Biomedical subjects

A E Fleckenstein

Publications and source records attributed to A E Fleckenstein.

At least 37 records · Page 2Linked to original sources

PubMed1997

Oxygen radicals diminish dopamine transporter function in rat striatum.

Incubation of striatal synaptosomes with the oxygen radical generating enzyme, xanthine oxidase, decreased [3H]dopamine uptake: an effect attributable to a decreased Vmax. Concurrent incubation with the superoxide radical scavenger, superoxide dismutase, abolished the xanthine oxidase-induced decrease. These results indicate that, like methamphetamine administration in vivo, reactive oxygen species diminish dopamine transporter function in vitro. The significance of these findings to mechanisms responsible for effects of methamphetamine is discussed.

Animals↗

PubMed1997

Effect of methamphetamine on tryptophan hydroxylase activity: role of hyperthermia.

A single administration of methamphetamine (15 mg/kg, s.c.) decreased activity of the 5-hydroxytryptamine (5-HT)-synthesizing enzyme, tryptophan hydroxylase, in rat striatum 1 h after administration. Methamphetamine also increased core body temperatures by greater than 3 degrees C in these rats. Prevention of hyperthermia attenuated the methamphetamine-induced decrease in tryptophan hydroxylase activity. Core temperature at the time of injection (from 37.7 degrees C to 40 degrees C) did not influence the magnitude of this decrease. Moreover, augmenting, methamphetamine-induced hyperthermia (from approximately 41 to 42 degrees C) did not cause a further decrease in tryptophan hydroxylase activity. These data indicate that temperature contributes to, but is not solely responsible for, methamphetamine-induced 5-HT neuronal impairment.

Animals↗

PubMed1997

Methamphetamine-induced decrease in tryptophan hydroxylase activity: role of 5-hydroxytryptaminergic transporters.

Methamphetamine-induced 5-hydroxytryptaminergic neuronal damage purportedly involves transport of newly released dopamine from extracellular spaces into 5-hydroxytryptaminergic terminals. This hypothesis is based primarily on findings that dopamine is required for, whereas 5-hydroxytryptamine (5-HT) uptake inhibitors prevent, methamphetamine-induced deficits in 5-hydroxytryptaminergic neuronal function. This hypothesis is not, however, supported by findings presented in this study that 5-hydroxytryptaminergic neuronal damage, induced by p-chloroamphetamine, does not decrease [3H]dopamine uptake into rat brain synaptosomes prepared from 5-HT-transporter-containing tissue. Moreover, despite having greater affinity for the 5-HT transporter, citalopram has an IC50 for [1H]dopamine transport into these synaptosomal preparations that is considerably greater than that of fluoxetine. These data suggest that 5-HT transporters may not effect dopamine uptake and thereby methamphetamine-induced 5-hydroxytryptaminergic neuronal damage. Other possible mechanisms related to 5-HT uptake inhibitor attenuation of methamphetamine-induced deficits were investigated. Fluoxetine pretreatment prevented the methamphetamine-induced decrease in tryptophan hydroxylase activity: this effect cannot be attributed to altered body temperatures or brain concentrations of methamphetamine which suggests that neither, per se, is sufficient to impair 5-hydroxytryptaminergic neuronal function.

Animals↗

PubMed1997

A rapid and reversible change in dopamine transporters induced by methamphetamine.

Because high doses of methamphetamine promote free radical formation, and striatal dopamine transporters are rapidly inactivated by oxidative events, we determined the effect of a single high dose of methamphetamine on dopamine transporter activity in striatal synaptosomes. One hour after methamphetamine administration, dopamine uptake decreased by 48%. This dramatic decline was totally reversed by 24 h after treatment. These findings suggest that methamphetamine reversibly decreases dopamine transporter activity by oxidative mechanisms.

Animals↗

PubMed1997

Rapid and reversible effects of methamphetamine on dopamine transporters.

Reactive oxygen species decrease dopamine transporter (DAT) function in vitro. Because of this, and the finding that METH administration causes oxygen radical formation in vivo, the effects of METH administration on DAT activity in rat striatum were investigated. A single METH injection caused a dose-dependent (0-15 mg/kg) decrease in [3H]dopamine uptake into striatal synaptosomes prepared 1 h after METH administration; an effect attributable to a decreased Vmax of [3H]dopamine uptake. Similarly, multiple high-dose administrations of METH (10 mg/kg/dose; four doses at 2-h intervals) decreased DAT function. The decreases in DAT activity after either single or multiple METH administrations were reversed 24 h after treatment. [3H]5HT transport into striatal synaptosomes was also affected by METH treatment. Taken together, these data suggest that METH decreases DAT activity, perhaps through a reactive oxygen species-mediated mechanism. These findings may have important implications regarding the role of oxidative events in the physiological regulation of monoaminergic systems.

