Sertraline and cocaine-induced locomotion in mice. I. Acute studies.

The present study assessed the behavioral and pharmacokinetic interaction between the serotonin uptake blocker sertraline and cocaine in C57BL/6ByJ mice. Pretreatment with sertraline (1-32 mg/kg IP) did not affect the total amount of spontaneous locomotor activity during 50 min following administration of cocaine (15-40 mg/kg IP). At doses of sertraline (16 and 32 mg/kg) much higher than those found to inhibit ex vivo neuronal uptake of serotonin by 50% (1-2 mg/kg), the peak of cocaine-induced locomotor activity was shifted towards a later time.

5-HT3 receptor antagonists attenuate cocaine-induced locomotion in mice.

The 5-HT3 receptor antagonists ICS 205-930 and zacopride attenuated cocaine-induced locomotor activity in C57BL/6ByJ mice. In contrast, the aselective 5-HT1 and 5-HT2 receptor antagonist, methysergide did not affect the response to cocaine. The effect of the 5-HT3 receptor antagonists was not due to general sedation, because zacopride did not alter the locomotor response to caffeine.

Synthetic domains of cystatins linked to enkephalins are novel inhibitors of brain cathepsins L/B.

Cystatin domains or homologous sequences were synthesized and tested as inhibitors of papain, and rat brain cathepsins B and L. These domains included: I, an enzyme substrate binding site containing a -GG- cleavage site (YGGFL); II, known cystatin consensus sequences (-QVVAG- or -QLVSG-); and III, the proposed ancillary site for binding of chicken cystatin to papain (-IPWLN-). A Domain II analog QVVAG(K-NH2) inhibited cathepsin L and papain with Ki 1-4 X 10(-4) M but was inactive towards cathepsin B.

Inhibition of serotonin uptake into mouse brain synaptosomes by ionophores and ion-channel agents.

[3H]Serotonin uptake into mouse cerebrocortical synaptosomes was decreased by the K+ ionophore valinomycin, the K+ and Na+ ionophore gramicidin, and the proton ionophore carbonylcyanide m-chlorophenylhydrazone. The Na+/H+ exchanger monensin reduced uptake at non-depolarizing concentrations. Uptake was also decreased by inhibition of the Na+, K(+)-ATPase with ouabain and by tetrodotoxin-sensitive activation of voltage-dependent sodium channels with veratridine, batrachotoxin and scorpion venom.

Changes with aging in the levels of amino acids in rat CNS structural elements: IV. Methionine and basic amino acids.

This paper reports the distribution of methionine, histidine, lysine, arginine, and ornithine in 53 discrete brain areas of 3- and 29-month-old male Fischer 344 rats microdissected by the punch technique. Like that of the other amino acids were reported in previous papers of this series, the distribution of methionine and the basic amino acids was regionally highly heterogeneous. The ratios of levels in the areas of highest concentrations to levels in the areas of lowest concentration varied from 10 to 15 for these amino acids, except that it was 23 for arginine.

Changes with aging in the levels of amino acids in rat CNS structural elements: III. Large neutral amino acids.

This paper reports the concentrations of valine, leucine, isoleucine, phenylalanine, and tyrosine as determined in 53 discrete brain areas of 3- and 29-month-old male Fischer 344 rats microdissected by the punch technique. The levels of other amino acids in the same areas are reported in other papers of this series. The essential amino acids reported in this paper showed great regional heterogeneity, with concentrations in areas of the highest content being 9 to 12 times higher than levels in areas of the lowest content.

Calpain II activity and calpastatin content in brain regions of 3- and 24-month-old rats.

In previous studies, we found a significantly higher (100% or more) content of cathepsin D in the aging brain. In the present study, we determined activity of Ca2(+)-activated neutral protease requiring millimolar Ca2+ (calpain II, CANP II) and amount of its endogenous inhibitor, calpastatin, in extracts of various brain regions of 3-month-old and 24-month-old male Fischer-344 rats. Calpain II was separated from calpastatin in a single step (chromatography) and its activity was tested using as substrates [methyl-14C]alpha-casein, the cytoskeletal proteins desmin and actin, and a mixture of neurofilament triplet proteins and glial fibrillary acidic proteins (GFAP).

