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Biomedical subjects

A Hashim

Publications and source records attributed to A Hashim.

At least 37 records · Page 2Linked to original sources
PubMed1997

Reversal of phencyclidine-induced hyperactivity by glycine and the glycine uptake inhibitor glycyldodecylamide.

Phencyclidine (PCP) induces a psychotic state that closely resembles schizophrenia. In preclinical studies, PCP has been shown to induce its unique behavioral effects by blocking excitatory neurotransmission mediated at the N-methyl-D-aspartate (NMDA) receptors, suggesting that agents which potentiate NMDA receptor-mediated neurotransmission might have clinically beneficial effects. The present study demonstrates that the NMDA co-agonist glycine inhibits rodent hyperactivity induced by PCP, but not amphetamine. Glycyldodecylamide, a compound that blocks neuronal glycine uptake and which may therefore increase intrasynaptic glycine levels, inhibits PCP-induced hyperactivity more potently than glycine. These results complement recent clinical studies with glycine and suggest that glycine-uptake inhibitors, as well as glycine, may be beneficial in the treatment of PCP-induced psychosis and schizophrenia.

Amphetamine↗
PubMed1996

Metabolism of (-)-deprenyl and PF-(-)-deprenyl in brain after central and peripheral administration.

We examined the cerebral metabolism of L-deprenyl and its fluoro-derivative pF-deprenyl, assaying the parent compounds, their metabolites desmethyl deprenyl, L-amphetamine, and L-methamphetamine, and the fluoro analogs of these metabolites. We compared the levels of the metabolites after subcutaneous injection with those after intracerebral administration (via microdialysis) of the parent compounds. The assay of the parent compounds and their metabolites was by GC-MS measurement of the components of brain microdialysate samples. After their subcutaneous administration, deprenyl and F-deprenyl rapidly entered the brain and then their concentration decreased, with an approximate half-life of 4.5 h. After the intracerebral administration the diffusion from the site of administration was minor. A small fraction (a few percent) of the intracerebrally administered deprenyl was metabolized in situ in the brain possibly by a nonenzymatic process. Metabolism of pF-deprenyl was somewhat more rapid. The higher cerebral levels of metabolites after the subcutaneous administration indicate their exogenous origin-metabolism of parent compounds in the periphery and penetration of the brain by the metabolites.

Amphetamine↗
PubMed1996

Effect of ibogaine on cocaine-induced efflux of [3H] dopamine and [3H] serotonin from mouse striatum.

Ibogaine, an indole alkaloid with proposed antiaddictive properties, has structural similarity to serotonin and has been shown to have affinity to the kappa-opioid binding site. In addition to the dopamine system, the serotonin system is a major target for cocaine action and the opioid system can affect the serotonin system. Therefore, the present study examined the effect of ibogaine on cocaine-induced, electrically evoked efflux of [3H]dopamine and [3H]serotonin from striatal tissue incubated in vitro, and their modulation by the kappa-opioid system. Cocaine (10(-6) M) added in vitro increased tthe fractional efflux of both [3H]dopamine (FRS2/FRS1 = 2.42 +/- 0.36) and [3H]serotonin (FRS2/FRS1 = 1.31 +/- 0.06). Mice treated in vivo with ibogaine (40 mg/kg or 2 times 40 mg/kg, IP) and killed 2 or 18 h later still showed the cocaine-induced increase in [3H]dopamine, but [3H]serotonin efflux was not increased. The 5-HTIB agonist CGS-12066A (10(-6) M, added in vitro) increased [3H]dopamine release, but did not alter cocaine-induced efflux of [3H]dopamine. CGS-12066A did not affect [3H]serotonin release, but the cocaine-induced increase in [3H]serotonin was inhibited. CGS-12066A (1 mg/kg, SC) potentiated cocaine (25 mg/kg, SC)-induced locomotor activity. Ibogaine pretreatment reduced both the cocaine and the CGS-12066A cocaine-induced increase in locomotor activity. The kappa-opioid agonist U-62066 (10(-6) M, added in vitro) reduced both [3H] dopamine and [3H]serotonin release. This inhibitory effect was blocked by in vivo administration ibogaine. U-62066 did not alter cocaine-induced [3H]dopamine efflux, but reduced cocaine-induced [3H]serotonin efflux. In striatal tissue from ibogaine-pretreated mice, U-62066 restored the cocaine-induced increase in [3H]serotonin release. U-62066 (1 mg/kg, SC) potentiated cocaine-induced behavior and maintained an increased locomotor activity after ibogaine treatment. The results suggest that ibogaine may block the cocainemediated effects on serotonergic transmission, that subsequently modulate dopamine release. The kappa-opioid modulation of serotonergic transmission is also involved.

