Uptake In Rat Brain Research Articles

Blood-brain barrier penetration of felbamate.

The brain uptake index (BUI) method of Oldendorf was used to examine blood-brain barrier (BBB) drug transport in mice, rats, and rabbits; felbamate (FBM) extraction (E) in a single transcapillary passage was 5-20%, and drug uptake in rat brain was not concentration-dependent. Like diazepam, FBM was retained in mouse brain. To ensure that radioactivity measurements reflected the disposition of parent drug and not some metabolite, extracts of mouse brain were prepared for further analysis. No FBM metabolites were detected in brain 5 min after administration: In silica gel thin-layer chromatography (TLC), a single [14C]FBM peak was detected--Rf = 0.504 (70:30 acetone:hexane). Confirmatory high-performance liquid chromatography (HPLC) separations [30% methanol, 1.3 ml/min, C18 column, ultraviolet (UV) detection 254 nm] indicated a single peak containing greater than 93% of the radioactivity in the FBM fraction (12-min retention time). In a single transit through the liver (a nonbarrier tissue with fenestrated capillaries), FBM E was 82%. The octanol:buffered saline partition coefficient of FBM was (log PFBM =) 0.54 +/- 0.01. Thus, lipid-mediated BBB penetration of FBM is similar to that of phenytoin (PHT) and phenobarbital (PB). Plasma proteins do not affect FBM entry to the brain: neither human serum, nor bovine or human serum albumin (BSA, HSA), nor human alpha 1 acid glycoprotein (orosomucoid) significantly modified BBB FBM extraction. Erythrocyte-borne FBM may also dissociate and gain access to the brain in a single transcapillary passage. Differences between newborn and adult rabbit BBB FBM extraction and between different anesthetic agents are attributable to cerebral blood flow (CBF) rates. The permeability-surface area products (PS = [CBF].[E]) for FBM in rats, rabbits, and mice were 0.09, 0.16 and 0.30 ml/min/g, respectively. Preliminary autoradiographic analyses of frozen brain sections suggest that [14C]FBM distributes relatively uniformly throughout the brain and that minor variations apparently are a function of differing CBF rates.

Atrial natriuretic peptide inhibits amiloride-sensitive sodium uptake in rat brain.

Both atrial natriuretic peptide (ANP) and its receptors are present in the central nervous system, but effects of ANP on brain are unclear. In the present study, we evaluated both the effects of ANP on sodium uptake, and a possible effector mechanism, the putative intracellular second messenger guanosine 3',5'-cyclic monophosphate (cGMP), in rat brain synaptosomes. In the presence of ANP (10(-7) M), the basal level of sodium uptake in synaptosomes was reduced (n = 6) from the control value of 1.90 +/- 0.06 to 1.73 +/- 0.04 (SE) nmol/mg protein at 5 min, P less than 0.05. The observed reduction of sodium uptake by ANP was not influenced by blockade of the other important pathways for sodium uptake. Addition of either a sodium channel blocker (tetrodotoxin) or an inhibitor of Na(+)-K(+)-adenosinetriphosphatase (ATPase) (ouabain) did not affect sodium uptake in the presence of ANP. However, the reduction of sodium uptake was completely blocked by addition of amiloride. These findings suggest that ANP reduced sodium uptake via inhibition of an amiloride-sensitive pathway for sodium uptake. cGMP is a major intracellular second messenger for ANP in other tissues. We found that after stimulation with 10(-7) M ANP, synaptosomal cGMP increased significantly from 58.0 +/- 9.5 to 73.5 +/- 10.6 fmol/mg protein (P less than 0.01). When an analogue of cGMP, 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP), was added to synaptosomes, amiloride-sensitive sodium uptake was again inhibited, by a similar amount as occurred with ANP. It appears that in rat brain, ANP inhibits amiloride-sensitive sodium uptake via a pathway involving intracellular production of cGMP.