Animals↗

PubMed1997

Interaction between hyperthermia and oxygen radical formation in the 5-hydroxytryptaminergic response to a single methamphetamine administration.

Administration of a single high dose of methamphetamine (METH) causes a rapid and reversible decrease in the activity of the tryptophan hydroxylase (TPH), the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine. This effect can be reversed completely by exposing the METH-impaired enzyme to a reducing environment, which suggests that the decrease in TPH activity is a reversible oxidative consequence of free radical formation. Consistent with this hypothesis, a single METH administration to male rats increased oxygen radical formation, as demonstrated by increased striatal dihydroxybenzoic acid formation after coadministration of salicylate with METH. Prevention of METH-induced hyperthermia attenuated both the increase in dihydroxybenzoic acid formation and the decrease in TPH activity observed 1 h after METH administration. These data suggest that both reactive oxygen species and hyperthermia contribute to the acute decrease in TPH activity which results from a single METH administration.

Animals↗

PubMed1997

Role of endogenous dopamine in the neurochemical deficits induced by methcathinone.

Multiple administrations of methcathinone caused persistent deficits in monoaminergic systems, as reflected by decreases in dopamine and 5-hydroxytryptamine uptake capacity, tissue content and associated rate-limiting synthetic enzyme activities. Because dopamine has been implicated in mediating such effects after administration of related amphetamine analogs, its role in effecting methcathinone-induced monoaminergic neuronal impairment was assessed. A single high-dose administration of methcathinone increased striatal dopamine release, as measured by microdialysis in conscious rats and reflected by increases in striatal neurotensin-like immunoreactivity. Dopaminergic deficits observed 18 hr after a multiple-dose treatment with methcathinone were prevented by pretreatment with the selective D1 antagonist SCH23390 and D2 receptor antagonist eticlopride, but 5-hydroxytryptaminergic deficits were not altered. 5-Hydroxytryptaminergic changes did not occur in animals depleted of striatal dopamine by 6-hydroxydopamine lesions. These results indicate that dopaminergic systems are profoundly affected by methcathinone administration and that dopamine likely contributes to the monoaminergic effects of this stimulant.

Animals↗

PubMed1996

Highly potent cocaine analogs cause long-lasting increases in locomotor activity.

Three cocaine analogs were compared with cocaine for the capacity to affect: (1) dopamine transporter binding and function; and (2) locomotor activity. RTI-55 (3 beta-[4-iodophenyl]tropane-2 beta-carboxylic acid methyl ester tartrate), RTI-121 (3 beta-[4-iodophenyl] tropan-2 beta-carboxylic acid isopropyl ester hydrochloride) and RTI-130 (3 beta-[4-chlorophenyl-2 beta-[1,2,4-oxadiazol-3-phenyl-5-yl]tropane hydrochloride) competed for [3H]WIN 35428 binding in rat striatum in vitro, with IC50 values at least 50-fold less than that of cocaine. These analogs inhibited [3H]dopamine transport into rat striatal synaptosomes, with IC50 values again less (at least 100-fold) than that for cocaine. Intravenous RTI-55, RTI-121 or RTI-130 injection effected dose-related increases in locomotor activity in mice, with estimated relative potencies at least 10-fold greater than that of cocaine. These increases were long lasting: whereas increased activity ceased within 2 h after cocaine administration, increased locomotion was observed at least 10 h after RTI-55, RTI-121, or RTI-130 administration. Parallel line analysis indicated that the slopes of the ascending portion of the RTI-121 and RTI-130 dose-response curves differed from that of cocaine, suggesting the involvement of mechanisms different from that of cocaine.

Analysis of Variance↗

PubMed1996

Recovery of dopamine transporter binding and function after intrastriatal administration of the irreversible inhibitor RTI-76 [3 beta-(3p-chlorophenyl) tropan-2 beta-carboxylic acid p-isothiocyanatophenylethyl ester hydrochloride].