Adrenergic beta-Antagonists↗
PubMed1996

The effect of ibogaine on Sigma- and NMDA-receptor-mediated release of [3H]dopamine.

The indole alkaloid ibogaine has been suggested to have potential for inhibiting dependency on stimulant drugs. Radioligand binding studies have suggested possible multisite actions of ibogaine: affinity at the kappa-opioid, NMDA, and sigma receptors, with effects on dopamine (DA) release. To further investigate the multiplicity of sites of action of ibogaine and the presynaptic regulation of the DA release, the effect of ibogaine on NMDA- and sigma-receptor-mediated efflux of [3H]DA was measured in striatal tissue from C57BL/6By mice. Striatal tissue was incubated in vitro with [3H]DA and the effect on DA release was measured. Both NMDA (25 microM) alone increased the efflux of DA. (+/)-Pentazocine (100 nM) did not inhibit the NMDA-evoked release. MK-801 (5 microM) completely inhibited the NMDA-evoked release and inhibited the (+/-)-pentazocine-evoked release by 49%. Ibogaine (10 microM) itself increased the efflux of DA; at 1 microM it was without effect. Ibogaine (1 microM) inhibited the NMDA-evoked release of DA by 31% and inhibited the (+/-)-pentazocine-evoked release by 48%. In addition, the level of basal release of DA obtained after the NMDA- or (+/)-pentazocine-evoked-release remained higher in the tissue exposed to ibogaine throughout. The results suggest that sigma receptors can regulate the release of DA, along with an action at the NMDA receptor. We previously reported action of ibogaine at the kappa-opioid site. The elevated basal release of DA in the presence of ibogaine after NMDA- or (+/-)-pentazocine-evoked release may reflect the ibogaine-induced removal of the tonically active kappa-opioid system that acts presynaptically to reduce dopamine release. The kappa-opioid system also appears to be inhibitory on both the NMDA and sigma receptors.

Animals↗
PubMed1995

The effect of ibogaine on kappa-opioid- and 5-HT3-induced changes in stimulation-evoked dopamine release in vitro from striatum of C57BL/6By mice.

Ibogaine is an indole alkaloid that has been suggested to have potential efficacy for interrupting dependency on stimulant drugs. The kappa-opioid and serotonin 5-HT3 systems may be involved in the action of ibogaine, related to their modulation of dopaminergic transmission. The kappa-opioid agonist U 62066 attenuated the in vitro stimulation-evoked efflux of tritium label from striatal tissue prelabeled with [3H]dopamine. In mice pretreated with ibogaine.HCI (40 mg/kg IP given 2 h prior or 2 x 40 mg/kg and animals killed 18 h later), the inhibitory effect of U 62066 on stimulation-evoked release of tritium was eliminated. The 5-HT3 agonist phenylbiguanide had a biphasic effect on stimulation-evoked release of tritium; at 10(-6) M phenylbiguanide, stimulation-evoked release was attenuated. At 10(-5) M the basal outflow of tritium was increased. Ibogaine pretreatment had no effect on basal or stimulation-evoked release in the presence of 10(-6) M phenylbiguanide, but increased the stimulation-evoked outflow of tritium in the presence of 10(-5) M phenylbiguanide. Cocaine (10(-6) M), a dopamine uptake blocker, increased the electrically-evoked release of dopamine; ibogaine pretreatment did not affect the enhanced electrically-induced release of [3H]dopamine by in vitro cocaine. The effects of ibogaine on the kappa-opioid and 5-HT3 receptors, located presynaptically on striatal dopamine terminals, modulating dopamine release may partly underlie its putative antiaddictive properties.

Animals↗
PubMed1994

Effect of ibogaine on serotonergic and dopaminergic interactions in striatum from mice and rats.

The effect of ibogaine (Endabuse, NIH 10567) on serotonin uptake and release, and on serotonergic modulation of dopamine release, was measured in striatal tissue from rats and mice. Two hours after treatment in vivo with ibogaine (40 mg/kg i.p.) the uptake of labeled [3H]serotonin and [3H]dopamine uptake in striatal tissue was similar in the ibogaine-treated animal to that in the control. The 5HT1B agonist CGS-12066A (10(-5) M) had no effect on stimulation-evoked tritium release from mouse or rat striatal tissue preloaded with [3H]serotonin; however, it elevated tritium efflux from striatal tissue preloaded with [3H]dopamine. This increase was not seen in mice treated with ibogaine 2 or 18 hours previously, or in rats treated 2 hours before. Dopamine autoreceptor responses were not affected by ibogaine pretreatment in either mouse or rat striatal tissue; sulpiride increased stimulation-evoked release of tritium from tissue preloaded with [3H]dopamine. The long-lasting effect of ibogaine on serotonergic functioning, in particular, its blocking of the 5HT1B agonist-mediated increase in dopamine efflux, may have significance in the mediation of its anti-addictive properties.

