reduced elimination rate alone. Possible mechanisms to account for increased circulating levels of antibiotic in the presence of probenecid are discussed in the light of previous observations on probenecid induced changes in tissue distribution of beta-lactam antibiotics.

Adolescent↗
PubMed1981

The effect of probenecid on the pharmacokinetics and distribution of cefoxitin in healthy volunteers.

1 Cefoxitin was given by acute intravenous injection to six healthy volunteers, in a crossover study to investigate the effects of concurrent probenecid administration. 2 Serum antibiotic concentrations were determined by microbiological assay. Cefoxitin concentrations were simultaneously determined in the fluid of blisters produced by topical cantharides. All antibiotic was accounted for in the urine. 3 Cefoxitin was administered by intravenous infusion, subsequent to a loading dose, to produce steady state levels in the region of 10 microgram/ml, in one volunteer. The procedure was later repeated after prior administration of probenecid in the same subject. 4 Pharmacokinetic analyses indicated significant changes only in the parameters associated with renal excretion of drugs. Clearance was reduced by half. 5 The absolute and relative amounts of antibiotic in the central and peripheral compartments were calculated for both modes of administration. In the acute study probenecid produced a small change in distribution away from the peripheral or tissue compartment, towards the central compartment. 6 There was no elevation of initial serum concentrations and sustained levels of antibiotic could be accounted for principally by retarded excretion produced by probenecid, with little contribution by alteration in the disposition of antibiotic. 7 The sustained serum levels of cefoxitin that resulted from its decreased excretion were also reflected in blister fluid. It was concluded that the sustained cefoxitin levels produced by probenecid resulted in similar raised levels in the peripheral or "tissue' compartment, since the redistribution away from the peripheral compartment did not contribute materially to other changes in disposition of drug.

Adult↗
PubMed1994

The renal clearance of cefuroxime and ceftazidime and the effect of probenecid on their tubular excretion.

1. The renal tubular excretion of cefuroxime and ceftazidime in relation to the coadministration of probenecid was investigated in eight and two healthy subjects, respectively. 2. Cefuroxime or ceftazidime were administered by i.v. infusion and 1 g probenecid was administered orally after steady state plasma concentrations of the cephalosporin were reached. 3. In a second session the same antibiotic was administered at increasing infusion rates such that three different levels of plasma drug concentration were achieved. 4. The renal clearance of antibiotic was calculated based upon unbound plasma concentration, and tubular clearance was estimated by subtracting inulin clearance from the renal clearance of the antibiotic. 5. Non-linear regression analysis was used to estimate parameters describing the saturability of tubular excretion and the effect of probenecid inhibition, i.e. EC50 and Rtub,max, could be established for cefuroxime: EC50 was 248 (s.d. 130) mg l-1 and Rtub,max was 1.852 (s.d. 0.577) mg h-1. Tubular excretion of ceftazidime was practically zero. The EC50 of probenecid for inhibition of the tubular excretion of cefuroxime was 0.80 (s.d. 0.31) mg l-1. 6. The results indicate that in the therapeutic plasma concentration range of cefuroxime its renal clearance is not saturated. Probenecid at therapeutic doses will block tubular excretion of cefuroxime almost completely.

Administration, Oral↗
PubMed1989

Probenecid effect on cefuroxime pharmacokinetics in calves.

Cefuroxime pharmacokinetics were studied in unweaned calves. The antibiotic was administered at 10 mg/kg to six calves i.v., to 12 calves i.m. and to ten of the previous 12 calves i.m. at 10 mg/kg together with probenecid at 40 mg/kg. Intramuscular doses of cefuroxime alone at 20 mg/kg were given to seven calves; to five of these calves cefuroxime was also given together with probenecid at 40 mg/kg and at 80 mg/kg. The serum concentration-time data were analyzed using statistical moment theory (SMT). The elimination half-life (t1/2) was 69.2 min (harmonic mean) after i.v. and 64.8 min and 64.9 min following i.m. administration of the lower and higher dose, respectively. Co-administration of probenecid did not affect the t1/2. The mean residence time (MRT) was 80.9 +/- 23.5 min (mean +/- SD) after i.v. and 117.8 +/- 9.3 min and 117.7 +/- 5.4 min after i.m. administration of cefuroxime at 10 and 20 mg/kg, respectively. The MRTi.m. following administration of cefuroxime at 10 mg/kg together with probenecid at 40 mg/kg was 140.0 +/- 8.8 min. The MRTi.m. values were 132.8 +/- 2.3 min and 150.8 +/- 5.1 min after cefuroxime was given at 20 mg/kg together with probenecid at 40 mg/kg or 80 mg/kg, respectively. The total body clearance (ClT) was 3.56 +/- 1.11 ml/min/kg and the volume of distribution at steady state (Vd(ss] 0.270 +/- 0.051 l/kg. The MIC90 values of cefuroxime were 16 micrograms/ml for E. coli and Salmonella isolates, 0.5 microgram/ml for Pasteurella multocida and 2.0 micrograms/ml for P. haemolytica.