Neurochemical and Pharmacological Properties of Tianeptine, A Novel Antidepressant

Tianeptine is a tricyclic antidepressant with an unusual chemical structure (a long lateral chain grafted on to a substituted dibenzothiazepin nucleus), and with biochemical and animal-behavioural properties which are strikingly different from those of classical tricyclics. Unlike the latter, which decrease serotonin (5-HT) uptake, acute and chronic tianeptine treatment enhances 5-HT uptake in rat brain and in rat and human platelets ex vivo. In vivo, tianeptine potentiates the depletion of rat brain 5-HT by 4-methyl-alpha-ethyl metatyramine and increases rat hippocampal 5-HIAA; 5-HT uptake inhibitors (e.g. fluoxetine) have opposite effects. On iontophoretic injection into CA1 pyramidal cells, tianeptine shortens the period of neuronal hypoactivity caused by GABA or 5-HT, whereas other tricyclics prolong it, and it enhances attention, learning, and memory in laboratory animals, while classical tricyclics have opposite effects. However, the relationships between these effects of tianeptine in animal experiments and their relevance to clinical findings remain to be determined.

Characterization of radioiodinated TISCH: a high-affinity and selective ligand for mapping CNS D1 dopamine receptor.

In developing CNS D1 dopamine receptor-imaging agents with improved specificity and longer brain retention, an iodinated D1 ligand was synthesized. In vitro and in vivo radiolabeling studies of a new iodinated benzazepine, TISCH [7-chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine], an analog of SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin e), were investigated. After an intravenous injection, the R(+) isomer of TISCH showed high brain uptake in rats (2.20 and 0.57% dose per whole brain at 2 and 60 min, respectively). The striatum/cerebellum ratio increased progressively with time (12 at 60 min). Ex vivo autoradiography of rat brain sections, after intravenous injection of R(+)-[125I]TISCH, displayed the highest uptake in striatum and substantia nigra, regions known to have a high concentration of D1 receptors, whereas the S(-) isomer displayed no specific uptake. Furthermore, the specific uptake can be blocked by pretreatment with SCH 23390. In vitro binding studies using the rat striatum tissue preparation showed high specific and low nonspecific bindings (KD = 0.21 +/- 0.03 nM). The rank order of potency exhibiting high specificity to the D1 receptor was SCH 23390 greater than (+/-)-TISCH greater than (+)-butaclamol = (+/-)-FISCH [7-chloro-8-hydroxy-1-(4'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine] much greater than WB4101 = spiperone greater than dopamine, serotonin, (+/-)-propranolol, and naloxone. Imaging studies in a monkey with the resolved isomer, R(+)-[123I]TISCH, demonstrated a high uptake in the basal ganglia and prolonged retention. The preliminary data suggest that R(+)-TISCH is selective for the CNS D1 receptor and is potentially useful for in vivo and in vitro pharmacological studies. When labeled with iodine-123, it may be suitable for noninvasive imaging in humans.

Extracellular volume decreases while cell volume is maintained by ion uptake in rat brain during acute hypernatremia.