Animals↗
PubMed1994

Ibogaine reduces preference for cocaine consumption in C57BL/6By mice.

After a period of forced exposure to 300 mg/l cocaine HCl in drinking water for a period of one week, followed by forced exposure to 200 mg/l cocaine for an additional week, male C57BL/6By mice developed a preference for cocaine when given a choice of drinking either water or a solution containing cocaine (200 mg/l). The mean daily intake of cocaine during the choice period was 26 +/- 1 mg/kg or, when expressed as the ratio of cocaine over total fluid intake, represented a cocaine preference of 71 +/- 2%. Administration of ibogaine HCl (40 mg/kg, two injections 6 h apart) two weeks after the beginning of the choice period reduced the cocaine preference for at least five days; the mean daily intake of cocaine was reduced by 38% (to 16 +/- 1 mg/kg per day; p < 0.05) and cocaine preference was reduced to 41 +/- 2% (cocaine fluid consumption/total fluid intake). An acute challenge injection of cocaine (25 mg/kg SC) produced a significant increase in cocaine-induced locomotor activity and stereotypy in mice previously exposed to cocaine in their drinking water (cocaine choice group). Five days after ibogaine administration, locomotor and stereotypy activity were significantly lower after a challenge injection of cocaine (25 mg/kg SC). Brain levels of cocaine 35 min after the challenge injection of cocaine were approximately 25% higher in ibogaine-treated mice (7.2 +/- 0.5 and 9.3 +/- 0.8 micrograms/g wet wt for water vs. mice treated with water plus ibogaine and 9.3 +/- 0.2 and 11.8 +/- 0.7 micrograms/g wet wt for cocaine drinking vs. cocaine drinking plus ibogaine treatment).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Acetyl-L-carnitine releases dopamine in rat corpus striatum: an in vivo microdialysis study.

The effect of acetyl-L-carnitine, a compound reported to be beneficial for senile patients, on the release of dopamine (DA) from the striatum was studied by using in vivo brain dialysis in anesthetized rats coupled with HPLC-electrochemical detection. Striatal infusion of acetyl-L-carnitine increased the efflux of DA with no apparent changes in efflux of DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA). The DA-releasing effect of acetyl-L-carnitine was concentration- and Ca(2+)-dependent, and was abolished by omega-conotoxin fraction GVIA and tetrodotoxin, inhibitors of the voltage-dependent Ca2+ and Na+ channels, respectively. Nomifensine, an inhibitor of DA reuptake did not alter the DA-releasing property of acetyl-L-carnitine. DA released from the striatum by acetyl-L-carnitine was decreased by reserpine pretreatment whereas the d-amphetamine-evoked DA outflow was not affected. In contrast to acetyl-L-carnitine, d-amphetamine reduced the extracellular concentrations of DOPAC and HVA. We conclude from the present data that acetyl-L-carnitine evokes DA release from the vesicular pools of the nigrostriatal dopaminergic neurons by a Ca(2+)-dependent, exocytotic process.

Acetylcarnitine↗
PubMed1992

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. The cholinergic antagonists mecamylamine and atropine, the dopaminergic antagonists haloperidol and sulpiride, and the excitatory amino acid antagonist kynurenic acid all inhibited the nicotine-induced increase of extracellular dopamine in the striatum. The fact that kynurenic acid almost completely prevented the effects of nicotine, and nicotine at this concentration produced a 6-fold increase of glutamic acid release, suggests that the effect of nicotine is mainly mediated via glutamic acid release.

Animals↗
PubMed1992

Ibogaine antagonizes cocaine-induced locomotor stimulation in mice.