Animals↗
PubMed1998

Effect of probenecid on breathing movements and cerebral clearance of prostaglandin E2 in fetal sheep.

1. Intravenous infusion of probenecid (79-160 mg kg-1) into unanaesthetized fetal sheep (127-143 days gestation) in utero significantly decreased the incidence and amplitude of spontaneous breathing movements, but did not change the incidence of low voltage electrocortical (ECoG) activity, plasma prostaglandin E2 (PGE2) concentrations, blood gases or pH. 2. In fetuses pretreated with paracetamol (350 mg kg-1) to inhibit PG synthase activity, infusion of probenecid did not change the mean incidence or amplitude of breathing movements, indicating that the inhibitory effect of probenecid on breathing movements required the presence of active PG synthesis. 3. Probenecid infusion in four unanaesthetized fetuses significantly increased the PGE2 concentrations in cisternal cerebrospinal fluid (CSF) by 6.6 +/- 1.5-fold (P < 0.05). 4. In pentobarbitone-anaesthetized, exteriorized fetuses, probenecid infusion decreased the clearance of [3H]PGE2 from CSF during ventriculo-cisternal perfusion of artificial CSF containing [3H]PGE2. 5. These results suggest that there is active transport of PGs from CSF to blood in fetal sheep from at least 127 days gestation. Inhibition of this transport results in the accumulation of PGs within interstitial fluid of the brain, one effect of which is to suppress the spontaneous activity of the respiratory centres.

Anesthesia, General↗
PubMed1970

Acid metabolites of monoamines in avian brain; effects of probenecid and reserpine.

1. The concentration of the dopamine (DA) metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the anterior part of the nucleus basalis of pigeon brain was found to be 0.17 +/- 0.01 mug/g, which is about one-fifth of the concentration of homovanillic acid (HVA) in this region. In the chicken, the concentration of HVA in the (entire) nucleus basalis was 0.06 +/- 0.006 mug/g, lower than in any other species examined, and giving a ratio of DA to HVA of about 50. The concentration of DOPAC in the 8 day old chick was 0.053 +/- 0.002 mug/g.2. Probenecid, 200 mg/kg intramuscularly, doubled the content of DOPAC in the nucleus basalis of the pigeon and increased the concentration of HVA in both the pigeon and the chicken by a factor of 4 to 5. These findings demonstrate the existence, in avian brain, of an active transport mechanism for the removal of acidic substances and explain the low concentrations of the acids found in bird brain.3. A method is described for the estimation of 5-hydroxytryptamine (5-HT) and 5-hydroxyindolylacetic acid (5-HIAA) in the same tissue sample. Probenecid caused an increase in the 5-HIAA content but produced no change in the 5-HT content of the nucleus basalis of pigeon brain.4. Reserpine caused a fall in the content of acidic DA metabolites in the nucleus basalis of the pigeon. The effect was more pronounced after raising the concentration of these acids with probenecid.5. Treatment of pigeons with pargyline (100 mg/kg 17 hr before decapitation) did not significantly increase the DA content of the nucleus basalis, but it prevented to some extent the loss in DA caused by reserpine.6. Pigeons and chickens were sedated by probenecid. The deepest sedation occurred at about the same time as the greatest increase in the acidic amine metabolites in the brain.7. Intracisternal injection of HVA in the pigeon and intravenous injection of large amounts of HVA, DOPAC, 5-HIAA or 3,4-dimethoxyphenylacetic acid into newly hatched chicks did not produce any sedation or other effects on behaviour. In contrast, injection of sodium gamma-hydroxybutyrate caused paralysis followed by prostration and eye closure.8. Estimation of the concentration of HVA in the brain of the young chick after intravenous injection of the acid (100 mg/kg) showed that the concentration was of the same order of magnitude as it is in animals given probenecid; this suggests that the sedation which follows probenecid is not related to the accumulation of acidic amine metabolites.

Animals↗