Biomedical subjects

Sari Izenwasser

Publications and source records attributed to Sari Izenwasser.

12 recordsLinked to original sources

PubMed2003

Cocaine abusers have an overexpression of alpha-synuclein in dopamine neurons.

Alpha-synuclein is a presynaptic protein that has been implicated as a possible causative agent in the pathogenesis of Parkinson's disease. The native protein is a major component of nigral Lewy bodies in Parkinson's disease, and full-length alpha-synuclein accumulates in Lewy neurites. Here we present evidence that alpha-synuclein levels are elevated in midbrain dopamine (DA) neurons of chronic cocaine abusers. Western blot and immunoautoradiographic studies were conducted on postmortem neuropathological specimens from cocaine users and age-matched drug-free control subjects. The results demonstrated that alpha-synuclein levels in the DA cell groups of the substantia nigra/ventral tegmental complex were elevated threefold in chronic cocaine users compared with normal age-matched subjects. The increased protein levels in chronic cocaine users were accompanied by changes in the expression of alpha-synuclein mRNA in the substantia nigra and ventral tegmental area. Although alpha-synuclein expression is prominent in the hippocampus, there was no increase in protein expression in this brain region. The levels of beta-synuclein, a possible negative regulator of alpha-synuclein, also were not affected by cocaine exposure. Alpha-synuclein protein levels were increased in the ventral tegmental area, but not the substantia nigra, in victims of excited cocaine delirium who experienced paranoia, marked agitation, and hyperthermia before death. The overexpression of alpha-synuclein may occur as a protective response to changes in DA turnover and increased oxidative stress resulting from cocaine abuse. However, the accumulation of alpha-synuclein protein with long-term cocaine abuse may put addicts at increased risk for developing the motor abnormalities of Parkinson's disease.

Blotting, Western↗

PubMed2003

Synthesis of dopamine transporter selective 3-[2-(diarylmethoxyethylidene)]-8-alkylaryl-8-azabicyclo[3.2.1]octanes.

A series of 3-[2-(diarylmethoxyethylidene)]-8-alkylaryl-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine and serotonin transporters. The 8-phenylpropyl analogues 8a (K(i)=4.1 nM) and 8b (K(i)=3.7 nM) were the most potent compounds of the series with binding affinities 3 times greater than GBR-12909. In addition, 8a (SERT/DAT=327) was over 300-fold more selective for the dopamine transporter than the serotonin transporter.

Animals↗

PubMed2002

Cocaine differentially alters behavior and neurochemistry in periadolescent versus adult rats.

This study examined whether there are differences in the behavioral and neurochemical effects of cocaine in periadolescent rats compared to adult rats. Periadolescent (postnatal days 28-35) and adult rats were injected with cocaine or vehicle for 7 days. Ten days later (day 17), rats either were challenged with cocaine, or dopamine transporter and receptor and serotonin transporter binding were examined. Adult rats became sensitized to the locomotor-activating effects of cocaine and there were increases in dopamine transporter density in the caudate putamen compared to vehicle-treated adult rats. In addition, serotonin transporter densities were increased in the ventromedial caudate putamen, nucleus accumbens shell, and the olfactory tubercle in cocaine-treated adult rats compared to vehicle-treated adult rats. In contrast, periadolescent rats did not show sensitization to cocaine and there was no effect of cocaine on either dopamine or serotonin transporter densities. These findings suggest that there are different neurochemical and behavioral adaptations to repeated cocaine administration in periadolescent versus adult rats.

Age Factors↗

PubMed2002

Synthesis and dopamine transporter binding affinities of 3alpha-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes.

A series of 3alpha-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine transporter. The unsubstituted analogue 7b (K(i)=98nM) was the most potent compound of the series with binding affinity three-times greater than cocaine and only 5-fold less than GBR-12909. The structure-activity data for 7a-f suggests that these compounds may be binding at the dopamine transporter in a similar fashion to GBR 12909.

Bridged Bicyclo Compounds↗

PubMed2002

Chronic cocaine increases kappa-opioid receptor density: lack of effect by selective dopamine uptake inhibitors.