Ibogaine (40 mg/kg i.p.), when given 2 hours before an acute injection of cocaine (25 mg/kg s.c.) to C57BL/6 mice, reduced the cocaine-induced locomotor stimulation. Such stimulation was also reduced in the ibogaine-treated mice when a second injection of cocaine was given 24 hr later. Thus, the reduction in locomotor activity was not just the short-term depression of locomotor activity seen after ibogaine administration. When mice were given a daily injection of cocaine for 3 days and ibogaine was given after the cocaine injection on day 3, and again on day 4, cocaine-induced locomotor activity was reduced three hours later on day 4. On days 5 and 9 of the cocaine administration, with no further ibogaine treatment ambulatory counts were still lower in the ibogaine-pretreated mice. Locomotor stimulation induced by amphetamine (10 mg/kg) was not affected by ibogaine. An acute injection of ibogaine resulted in a transient increase in turnover of dopamine, as indicated by the increase in the ratio of metabolites of the dopamine to dopamine, followed by a decrease in the metabolites in striatum and frontal cortex 24 hr later. In vivo treatment with ibogaine did not affect the binding of [3H]WIN 35,248 to the cocaine binding site in striatal tissue measured in vitro. In addition, ibogaine added in vitro had a weak affinity to the WIN 35,248 binding site (IC50 for cocaine = 120 nM and for ibogaine = 1,500 nM). The results suggest that ibogaine may have induced a selective change in the dopaminergic system that results in a decrease in responsiveness to cocaine that persisted for at least 1 week.

Amphetamine↗
PubMed1992

Ibogaine reduces amphetamine-induced locomotor stimulation in C57BL/6By mice, but stimulates locomotor activity in rats.

The effect of ibogaine hydrochloride on locomotor stimulation induced by d-amphetamine sulfate was tested in male C57BL/6By mice and in female Sprague-Dawley rats. In mice, locomotor stimulation induced by d-amphetamine at 1 or 5 mg/kg s.c. was reduced by prior administration of one or two injections of ibogaine (40 mg/kg), given 2 or 18 hours earlier. This reduction in locomotor activity persisted for two days. Locomotor stimulation induced by a higher dose (10 mg/kg) of d-amphetamine was not reduced by such prior administration of ibogaine. A lower dose of ibogaine (20 mg/kg) did not reduce the subsequent locomotor activity induced by d-amphetamine. Ibogaine decreased striatal dopamine levels, while d-amphetamine increased them. Ibogaine treatment (2 x 40 mg/kg, 18 hours apart) induced a decrease by 30% in the level of striatal dopamine and its metabolites measured in tissue extracts 3 hours after the second ibogaine injection. One hour after d-amphetamine (5 mg/kg) administration, the level of striatal dopamine increased by 26%. Although the level of striatal dopamine was initially lower in the ibogaine-pretreated mice, d-amphetamine (5 mg/kg) administration induced an increase in striatal dopamine and its metabolites. The effect of ibogaine seems to be species specific, since in rats pretreated with ibogaine 18 hours before d-amphetamine, locomotor stimulation induced by d-amphetamine was further increased. In addition, the in vitro electrical-evoked release of [3H]dopamine from striatal tissue was either unchanged or inhibited in the presence of d-amphetamine, and after ibogaine pretreatment in vivo, the release of tritium in the presence of d-amphetamine was inhibited or stimulated in mice and rats, respectively.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Effect of acetyl-L-carnitine on the dopaminergic system in aging brain.

We studied the effect of acetyl-L-carnitine (ALCAR) on dopamine release and the effect of long-term acetyl-L-carnitine treatment on age-related changes in striatal dopamine receptors and brain amino acid levels. In striatal tissue that had been incubated with [3H]dopamine, acetyl-L-carnitine increased the release of [3H]dopamine evoked by electrical stimulation. In striatal tissue from aged mice administered acetyl-L-carnitine for 3 months, the release of [3H]dopamine evoked by electrical stimulation was higher than that of its aged control; the release after a second stimulation was similar in the two groups. There was a significant decline in the number of D1 striatal dopamine receptors with age. The Bmax was 51% lower in 1.5-year-old mice than in 4-month-old animals. Administration of acetyl-L-carnitine for 3 months diminished the reduction in the binding of [3H]SCH-23390. [3H]Spiperone binding to D2 receptors was not decreased with age and was not affected by acetyl-L-carnitine treatment. Age-related decreases in levels of several amino acids were observed in several brain regions. Acetyl-L-carnitine lessened the reduction in the level of taurine only in the striatum. The findings confirm the multiple effects of acetyl-L-carnitine in brain, and suggest that its administration can have a positive effect on age-related changes in the dopaminergic system.

Acetylcarnitine↗
PubMed1991

Carrier-mediated efflux of [3H]dopamine and [3H]1-methyl-4-phenylpyridine: effect of ascorbic acid.

