Neurons in the basal forebrain project to the cortex in a complex topographic organization that reflects corticocortical connectivity patterns: an experimental study based on retrograde tracing and 3D reconstruction.

The most prominent feature of the Basal Forebrain (BF) is the collection of large cortically projecting neurons (basal nucleus of Meynert) that serve as the primary source of cholinergic input to the entire cortical mantle. Despite its broad involvement in cortical activation, attention, and memory, the functional details of the BF are not well understood due to the anatomical complexity of the region. This study tested the hypothesis that basalocortical connections reflect cortical connectivity patterns.

Lead (Pb+2) promotes apoptosis in newborn rat cerebellar neurons: pathological implications.

Despite mandated reduction in environmental lead (Pb++), such exposure still poses a public health hazard for children, with devastating effects on CNS development. To replicate aspects of this neurotoxicity, we used cultured granule cells from newborn rat cerebella to study whether apoptotic or necrotic death is the major consequence of exposure to low micromolar concentrations of Pb++. At a low dose, 1 microM (EC50 approximately equal to 10 microM), Pb++ does not affect glutamate-induced neuronal necrosis but promotes neuronal apoptosis, as characterized morphologically by cell shrinkage and chromatin condensation, biochemically by the typical internucleosomal DNA fragmentation and functionally by dependence on new synthesis of macromolecules (cycloheximide- and actinomycin D-sensitive).

The density and distribution of six GABAA receptor subunits in primary cultures of rat cerebellar granule cells.

In cultured cerebellar granule neurons (seven days in vitro) the expression of GABAA receptor subunits was quantified by using freeze-fracture immunocytochemical techniques with antibodies that specifically recognize the alpha 1, alpha 6, beta 2-3, gamma 2 and delta subunits of the GABAA receptor. In some experiments we have also used a less specific antibody that recognizes several alpha receptor subunits (alpha-total). The specificity of these antibodies was verified in human embryonic kidney cell line no.

Glutamatergic receptor kinetics are not altered by perinatal exposure to aspartame.

Observation of reduced levels of glutamic acid and aspartic acid in brain of weanling rats exposed perinatally to aspartame prompted a study of the effect of this food additive on glutamatergic receptor kinetics. Aspartame 500 mg/kg/day in drinking water was administered to Sprague-Dawley rats throughout gestation and lactation. Brain was excised from weanlings 20-22 days old, and kinetics of the N-methyl-D-aspartate receptor and total glutamatergic binding in cerebral cortex and hippocampus were found to be unaffected by perinatal exposure to high levels of aspartame.

Imidazenil, a partial positive allosteric modulator of GABAA receptors, exhibits low tolerance and dependence liabilities in the rat.

Long-term treatment of rats with full (triazolam) or selective (diazepam) allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptors rapidly induced tolerance to the protective effect of these drugs against bicuculline-induced convulsion. In contrast, long-term administration of partial allosteric modulators (imidazenil and bretazenil) of GABAA receptors, in doses equipotent to those of diazepam and triazolam that induce anticonvulsant tolerance, failed to elicit such a tolerance. Furthermore, no cross-tolerance was observed between diazepam and imidazenil.

Effect of nicotine on levels of extracellular amino acids in regions of the rat brain in vivo.

The local effect of nicotine on the extracellular levels of amino acids was examined in the striatum and frontal cortex of rats using microdialysis in vivo. The perfusion of 1 mM nicotine in Ringer's solution increased the extracellular levels of aspartic and glutamic acids by 40-50% in the striatum and had no effect on the levels of serine, glycine, glutamine, taurine or threonine. This effect of nicotine was dose- and Ca-dependent.

Effect of acetyl-L-carnitine on extracellular amino acid levels in vivo in rat brain regions.

Acetyl-L-carnitine (ALCAR) was found to have beneficial effects in senile patients. In recent years many of its effects on the nervous system have been examined, but its mechanism(s) of action remains to be elucidated. We previously reported that it causes release of dopamine in the striatum.

Proteolytic activity is altered in brain tissue of rats upon chronic exposure to ozone.

Tissue from pons medulla of rats exposed in vivo to various levels of ozone was assayed for calpain and cathepsin D activity. Chronic exposure to ozone increased calpain activity, which was 35% to 46% higher in the homogenates of animals exposed to 1.0 ppm ozone than in those of animals exposed to 0.

Peroxidative stress effects on calpain activity in brain of young and adult rats.

Three hours after administration of the pro-oxidant 2-cyclohexen-1-one, calpain activity was significantly reduced in the brain of young rats, but not in the brain of adult rats, and cathepsin D activity remained unchanged. Addition of isovalerylcarnitine to the incubation medium increased calpain activity 5-7-fold, counteracting the effect of the pro-oxidant.

Dopamine efflux from striatum after chronic nicotine: evidence for autoreceptor desensitization.