Continuous infusion of cocaine or the selective dopamine uptake inhibitors GBR 12909 or RTI-117 increases locomotor stimulation, to which partial tolerance occurs. In addition, all three drugs produce significant decreases in tyrosine hydroxylase immunoreactivity in caudate putamen and nucleus accumbens core, suggesting a decreased dopaminergic tone. An interaction between cocaine and opioids has long been documented. Chronic cocaine significantly increases mu and kappa-opioid receptors and treatment with a kappa-opioid agonist markedly reduces the behavioral effects of cocaine. In addition, chronic cocaine, but not GBR 12909, increases prodynorphin gene expression in caudate putamen. To further understand the interaction between cocaine and the kappa-opioid system, the effects of a chronic continuous infusion for 14 days of cocaine or one of the selective dopamine uptake inhibitors GBR 12909 or RTI-117 via osmotic minipump were examined on kappa-opioid receptors using the selective kappa-opioid ligand [3H] U-69593. [3H] U-69593 binding density was significantly increased in caudate putamen, nucleus accumbens shell, claustrum, and endopiriform nucleus after cocaine, while neither GBR 12909 nor RTI-117 had any effect. The increased kappa-opioid receptor densities observed following cocaine are likely not related to dopamine uptake inhibition, since they were not produced by selective dopamine uptake inhibitors. These findings suggest that regulation of kappa-opioid receptors by cocaine may be via inhibition of serotonin or norepinephrine uptake, by a combination of effects on two or three monoamine transporters, or by a mechanism unrelated to transporter inhibition.

Animals↗

PubMed2002

Synthesis and biological evaluation at nicotinic acetylcholine receptors of N-arylalkyl- and N-aryl-7-azabicyclo[2.2.1]heptanes.

A new series of N-arylalkyl-substituted 7-azabicyclo[2.2.1]heptanes and N-aryl-substituted 7-azabicyclo[2.2.1]heptanes were synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors. The in vitro binding affinities (K(i)) of the 7-azabicyclo[2.2.1]heptane derivatives were measured by inhibition of [(3)H]cytisine binding to rat brain tissue. The most potent ligand of the series was found to be N-(3-pyridylmethyl)-7-azabicyclo[2.2.1]heptane (5b, K(i) = 98 nM). The chloro analogue (5a, K(i) = 245 nM) 5a and epibatidine (1) produced dose-dependent analgesia in both hotplate and tail-flick tests when administered subcutaneously. However, when compounds 1 and 5a,b were administered intrathecally, all produced analgesia in the tail-flick test but only 5a produced analgesia in the hotplate test.

Analgesics, Non-Narcotic↗

PubMed2002

Synthesis and biological evaluation of 2-substituted 3beta-tolyltropane derivatives at dopamine, serotonin, and norepinephrine transporters.

A series of eight 2-substituted 3-tolyltropane derivatives were synthesized, and the in vitro and in vivo biological activities as dopamine uptake inhibitors were determined. From the in vitro structure-activity data, it is apparent that a tolyl group in the 2-position, independent of the stereochemical attachment to the tropane ring system, provided compounds (9-12, 14) that exhibit high-affinity binding at the dopamine transporter (DAT). Although a slight stereochemical preference in binding affinity at the DAT was observed for the 2beta-(R)-alcohol 10 over the 2beta-(S)-isomer 11, no significant differences in behavioral effects were observed. Furthermore, despite a relatively low potency of 10 for the inhibition of dopamine uptake compared to its affinity for the DAT, its behavioral profile did not vary significantly from cocaine. These data indicate that a behavioral characterization of compounds is a critical feature of efforts to discover pharmacological treatments for cocaine abuse.

Animals↗

PubMed2002

Regulation of dynorphin gene expression by kappa-opioid agonist treatment.

The effects of K-opioid agonist treatment on prodynorphin mRNA expression in the rat brain were studied. Rats were treated with the selective kappa-opioid agonist U-69593 or vehicle for 5 days and prodynorphin mRNA was measured on day 8 (3 days after the last injection) or 22 (17 days after the last injection). On day 8 prodynorphin mRNA was increased in the hypothalamus and decreased in the striatum, frontal cortex, and hippocampus of rats treated with U-69593. On day 22, prodynorphin mRNA was increased in the hypothalamus, frontal cortex and striatum of U-69593 treated rats. These findings suggests that kappa-opioid receptor agonist treatment has long-term, continually changing effects on prodynorphin mRNA expression.

Animals↗

PubMed2002

Pretreatment with methylphenidate sensitizes rats to the reinforcing effects of cocaine.