1. Regulation of brain extracellular and intracellular water content, regarded as volume, and electrolytes in response to 90 min of hypernatremia has been studied in the cerebral cortex of rats under urethane anaesthetic. 2. Total tissue electrolytes and water were partitioned between extracellular and intracellular compartments based on measurements made in two series of experiments. In one, tissue samples were collected and analysed for total water, Na+, K+ and Cl-. In the other, tissue extracellular volume fraction, [Na+] and [K+] were measured in situ using ion-selective microelectrodes. 3. Osmotically induced water loss from cerebral cortex was less than that predicted for ideal osmotic behaviour, revealing a degree of volume regulation, and this regulation was associated with net tissue uptake of Na+, Cl- and K+. 4. Total water content was 3.77 g H2O (g dry weight)-1 in control cortex and this decreased by 7% after 30 min of hypernatremia and then remained relatively stable at this value. Control extracellular water content, based on an extracellular volume fraction of 0.18, was 0.88 g H2O (g dry weight)-1. Control intracellular water content, estimated as the difference between total and extracellular water contents, was 2.89 g H2O (g dry weight)-1. After 30 min of hypernatremia, extracellular water content decreased by an average of 27% but intracellular water did not change. This indicates selective regulation of cell volume. By 90 min the extracellular water content had decreased by 47% and the loss in extracellular water content appeared to be accompanied by a roughly equivalent increase in intracellular water content. The intracellular volume increase, however, was not statistically significant. The tortuosity of the extracellular space averaged 1.57 and increased to 1.65 during the hypernatremia. 5. Brain extracellular fluid and plasma [Na+] were roughly equal in control tissue. Both increased by 30 mu equiv (g H2O)-1 as a result of the hypernatremia, although extracellular [Na+] lagged behind the plasma value during much of the first 60 min of hypernatremia. Extracellular [K+] was homeostatically regulated at 3 mu equiv (g H2O)-1 independent of changes in plasma electrolytes. 6. Estimates of extracellular and intracellular ion content (mu equiv (g dry weight)-1) indicate that extracellular Na+, Cl- and K+ content decreased during hypernatremia, by 32, 21 and 42% respectively, whereas intracellular ion content increased by 100, 169 and 5% respectively. 7. It is concluded that during acute hypernatremia the extracellular space decreases in volume through the loss of water and electrolytes while the intracellular compartment maintains its water content and gains electrolytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased serotonin platelet uptake after tianeptine administration in depressed patients

Tianeptine is a new antidepressant drug reported to enhance serotonin (5-hydroxytryptamine [5-HT] uptake in rat brain. The effect of tianeptine on 5-HT platelet uptake was studied in 10 depressed patients treated for 28 days. Tianeptine increases V max of 5-HT platelet uptake during treatment without inducing any change in K m. As early as 2 hr after the first administration, V max increased significantly (+ 23%, α = 0.01). Although of a lesser magnitude. 5-HT platelet uptake remains increased after chronic administration (+ 14% on day 10 and + 13% on day 28). This suggests that tianeptine affects 5-HT platelet uptake sites, either directly or via an action on modulators of 5-HT uptake. These results, in contrast with the action of other tricyclic antidepressants, confirm the original action of tianeptine on 5-HT platelet metabolism.

High affinity dopamine D2 receptor radioligands. 2. [ 125I]epidepride, a potent and specific radioligand for the characterization of striatal and extrastriatal dopamine D2 receptors

Epidepride, ( S)- N[1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxy-benzamide, the iodine analogue of isoremoxipride (FLB 457), was found to be a very potent dopamine D2 receptor antagonist. Optimal in vitro binding required incubation at 25°C for 4 h at pH 7.4 in a buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 and 1 mM MgCl 2. Scatchard analysis of in vitro binding to striatal, medial frontal cortical, hippocampal and cerebellar membranes revealed a K D of 24 pM in all regions, with Bmax's of 36.7, 1.04, 0.85, and 0.37 pmol/g tissue, respectively. The Hill coefficients ranged from 0.91–1.00 in all four regions. The IC 50's for inhibition of [ 125I]epidepride binding to striatal, medial frontal cortical, and hippocampal membranes for SCH 23390, SKF 83566, serotonin, ketanserin, mianserin, naloxone, QNB, prasozin, clonidine, alprenolol, and norepinephrine ranged from 1 μM to > 10 μM. Partial displacement of [ 125I]epidepride by nanomolar concentrations of clonidine was noted in the frontal cortex and hippocampus, but not in the striatum. Scatchard analysis of epidepride binding to α 2 noradrenergic receptors in the frontal cortex and hippocampus revealed an apparent K D of 9 nM. At an epidepride concentration equal to the K D for the D2 receptor, i.e. 25 pM, no striatal α 2 binding was seen and only 7% of the specific epidepride binding in the cortex or hippocampus was due to binding at the α 2 site. Correlation of inhibition of [ 3H]spiperone and [ 125I]epidepride binding to striatal membranes by a variety of D2 ligands revealed a correlation coefficient of 0.99, indicating that epidepride labels a D2 site. In vitro autoradiography revealed high densities of receptor binding in layers V and VI of prefrontal and cingulate cortices as well as in striatum. In vivo rat brain uptake revealed a hippocampal:cerebellar and frontal cortical:cerebellar ratio of 2.2:1 which fell to 1.1:1 following haloperidol pretreatment. These properties suggest that [ 125I]epidepride is a superior radioligand for the in vitro and in vivo study of striatal and extrastriatal dopamine D2 receptors.