Effects of in vivo, intrastriatal administration of RTI-76 ¿3 beta-(3-p-chlorophenyl) tropan-2 beta-carboxylic acid p-isothiocyanato-phenylethyl ester hydrochloride¿, an irreversible inhibitor of dopamine transporter (DAT) binding in vitro, on [125I]RTI-55 ¿3 beta-[4-iodophenyl]tropan-2 beta-carboxylic acid methyl ester tartrate¿ binding to striatal DAT in vitro were examined in male rats. Effects on [3H]DAT and D1 dopamine receptor binding in vitro after intrastriatal RTI-76 injection were also determined. One hour after direct intrastriatal injection, RTI-76 caused a dose-related increase in KD for [125I]RTI-55 binding in vitro in striatal tissue, without affecting transporter maximum binding (Bmax). In contrast, 24 hr after administration, RTI-76 caused a dose-related decrease in striatal DAT Bmax without affecting KD, a decrease that reversed over the next several days. Transport of [3H]dopamine into synaptosomes was decreased similarly. Intrastriatal injection of reversible inhibitors of DAT, such as cocaine or WIN-35428 ¿3 beta-[4-fluorophenyl]tropan-2 beta-carboxylic acid methyl ester tartrate), was without effect on transporter binding 1 and 6 days after administration. RTI-76 had little effect on [3H]SCH-23390 ¿R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine¿ binding 1 or 24 hr after intrastriatal injection, indicating at least some selectivity of RTI-76 for DAT. The RTI-76-induced decrease in Bmax, as well as the concurrent decrease in [3H]DAT, were reversible, with the T1/2 of transporter recovery estimated to be 6 days.

Animals↗

PubMed1994

Histaminergic neurons mediate restraint stress-induced activation of central 5-hydroxytryptaminergic neurons in the rat.

The role of histamine in mediating restraint stress-induced increases in the activity of central 5-hydroxytryptaminergic neurons was evaluated in male rats. 5-Hydroxytryptaminergic neuronal activity was estimated by measuring concentrations of the 5-hydroxytryptamine (5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens and suprachiasmatic nucleus which contain terminals of these neurons. Placement of rats within restraining tubes rapidly increased (within 10 min) 5-HIAA concentrations in the nucleus accumbens and suprachiasmatic nucleus. Depletion of neuronal histamine by alpha-fluoromethylhistidine or antagonism of histamine H1 receptors by mepyramine prevented stress-induced increases in 5-HIAA concentrations, whereas blockade of histamine H2 receptors by zolantidine was without effect. Neither alpha-fluoromethylhistidine, mepyramine nor zolantidine affected basal 5-HIAA concentrations in either brain region. These results indicate that histaminergic neurons mediate stress-induced increases in the activity of central 5-hydroxytryptaminergic neurons via an action at histamine H1 receptors.

Animals↗

PubMed1994

Differential role of histamine in mediating stress-induced changes in central dopaminergic neuronal activity in the rat.

The role of histamine in mediating restraint stress-induced alterations in dopaminergic neuronal activity and alpha-melanocyte-stimulating hormone (alpha MSH) secretion was evaluated in male rats. Dopaminergic neuronal activity was estimated by measuring concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in brain regions containing terminals of these neurons. Physical restraint increased DOPAC concentrations in nucleus accumbens and decreased DOPAC concentrations in the intermediate lobe of the pituitary, but was without effect on DOPAC concentrations in either the striatum or median eminence. These data indicate that restraint stress increases mesolimbic, decreases periventricular-hypophysial, and is without effect on nigrostriatal or tuberoinfundibular dopaminergic neuronal activity. Neither depletion of neuronal histamine by alpha-fluoromethylhistidine, blockade of H1 receptors by mepyramine, nor blockade of H2 receptors by zolantidine prevented the stress-induced increase in DOPAC concentrations in the nucleus accumbens suggesting that histaminergic neurons are not major contributors to stress-induced increases in mesolimbic dopaminergic neuronal activity. In contrast, alpha-fluoromethylhistidine- and mepyramine-, but not zolantidine-treatment prevented the stress-induced decrease in DOPAC concentrations in the intermediate lobe. Restraint stress increased alpha MSH secretion; this increase was not prevented by alpha-fluoromethylhistidine, mepyramine, or zolantidine. These data indicate that histaminergic neurons mediate the stress-induced decrease in periventricular-hypophysial dopaminergic neuronal activity through an action at H1 receptors, but do not effect stress-induced alpha MSH secretion.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Histaminergic neurons mediate restraint stress-induced increases in the activity of noradrenergic neurons projecting to the hypothalamus.