Effects of social isolation and the time of day on testosterone levels in plasma of C57BL/6By and BALB/cBy mice.

Adult male C57BL/6By and BALB/cBy mice were housed either in large groups (20 per cage) or individually, and levels of plasma testosterone were measured in samples taken in the morning (9 to 10 A.M.) and in the evening (9 to 10 P.

D-tartrate alters uptake of [3H]dopamine into brain synaptic vesicles.

The use of D-tartrate containing media for measuring uptake of catecholamines into brain synaptic vesicles alters the properties of transport. Absolute concentrations of inhibitors determined in competition studies should be viewed with caution.

[14C]guanidinium ion influx into Na+ channel preparations from mouse cerebral cortex.

[14C]Guanidinium ion influx into Na+ channel preparations from mouse and rat cerebral cortex (purified synaptosomes, and synaptoneurosomes) was characterized and its properties were compared with those for 22Na+ influx. Tetrodotoxin-sensitive influx of [14C]guanidinium ion was stimulated by aconitine, veratridine, and batrachotoxin with a K0.5 of 7, 5 and 0.

The effect of nicotine on catecholaminergic storage vesicles.

The present study examined the action of nicotine on the accumulation of [3H]dopamine into synaptic vesicles prepared from mouse cerebral cortex or bovine striatum. Nicotine was shown to be a weak inhibitor of [3H]dopamine accumulation, with an IC50 of approximately 0.2-0.

Comparison of characteristics of dopamine uptake and mazindol binding in mouse striatum.

Biochemical and pharmacological studies suggest that the binding of [3H]mazindol is functionally related to the dopamine uptake carrier complex in rodent striatum. In order to study further the relationship between the substrate recognition site for dopamine uptake and the high-affinity binding site for mazindol the uptake of [3H]dopamine and the binding of [3H]mazindol was studied in BALB/cBy mouse striatum in various buffers (Tris, HEPES, bicarbonate-phosphate). Kinetic analysis showed that the Kd of the binding of [3H]mazindol and the Km of the uptake of [3H]dopamine was changed by different sodium concentrations and/or by the presence of Tris, while the Bmax and the Vmax remained essentially the same.

Evidence for a common site of action of lidocaine and carbamazepine in voltage-dependent sodium channels.

The finding that the development of lidocaine-kindled seizures is blocked by carbamazepine suggests an interaction of carbamazepine with local anesthetic mechanisms. To study the site of interaction, the effects of lidocaine, carbamazepine and another anticonvulsant drug, phenytoin on scorpion venom-enhanced specific binding of [3H]batrachotoxinin A 20-alpha-benzoate to the sodium channel gating complex were examined in vitro in a rat brain hippocampus preparation. Lidocaine shifted the concentration inhibition curve of carbamazepine to the right and vice versa.

Increase in cathepsin D activity in rat brain in aging.

Cathepsin D-like activity in homogenates of five brain areas of 3-month-old and 24-month-old Fischer 344 rats was measured. With hemoglobin as substrate at pH 3.2, more than 90% of the activity was inhibited by pepstatin.

Phosphoinositide hydrolysis induced by depolarization and sodium channel activation in mouse cerebrocortical slices.

Carbachol, a muscarinic receptor agonist and the sodium channel-activating agents, scorpion venom, veratridine, batrachotoxin and aconitine, were shown to stimulate the formation of [3H]inositol phosphates in [3H]inositol-labelled miniprisms, obtained from the cerebral cortex of the mouse. The inositol response to the Na+ channel-activating agents was inhibited by the sodium channel blocker tetrodotoxin (TTX), while the response induced by carbachol was partially resistant to TTX. The response to scorpion venom and the TTX-insensitive portion of the response to carbachol was additive, indicating different mechanisms.

Role of ions and membrane potential in uptake of serotonin into plasma membrane vesicles from mouse brain.

Plasma membrane vesicle preparations from mouse cerebral cortex actively accumulated [3H]serotonin upon the imposition of a K+ gradient (in greater than out), a Na+ gradient (out greater than in), and the presence of external Cl-. Maximal stimulation of uptake by internal K+ occurred at 15 mM and half-maximal stimulation at 2 mM. Internal K+ did not enhance uptake merely via generation of a membrane potential because simultaneous parallel increases in internal and external K+ concentration also stimulated uptake.