Evaluation of technetium 99m cyclobutylpropylene amine oxime as a potential brain perfusion imaging agent for SPET

Technetium 99m d,l-cyclobutylpropylene amine oxime (99mTc-CBPAO) has been developed as a brain-imaging agent for single photon emission tomography (SPET). 99mTc-CBPAO can be prepared using a simple labelling procedure suitable for routine clinical use. It has a high in vitro stability, as has been demonstrated by high-pressure liquid chromatography (HPLC) analysis. This shows that 3 h after labelling, less than 5% of the primary lipophilic complex which is capable of crossing the blood-brain barrier (BBB) converts to a secondary hydrophilic complex. Brain uptake (% dose/g wet tissue) of 99mTc-CBPAO, determined at 5 and 30 min after injection in two groups of six adult male Sprague-Dawley rats, was found to be 0.74 +/- 0.06 and 0.73 +/- 0.13 (mean +/- SD), respectively. These values are not significantly different from those obtained repeating the experiment with 99mTc-labelled hexamethylpropylene amine oxime (99mTc-HMPAO) (0.72 +/- 0.15 at 5 min and 0.88 +/- 0.24 at 30 min after injection). Since the rat brain uptake of 99mTc-CBPAO remained unchanged for a period of time suitable for tomographic study, the comparison of the two tracers was extended to two groups of ten patients. The latter were affected by neurological and psychiatric disorders and were studied with SPET. Human brain uptake (% dose/cc cortical grey matter) of 99mTc-CBPAO and 99mTc-HMPAO were 3.04 +/- 0.57 and 4.22 +/- 0.46 (mean x 10(-3) +/- SD x 10(-3), respectively, with a 32% significant difference. In two other groups of five patients, the first transit time-activity curves of the two tracers were compared.(ABSTRACT TRUNCATED AT 250 WORDS)

Phospholipase A2 and 3H-hemicholinium-3 binding sites in rat brain: a potential second-messenger role for fatty acids in the regulation of high-affinity choline uptake

The involvement of phospholipase A2 (PLA2) and fatty acid release in the regulation of sodium-dependent high-affinity choline uptake in rat brain was assessed in vitro through the use of the specific binding of 3H-hemicholinium-3 (3H-HCh-3). Addition of arachidonic acid and other unsaturated fatty acids to rat striatal membranes in vitro resulted in a dose-dependent, temperature-independent activation of 3H-HCh-3 binding. Scatchard analysis revealed that these changes in binding result from a 2-fold increase in the affinity and capacity of 3H-HCh-3 binding. Saturated fatty acids, lysophospholipids, and phospholipids did not affect specific 3H-HCh-3 binding. Addition of defatted BSA to membranes, which had been treated previously with arachidonic acid, completely reversed the increase in specific 3H-HCh-3 binding. However, several inhibitors of fatty acid metabolism, including nordihydroguaiaretic acid, indomethacin, catalase, and superoxide dismutase, did not alter arachidonic acid-induced changes in 3H-HCh-3 binding, suggesting that unsaturated fatty acids, and not their metabolites, are directly responsible for the observed activation of specific 3H-HCh-3 binding. Additionally, unsaturated fatty acids dose-dependently inhibited high-affinity 3H-choline uptake in rat striatal synaptosomes, apparently due to the disruption of synaptosomal integrity. The phospholipase A2 inhibitors quinacrine hydrochloride, trifluoperazine, and 4-bromophenacylbromide dose-dependently inhibited potassium depolarization-induced activation of specific 3H-HCh-3 binding in slices of rat brain in vitro. Similarly, both quinacrine and trifluoperazine inhibited the metabolism of phospholipids and the release of fatty acids evoked by either elevated KCl or calcium ionophore A23187. These results support the involvement of PLA2 and subsequent fatty acid release in the increase of 3H-HCh-3 binding in cholinergic neurons and suggest that activation of PLA2 may be the penultimate step in regulating the velocity of sodium-dependent choline transport.