Repeated administration of cocaine produces sensitization to its locomotor-activating effects and increases the rate at which cocaine self-administration behavior is acquired. Methylphenidate is administered clinically on a daily basis, predominantly to children and adolescents, for the treatment of attention-deficit hyperactivity disorder (ADHD). It has been demonstrated previously that pretreatment with methylphenidate administered to periadolescent rats decreased the latency to acquisition of cocaine self-administration. Since methylphenidate is often also administered to adults with ADHD, the present study was conducted to determine the effects of prior administration of methylphenidate (5 or 20 mg/kg/day for 9 days) to adult rats on the rate of acquisition for cocaine self-administration (0.25 mg/kg/infusion). The higher dose of methylphenidate significantly decreased the latency for acquisition of this behavior, suggesting that the rats were sensitized to the reinforcing effects of cocaine after treatment with methylphenidate. These findings add to the growing body of evidence suggesting cross-sensitization between the behavioral effects of psychostimulants. Further, insofar as self-administration is a reliable measure of abuse liability, these data suggest that a short-duration pretreatment with a high dose of methylphenidate to adults increases vulnerability to cocaine abuse.

Animals↗

PubMed2002

Tolerance and sensitization to the locomotor-activating effects of cocaine are mediated via independent mechanisms.

Tolerance or sensitization to the locomotor-activating effects of cocaine occurs depending upon the treatment regimen that is used. When cocaine is injected on a daily basis, sensitization occurs, whereas continuously infused cocaine leads to tolerance. Male Sprague-Dawley rats were treated for 7 days with continuous cocaine (50 mg/kg/day) via subcutaneously implanted osmotic minipumps, after which the pumps were removed. Locomotor activity was measured for 1 h each day. Some rats were challenged with an injection of cocaine (7.5, 15 or 30 mg/kg) either 2 or 9 days after pump removal. Two days after the pumps were removed (Day 10), there were no significant differences between cocaine- or saline-treated rats in the amount of locomotor activity produced by the challenge injections. However, cocaine-treated rats challenged with cocaine 9 days after pumps were removed (Day 17) exhibited significant tolerance, as evidenced by a shift downward of the cocaine curve, as compared to saline controls. When the rats were injected again on the next day (Day 18), the activity levels of both groups increased, as compared to the effects observed on Day 17. Thus, although the cocaine-treated rats were still tolerant compared to the saline-treated rats, they were sensitized compared to their previous response to a challenge injection. These findings indicate that tolerance and sensitization to the locomotor-activating effects of cocaine can exist simultaneously, which suggests that they are mediated by separate mechanisms.

Animals↗

PubMed2002

Dopamine transport function is elevated in cocaine users.

Dopaminergic transmission has been suggested to be a primary mechanism mediating reinforcement, withdrawal and craving associated with psychostimulant addiction. Pyscho-stimulants attenuate dopamine transporter (DAT) clearance efficiency, resulting in a net increase in synaptic dopamine levels. Re-uptake rate is determined by the number of functional DAT molecules at the membrane surface. Previous in vivo imaging studies in humans and in vitro studies in post-mortem human brain have demonstrated that chronic cocaine abuse results in a neuroadaptive increase in DAT-binding site density in the limbic striatum. Whether this increase in DAT availability represents an increase in the functional activity of the transporter is unknown. Here, we present evidence that DAT function is elevated by chronic cocaine abuse. The effect of increasing post-mortem interval on the functional viability of synaptosomes was modeled in the baboon brain. Baboon brains sampled under conditions similar to human brain autopsies yielded synaptosomal preparations that were viable up to 24 h post-mortem. Dopamine (DA) uptake was elevated twofold in the ventral striatum from cocaine users as compared to age-matched drug-free control subjects. The levels of [3H]DA uptake were not elevated in victims of excited cocaine delirium, who experienced paranoia and marked agitation prior to death. In keeping with the increase in DAT function, [3H]WIN 35,428 binding was increased in the cocaine users, but not in the victims of excited delirium. These results demonstrate that DA uptake function assayed in cryopreserved human brain synaptosomes is a suitable approach for testing hypotheses of the mechanisms underlying human brain disorders and for studying the actions of addictive drugs in man.

Adult↗

PubMed1988

Potentiation of morphine analgesia by D-amphetamine is mediated by norepinephrine and not dopamine.

Morphine will raise the threshold for escape from aversive electrical stimulation delivered to the mesencephalic reticular formation and this effect is potentiated by D-amphetamine. In order to study the roles which dopamine and norepinephrine play in modulating opiate analgesia, the effects of amfonelic acid, an indirect dopamine agonist, and nisoxetine, a selective norepinephrine reuptake blocker, were determined alone and in combination with morphine using this supraspinal model of analgesia. Amfonelic acid alone produced hyperalgesia and completely antagonized the analgesic effect of morphine. Nisoxetine had no effect by itself, however, it potentiated the analgesic effect of morphine when the two drugs were administered concomitantly. These findings suggest that norepinephrine and not dopamine plays a predominant role in the potentiation of opiate analgesia by D-amphetamine.

Amphetamine↗