The role of histamine in mediating restraint stress-induced increases in the activity of noradrenergic neurons projecting to the hypothalamus was evaluated in male rats. Noradrenergic neuronal activity was estimated by measuring concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in the paraventricular and medial preoptic nuclei which contain terminals of these neurons. Placement of rats within restraining tubes rapidly increased MHPG but not norepinephrine concentrations in the paraventricular and medial preoptic nuclei. Depletion of neuronal histamine by alpha-fluoromethylhistidine and antagonism of H1 receptors by mepyramine attenuated, whereas blockade of H2 receptors by zolantidine did not prevent the stress-induced increases in MHPG concentrations. Neither mepyramine nor zolantidine affected MHPG concentrations in hypothalamic regions of nonstressed rats. These results indicate that histaminergic neurons contribute to the stress-induced increase the activity of noradrenergic neurons projecting to the hypothalamus via an action at H1 receptors.

Animals↗

PubMed1994

Effects of histamine on 5-hydroxytryptaminergic neuronal activity in the rat hypothalamus.

Effects of pharmacological manipulations which mimic or enhance histaminergic neuronal transmission were determined on the activity of 5-hydroxytryptaminergic neurons projecting to the hypothalamus of male rats. Intracerebroventricular administration of histamine decreased 5-hydroxytryptamine (5-HT) and increased 5-hydroxyindoleacetic acid (5-HIAA) concentrations in several hypothalamic nuclei; these effects were blocked by the histamine H1 receptor antagonist mepyramine but not the histamine H2 receptor antagonist zolantidine. Blockade of the 5-HT reuptake system by fluoxetine did not prevent histamine-induced decreases in 5-HT concentrations suggesting that histamine is not transported into nerve terminals via the 5-HT reuptake system to subsequently displace 5-HT stores. These data suggest that exogenous histamine increases 5-hydroxytryptaminergic neuronal activity through an action at histamine H1 receptors. In contrast, neither the histamine H3 receptor antagonist thioperamide, the histamine-N-methyltransferase inhibitor metoprine, nor combined thioperamide-metoprine treatment affected concentrations of 5-HT or 5-HIAA suggesting these agents, which purportedly enhance endogenous histaminergic transmission, do not affect 5-hydroxytryptaminergic neuronal activity. These results reveal that procedures commonly employed to study central actions of histamine differentially affect 5-hydroxytryptaminergic neuronal activity in the rat hypothalamus.

Animals↗

PubMed1994

Activation of noradrenergic neurons projecting to the diencephalon following central administration of histamine is mediated by H1 receptors.

The effect of histamine on the activity of noradrenergic neurons terminating in discrete regions of the diencephalon was examined in male rats. Noradrenergic neuronal activity was estimated by measuring the concentration of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylethyleneglycol [MHPG] in the medial zona incerta [MZI] and in the dorsomedial [DMN], periventricular [PeVN] and medial preoptic hypothalamic nuclei [MPN]. The intracerebroventricular administration of histamine effected a time-related increase in MHPG concentrations in the MZI, DMN, PeVN and MPN; these effects were blocked by the H1 antagonist mepyramine but not the H2 antagonist zolantidine. Neither mepyramine nor zolantidine affected basal MHPG concentrations in any of the brain regions examined. These results indicate that central administration of histamine increases the activity of noradrenergic neurons projecting to the diencephalon via an action at H1 but not H2 receptors.

Animals↗

PubMed1994

Differential effects of histamine on the activity of hypothalamic dopaminergic neurons in the rat.