(.+-.)-7-Chloro-8-hydroxy-1-(4'-[125I]iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine: a potential CNS D-1 dopamine receptor imaging agent

Synthesis, radiolabeling, and in vitro and in vivo properties of an iodinated benzazepine, (+/-)-7-chloro-8-hydroxy-1-(4'-[125I]iodophenyl)-3- methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, [125I]FISCH, as a potential imaging agent for evaluation of central nervous system (CNS) D-1 dopamine receptors in humans, were investigated. After an iv injection, this benzazepine derivative showed good brain uptake in rats (2.27, 1.40, 0.55% dose/whole brain at 2, 15, and 60 min, respectively). The striatum/cerebellum ratio was high (2.47 at 60 min after the injection). The binding affinity of this agent in rat striatum tissue preparation displayed a Kd of 1.43 +/- 0.15 nM. Competition data (in vitro) showed the following rank order of potency: SCH-23390 greater than (+/-)-FISCH greater than (+/-)-IBZP much greater than apomorphine greater than WB 4010 greater than ketanserin approximately spiperone. The preliminary data suggest that the agent is highly selective for the CNS D-1 receptor.

Triiodothyronine bound to red blood cells is not available for transport through the blood-brain barrier.

Many steroid and thyroid hormones and some drugs are bound by circulating red cells. Red cell-bound ligand may not be physiologically inert, as recent studies show that red cell-bound drug is available for uptake by brain. To investigate whether triiodothyronine (T3) is available for uptake by brain in vivo from the circulating red cell pool, the present investigations measure the effects of human erythrocytes on rat brain uptake of [125I]T3 in vivo. The fraction of circulating T3 available for uptake in vivo in the presence of 0, 2, 5, 10, 22, or 44% red cells was essentially identical to the fraction of [125I]T3 unbound in vitro. Therefore, [125I]T3 bound to red cells obtained from normal volunteers is not available for uptake by brain in vivo.

The effect of chronic ethanol consumption on [ 14C]deoxyglucose uptake in rat brain in vivo

The uptake of [ 14C]deoxyglucose by brains of rats that were given alcohol in drinking water for 7 months was investigated. There was a general, approximately 50%, increase in deoxyglucose uptake in brains of ethanol-treated rats with areas of the limbic system being particularly affected.

125I](±)FISCH: A new CNS D-1 dopamine receptor imaging ligand

Radiolabeling and in vitro and in vivo evaluation of an iodinated benzazepine: [ 125I] FISCH 7-Chloro-8-hydroxy-1-(4′-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, as a potential imaging agent for CNS D-1 dopamine receptors in animals, were investigated. After an iv injection, this benzazepine derivative showed good brain uptake in rats (2.70, 1.28, 0.48 %dose/whole brain at 2, 15 and 60 min, respectively). The striatum/cerebellum ratio was 2.50 at 60 min after the injection. The regional distribution in rat brain, as measured by ex vivo autoradiography, displayed highest uptake in the regions of the striatal complex and the substantia nigra, regions known to have a high concentration of D-1 dopamine receptors. Furthermore, this localized regional cerebral distribution was blocked by pretreatment with SCH-23390, a selective D-1 dopamine receptor antagonist. The in vitro binding affinity of this agent in rat striatum tissue preparation displayed a Kd of 1.43 ± 0.15 nM. Competition data ( in vitro) showed the following rank order of potency: SCH-23390 > (±)IBZP ⪢ apomorphine > 4101 ketanserin ∼ spiperone. The preliminary data suggest that this analog of SCH-23390 shows similar selectivity for the CNS D-1 receptor.