The carrier-mediated efflux of [3H]1-methyl-4-phenylpyridine (MPP+) and [3H]dopamine was examined in mouse striatal synaptosomal P2 fractions. Although the two compounds are transported by the same carrier, the translocation of the carrier-ligand complex is more rapid with MPP+ than with dopamine. With dopamine-stimulated efflux of preloaded [3H]dopamine, externally present dopamine at a concentration of 1.3 microM reduced the intrasynaptosomal concentration of [3H]dopamine by 50% (the ECR value) with 8 min of incubation. The ECR value of dopamine in promoting the efflux of [3H]MPP+, however, was only 0.15 microM. Similarly, ascorbic acid was weaker in enhancing the efflux of [3H]dopamine (ECR greater than 2000 microM) than that of [3H]MPP+ (ECR = 567 microM). This effect of ascorbic acid on the efflux of [3H]MPP+ was attenuated by mazindol, a blocker of dopamine uptake. It is proposed that ascorbic acid has a neuromodulatory role involving changes at the level of carrier-membrane translocation and/or orientation.

1-Methyl-4-phenylpyridinium↗
PubMed1991

Chronic nicotine-induced changes in dopaminergic system: effect on behavioral response to dopamine agonist.

The effect of chronic nicotine on dopamine-agonist-mediated locomotor activity response was measured in BALB/cBy and C57BL/6 mice. Mice were injected twice daily for 10 days with 1.2 mg/kg SC (-)-nicotine di-(+)tartrate. Subsequent locomotor activity response to apomorphine (1 mg/kg SC) was measured. Apomorphine induced hypomotility in both strains of mice, with the BALB/cBy mice showing a greater hypomotility compared to the C57BL/6 mice. The response to apomorphine was attenuated in both strains of mice that were treated previously with repeated injections of nicotine. The results suggest that chronic nicotine may induce changes in the dopaminergic system, which is reflected in altered behavioral response to a dopamine agonist.

Animals↗
PubMed1991

The effects of electroconvulsive shock on dopamine-1 and dopamine-2 receptor ligand binding activity in MPTP-treated mice.

To explore the possible therapeutic use of electric convulsive treatment in Parkinson's disease (PD), the authors examined the biochemical effects of electroconvulsive shock (ECS) on dopaminergic systems in a rodent model of PD, induced with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP increased dopamine turnover, as indicated by an increase in the ratio of the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to dopamine. [3H]Spiperone binding to the D2 site increased after lesioning of striatal dopamine terminals. With ECS alone, no changes were found in monoamine levels, brain monoamine oxidase activity, or the D2-labeled sites measured 24 hours after the last treatment. [3H]SCH-23390 binding to the D1 site increased after ECS. In MPTP-treated mice, ECS also increased [3H]SCH-23390 binding to the D1 site, whereas [3H]spiperone binding to the D2 site was unchanged compared to control or to only ECS-treated animals, and decreased compared to the MPTP-treated group that did not receive ECS. ECS appears to selectively modify both the D1 and D2 sites when given after MPTP, increasing the binding of a D1 radioligand and decreasing the binding of a D2 radioligand.

Animals↗
PubMed1989

Cerebral cortical concentrations of bioamines and their metabolites during arousal and after feeding in the little brown bat (Myotis lucifugus).

The concentrations of bioamines and their metabolites have been determined in March and April during arousal from hibernation in the cerebral cortex of the little brown bat (Myotis lucifugus). The patterns during arousal for dopamine and serotonin (5-HT) were similar with a significant fall in concentrations by 1 h of arousal, and an inverse relationship with their respective metabolites, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolacetic acid (5-HIAA). This suggests an acute release and metabolism of these bioamines with onset of arousal. During arousal, cerebral cortical concentrations of norepinephrine (NE) were not significantly changed. Levels of homovanillic acid were markedly depressed during hibernation and rose acutely with arousal. After arousal and 4 days of feeding in April, there was an increase in all bioamines and their metabolites studied except for NE. Of note is the marked decrease in the hibernating level of 5-HT and increase in its metabolite 5-HIAA from March to April, which may herald the natural termination of hibernation. Our results suggest that the brain of hibernators undergoes complex changes in the modulation of neurotransmitter systems which are consistent with both down- and up-regulation of neuronal activity in the maintenance of hibernation and the initiation of the arousal process.

Animals↗
PubMed1989

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., twice weekly for 4 weeks) was shown to inhibit monoamine oxidase B activity by 89%, and also to induce an up-regulation of the [3H]mazindol binding site associated with the striatal dopamine uptake carrier. Scatchard analysis indicated a 56% increase in the maximal number of [3H]mazindol binding sites in chronic L-deprenyl animals, but no effect on the affinity of these binding sites. The ability of L-deprenyl to up-regulate the [3H]mazindol-associated dopamine uptake carrier appears to be a result of its role as a dopamine uptake inhibitor.

3,4-Dihydroxyphenylacetic Acid↗