We examined the effect of chronic nicotine treatment on dopaminergic activity by measuring the effects of D1 and D2 dopamine (DA) receptor agonists and antagonists on tritium release from mouse striatum preloaded with [3H]DA. The radioactivity released during superfusion was separated on alumina columns and the distribution and efflux of [3H]DA and its main 3H-labeled metabolites were quantified. After preloading by incubation with [3H]DA, the electrical stimulation-evoked tritium overflow was higher in striatum prepared from nicotine-treated mice, whereas in vitro addition of nicotine caused a similar increase in tritium release from striatum of untreated and chronic nicotine-treated mice.

Dopamine releasing effect of phenylbiguanide in rat striatal slices.

The present study explored the mechanisms underlying the dopamine releasing effect of phenylbiguanide, a compound commonly used as a 5-HT3 receptor agonist. Phenylbiguanide, and also serotonin and 2-methyl-serotonin, enhanced the outflow of radioactivity from superfused rat striatal slices preloaded with [3H]dopamine. The presence of the dopamine uptake blocker nomifensin prevented the increase in outflow.

The distribution of cathepsin D activity in adult and aging human brain regions.

We measured the activity of cathepsin D, the major cerebral protease, in 50 separate areas of the central nervous system of adult and aged humans, using hemoglobin as the substrate. The activity showed significant regional heterogeneity, with average differences of 50-100% between the lower and higher level areas, and a more than threefold difference between the lowest and highest levels. The forebrain, midbrain, and hindbrain each had areas of high and low activity; cerebellum and cord areas were among those with low activity.

Radiolabeling of dopamine uptake sites in mouse striatum: comparison of binding sites for cocaine, mazindol, and GBR 12935.

This study addressed the possibility of a unique binding interaction between cocaine and the dopamine transporter as compared with other blockers of dopamine uptake. Cocaine binding sites in a fresh P2 fraction of mouse striatum were labeled with [3H]CFT, a phenyltropane analog of cocaine also known as WIN 35,428, and compared with sites labeled with [3H]mazindol or [3H]GBR 12935. Under the conditions used, homogeneous binding was observed that was inhibited monophasically by cocaine, CFT, and mazindol; the same potencies were observed with the three radioligands.

Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: role of glutamic acid.

We studied the effect of local administration of nicotine on the release of monoamines in striatum, substantia nigra, cerebellum, hippocampus, cortex (frontal, cingulate), and pontine nucleus and on the release of glutamic acid in striatum of rats in vivo, using microdialysis for nicotine administration and for measuring extracellular amine and glutamic acid levels. Following nicotine administration the extracellular concentration of dopamine increased in all regions except cerebellum; serotonin increased in cingulate and frontal cortex; and norepinephrine increased in substantia nigra, cingulate cortex, and pontine nucleus. Cotinine, the major nicotine metabolite, had no effect at similar concentrations.

Cocaine binding sites in mouse striatum, dopamine autoreceptors, and cocaine-induced locomotion.

BALB/cByJ mice received cocaine (25 mg/kg IP) once a day for 3 days, resulting in a greater locomotor response to cocaine on day 3 than on day 1. On day 4, a dose (0.03 mg/kg SC) of apomorphine, targeted at dopamine autoreceptors, caused the same degree of locomotor depression in cocaine- as in saline-pretreated mice.

Effect of metaphit on dopaminergic neurotransmission in rat striatal slices: involvement of the dopamine transporter and voltage-dependent sodium channel.

Metaphit, an isothiocyanate analog of phencyclidine (PCP), increased the basal release of radioactivity (outflow) from perfused rat striatal slices preloaded with [3H]dopamine above levels observed with the dopamine uptake blocker nomifensin. Preperfusing the slices with metaphit, followed by its removal, attenuated the amphetamine- or dopamine-induced outflow. In slices prepared from reserpine-pretreated rats, the metaphit (100 microM)-induced outflow was reduced to that observed with 10 microM nomifensin, suggesting a vesicular releasing effect of metaphit in addition to dopamine uptake blockade.

Sertraline and cocaine-induced locomotion in mice. II. Chronic studies.

The effects of repeated treatment with the serotonin uptake blocker sertraline on cocaine-induced locomotion in female C57BL/6ByJ mice were examined in three paradigms. First, when animals were treated for 2 weeks with a daily injection of 8 mg/kg IP of sertraline (or placebo) and challenged with cocaine (25 mg/kg IP) 1 h after the final sertraline injection, their cocaine-induced locomotion was the same as that of placebo-pretreated controls. Second, animals were treated for 2 weeks with cocaine (25 mg/kg IP once a day) (or saline) and then for 2 weeks with sertraline (8 mg/kg IP once a day) (or placebo).

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.

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.

Metaphit prevents locomotor activation induced by various psychostimulants and interferes with the dopaminergic system in mice.

Metaphit, an isothiocyanate analog of phencyclidine and a proposed phencyclidine receptor acylator, inactivated the carrier involved in the neuronal uptake of dopamine in in vitro experiments with preparations of the striatum in the mouse. In ex vivo experiments 2 and 24 hr after the intravenous administration of metaphit, no changes were observed either in the binding of [3H]cocaine to striatal membranes or in the uptake of [3H]dopamine into synaptosomes or slices. In in vivo experiments 24 hr after pretreatment with metaphit, selective labelling of uptake sites for dopamine in the striatum of the mouse with [3H]GBR 12935 was unaffected.