Regional and subcellular localization in human brain of [ 3H]paroxetine binding, a marker of serotonin uptake sites

The characteristics of the binding of [ 3H]paroxetine, a selective serotonin (5-HT) uptake blocker, were investigated in human brain. The K d value was 0.23 ± 0.07 nM , and the B max value was 190 ± 39 fmol/mg protein in the putamen. The capacity of various antidepressive drugs to inhibit [ 3H]paroxetine-specific binding in human brain was well correlated with their capacity to inhibit [ 3H]5-HT uptake in rat brain. The highest concentrations of [ 3H]paroxetine-specific binding sites were found in the substantia nigra, hypothalamus, and hippocampus. Lower values were obtained in the basal ganglia and the thalamus. The specific binding was very low in cerebral and cerebellar cortices. The regional distribution of [ 3H]paroxetine binding sites differs from that of [ 3H]ketanserin binding to S 2 serotonin receptors. The subcellular distribution of the [ 3H]paroxetine-specific binding sites obtained by differential centrifugation revealed a synaptosomal enrichment in the frontal cortex and striatum, whereas an enrichment in the microsomal fraction was found in striatum. The results show that [ 3H]paroxetine is a ligand of choice to label the 5-HT uptake molecular complex in human brain.

Characterization of [3H]paroxetine binding in rat brain.

The binding of the 5-hydroxytryptamine (5-HT, serotonin) uptake inhibitor [3H]paroxetine to rat cortical homogenates has been characterized. The effect of tissue concentration was examined and, with 0.75 mg wet weight tissue/ml in a total volume of 1,600 microliter, the binding was optimized with an apparent dissociation constant (KD) of 0.03-0.05 nM. Competition experiments with 5-HT, citalopram, norzimeldine, and desipramine revealed a high (90%) proportion of displaceable binding that fitted a single-site binding model. Fluoxetine and imipramine revealed, in addition to a high-affinity (nanomolar) site, also a low-affinity (micromolar) site representing approximately 10% of the displaceable binding. The specificity of the [3H]paroxetine binding was emphasized by the fact that 5-HT was the only active neurotransmitter bound and that the serotonin S1 and S2 antagonist methysergide was without effect on the binding. Both 5-HT- and fluoxetine-sensitive [3H]paroxetine binding was completely abolished after protease treatment, suggesting that the binding site is of protein nature. Saturation studies with 5-HT (100 microM) sensitive [3H]paroxetine binding were also consistent with a single-site binding model, and the binding was competitively inhibited by 5-HT and imipramine. The number of binding sites (Bmax) for 5-HT-sensitive [3H]paroxetine and [3H]imipramine binding was the same, indicating that the radioligands bind to the same sites. Lesion experiments with p-chloroamphetamine resulted in a binding in frontal and parietal cortices becoming undetectable and a greater than 60% reduction in the striatum and hypothalamus, indicating a selective localization on 5-HT terminals. Together these findings suggest that [3H]paroxetine specifically and selectively labels the substrate recognition site for 5-HT uptake in rat brain.

Unaltered 5-HT- and desipramine-sensitive [3H]imipramine binding and [3H]5-HT uptake in rat brain after chronic imipramine and norzimeldine treatment.