Chronic L-deprenyl does not alter the restoration of striatal dopamine in MPTP-lesioned mice.

The present study examined the effect of chronic L-deprenyl on dopaminergic terminal function after mouse striatal terminals were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 2 x 30 mg/kg s.c.).

Metaphit, an isothiocyanate analog of PCP, induces audiogenic seizures in mice.

Metaphit induces audiogenic seizures in mice. The most severe clonic/tonic seizures occur 18-24 h after metaphit administration. After 48 h the incidence of the seizure episodes begin to diminish.

Uptake of acetyl-L-carnitine in the brain.

Analysis in mouse brain slices of the uptake of acetyl-L-[N-methyl-14C]carnitine with time showed it to be concentrative, and kinetic analysis gave a Km of 1.92 mM and a Vmax of 1.96 mumol/min per ml, indicating the presence of a low-affinity carrier system.

Motor effects of intracaudate injection of excitatory amino acids.

In a study of the role of excitatory amino acid receptors in movement disorders, the effect of the injection of glutamate (Glu), aspartate (Asp), N-methyl-D-aspartate (NMDA), quisqualate (Qu), or kainate (K) into the rat striatum was investigated. Rats were microinjected unilaterally through chronically implanted guide cannulas and their motor behavior was recorded. After 10-25 min L-Glu produced reversible periodic choreiform movements lasting 5-10 sec and contraversive rotation lasting 1-2 min.

Dopamine D1 receptor and dopamine D2 receptor binding activity changes during chronic administration of nicotine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice.

The effect of nicotine on MPTP-induced changes in striatal dopamine receptors binding activity was investigated. Dopamine D1 and D2 receptors were labeled with [3H]SCH-23390 and [3H]spiperone respectively in BALB/cBy mice. With administration of only MPTP, which caused more than an 80% decrease in striatal dopamine level, binding of 0.

Chronic L-deprenyl-induced up-regulation of the dopamine uptake carrier.

L-Deprenyl is an inhibitor of monoamine oxidase B and dopamine uptake. Chronic L-deprenyl (10 mg/kg i.p.

The effect of caffeine on some mouse brain free amino acid levels.

Changes in free amino acids were examined in the central nervous system of mice treated with caffeine for three weeks. Caffeine was administered in the drinking water, and at the end of three weeks the level of caffeine in the cerebral cortex was 113 +/- 19 micrograms/g. When amino acid levels in cerebral hemispheres, midbrain, pons and medulla, and cerebellum were measured a significant increase in glutamine levels was found in all four regions.

Enkephalin analogs as substrates for the assay of brain cysteine proteinase (Cathepsin L) and its endogenous inhibitors.

A series of enkephalin-like peptides (X-Tyr-Gly-Gly-R-Pro) were synthesized for assay of cathepsin L and papain. Enzymes acted only at the Gly-Gly bond to release N-terminal dipeptides. When X = dansyl and R = Phe(NO2) the substrate was suited for continuous fluorimetric assay of rat brain cathepsin L (Km 45 microM, kcat/Km 1333 mM-1 sec-1).

Effect of cocaine and cocaine congeners on veratridine-induced depolarization in mouse cerebrocortical synaptoneurosomes.

Structure-activity relationships were determined for cocaine congeners in counteracting the depolarization induced by the action of veratridine on voltage-dependent sodium channels of synaptoneurosomes from mouse brain cortex, and their potency was compared to those determined previously on Na+ uptake and batrachotoxinin binding. Cocaine, norcocaine, (+)-pseudococaine, (-)-pseudococaine, (+)-neopseudococaine, benzoyltropine, benzoylpseudotropine, ecgonine methylester, atropine, WIN-35,428, WIN-35,140, WIN-35,065-3, WIN-35,004, and procaine were tested for their potency in inhibiting depolarization as measured by the distribution of the lypophilic cation [3H]triphenylmethylphosphonium across the membrane. All of the tested compounds inhibited the veratridine-induced depolarization in a competitive manner.