Several reports have shown heterogeneity of [3H]imipramine binding to brain membranes. Recently, a high affinity and 5-HT sensitive [3H]imipramine binding site of protein nature, that was suggested to be identical to the substrate recognition site for 5-HT uptake, was demonstrated. Since most studies on the regulation of the [3H]imipramine binding sites by antidepressants have used desipramine displaceable binding, which is heterogenous in nature and contains binding not related to 5-HT uptake sites, the present report studies the possible effects of chronic (3 weeks) administration of imipramine or norzimeldine (10 mg/kg intraperitoneally twice daily) on 5-HT sensitive [3H]imipramine binding sites. For comparison, desipramine sensitive binding was also studied, as well as the physiological correlate 5-HT uptake. There were no changes in either [3H]imipramine binding or 5-HT uptake after the antidepressant treatment.

In vivo binding of [ 18F]GBR 13119 to the brain dopamine uptake system

Regional rat brain uptake of [ 18F]GBR 13119, a high specific activity, positron-emitter labeled derivative of the potent dopamine uptake antagonist GBR 12935, is reported. Striatum to cerebellum ratios of 3 are obtained at 90 minutes post injection. Specific binding in striatum can be blocked by pretreatment with dopamine uptake system antagonists (mazindol, nomifensine) but not with receptor antagonists (spiperone, flupenthixol). [ 18F]GBR 13119 is proposed as a new positron-emitting radioligand for in vivo PET studies of the pre-synaptic dopamine uptake system.

Tianeptine, a selective enhancer of serotonin uptake in rat brain.

Tianeptine is a tricyclic agent provided with antidepressant activity in experimental models and in clinical trials. In vitro tianeptine and its two principal metabolites have no effects on monoamine uptake, release or neurotransmitter receptor binding. The biochemical effect of tianeptine in vivo after acute or repeated treatment indicates an enhanced serotonin uptake in cortex and hippocampus but not in mesencephalon, with no effect on noradrenaline or dopamine uptake. This enhanced serotonin uptake is not due to decrease in serotonin release, but is related to increase in the Vmax of the uptake carrier for serotonin. The fact that enhancers as well as inhibitors of serotonin uptake are provided with antidepressant activity challenge simple conclusion as to their mechanism of action. The possibility that increased serotonin uptake after repeated treatment may be related to the antidepressant activity exerted by these drugs, and drugs enhancing serotonin uptake might have antidepressant activity, with an earlier onset, is proposed.

Upregulation of imipramine binding and serotonin uptake by estradiol in female rat brain

This report describes the effect of chronic estradiol treatment on the serotonin transporter in the female rat brain. Both [3H]imipramine binding and [3H]serotonin uptake increased by 20-30% in the frontal cortex and hypothalamus of ovariectomized rats after 12 days of 17 beta-estradiol treatment. No differences were observed in the binding and uptake parameters as a function of the rats' estrous cycle or in untreated ovariectomized rats, as compared to controls. Estradiol in vitro, inhibits [3H]imipramine binding as well as serotonin uptake in rat brain and human platelets. Like serotonin, estradiol decreases the dissociation rate in vitro of [3H]imipramine from its binding site in a dose-dependent manner.

Comparison of [ 28Br]4-bromoantipyrine and [ 125I]4-iodoantipyrine: The kinetics of exchange reaction and biodistribution in rats

Kinetics and mechanism of isotope exchange reaction between [ 82Br]bromide anion and 4-bromoantipyrine (BrAP), and the iodine-bromine exchange reaction between [ 125I]iodide anion and BrAP were studied. The preparation of [ 82Br]BrAP followed by exponential exchange law, the kinetics of the exchange reaction is a second-order reaction with an activation energy of 23.3 kcal/mol. The optimal exchange condition for halogen exchange between [ 125I]iodide and BrAP was by a hydrothermal melt method at 110 °C and 5 min reaction time. The partition coefficient at pH 7.0 for IAP and BrAP was 20.9 and 13.5, respectively. However, BrAP, which displayed the lower partition coefficient, showed higher brain uptake in rats than that for IAP (2.0% dose/organ vs 1.74% dose/organ), at 2 min after an i.v. injection.