The effect of intracerebroventricular administration of histamine on hypothalamic dopaminergic neuronal activity was estimated in male rats by measuring concentrations of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in brain regions containing terminals or perikarya of these neurons. Three distinct, regionally specific neurochemical responses were apparent. In the median eminence and intermediate lobe of the pituitary, histamine affected neither DOPAC nor dopamine concentrations, suggesting no effect on tuberoinfundibular or periventricular-hypophysial dopaminergic neuronal activity. In the medial zona incerta and in the dorsomedial, rostral periventricular and medial preoptic hypothalamic nuclei, histamine effected a dose- and time-related increase in both DOPAC and dopamine concentrations; these effects were blocked by destruction of noradrenergic neurons projecting to these regions, suggesting that these changes are attributable to noradrenergic neuronal activation, and that histamine does not affect the activity of incertohypothalamic or periventricular-preoptic dopaminergic neurons located in these brain regions. In the suprachiasmatic, caudal periventricular and paraventricular hypothalamic nuclei, histamine effected a dose- and time-related increase in DOPAC, but not dopamine, concentrations; these effects were blocked by the H1 antagonist mepyramine, but not the H2 antagonist zolantidine. Destruction of noradrenergic neurons projecting to these regions did not prevent the histamine-induced increases in DOPAC concentrations. These data indicate that histamine increases the activity of dopaminergic neurons projecting to the suprachiasmatic, caudal periventricular and paraventricular nuclei via an action at H1 receptors. Overall, these results reveal that i.c.v. administration of histamine differentially affects the activity of the various dopaminergic neuronal systems of the rat hypothalamus.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Activation of mesolimbic dopaminergic neurons following central administration of histamine is mediated by H1 receptors.

The effect of intracerebroventricular administration of histamine on the activity of mesolimbic and nigrostriatal dopaminergic (DA) neurons was determined in male rats. The activity of these neurons was estimated by measuring: (1) the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after administration of a decarboxylase inhibitor, and (2) the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens and striatum, which contain the terminals of these neurons. Central administration of histamine increased both DOPA accumulation and DOPAC concentrations in the nucleus accumbens, but was without effect in the striatum. The increase in DOPAC concentrations in the nucleus accumbens occurred within 10 min and was sustained for at least 120 min. The H1 antagonist mepyramine blocked whereas the H2 antagonist zolantidine did not affect histamine-induced increases in DOPAC concentrations in the nucleus accumbens. Neither mepyramine nor zolantidine affected basal DOPAC concentrations in the nucleus accumbens. These results indicate that central administration of histamine stimulates mesolimbic DA neurons through an action at the H1 receptor, but has no effect upon the activity of nigrostriatal DA neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Evidence that histamine-stimulated prolactin secretion is not mediated by an inhibition of tuberoinfundibular dopaminergic neurons.

The effects of histamine on prolactin secretion and the activity of tuberoinfundibular dopaminergic (DA) neurons were examined in male rats. Tuberoinfundibular DA neuronal activity was estimated in situ by measuring the metabolism [concentration of 3,4-dihydroxyphenylacetic acid (DOPAC)] and synthesis [accumulation of 3,4-dihydroxyphenylalanine (DOPA) after administration of a decarboxylase inhibitor] of dopamine in the median eminence. Intracerebroventricular (icv) injection of histamine produced a dose- and time-dependent increase in plasma prolactin levels but had no effect on DOPA accumulation or DOPAC concentrations in the median eminence. These results indicate that the stimulation of prolactin secretion following icv histamine is not mediated by an inhibition of tuberoinfundibular DA neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Evidence that prolactin mediates the stimulatory effects of estrogen on tuberoinfundibular dopamine neurons in female rats.

The effects of ovariectomy and estrogen on prolactin secretion and/or the activity of tuberoinfundibular dopamine (TIDA) neurons were examined by either concurrently measuring concentrations of prolactin in plasma and 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence of female rats or by determining the rate of DA synthesis (accumulation of 3,4-dihydroxyphenylalanine (DOPA) after the administration of a decarboxylase inhibitor) in the median eminence. For comparison, concentrations of alpha-melanocyte-stimulating hormone (alpha MSH) in plasma and DOPAC in the intermediate lobe of the pituitary (an index of the activity of tuberohypophysial DA neurons) were also determined. Ovariectomy produced a time-dependent decrease in the accumulation of DOPA and the concentrations of DOPAC in the median eminence and prolactin in plasma with maximal effects occurring by 7 days. Estrogen administration to ovariectomized rats increased plasma prolactin and median eminence DOPAC concentrations to levels comparable to those in diestrous controls. In contrast, neither ovariectomy nor estrogen replacement altered the concentrations of alpha MSH in plasma or DOPAC in the intermediate lobe. Administration of the DA agonist bromocriptine blocked the ability of estrogen to increase plasma prolactin and median eminence DOPAC concentrations. Also, administration of antiserum to rat prolactin blocked the stimulatory action of estrogen on median eminence DOPAC concentrations. Taken together, these results indicate that the stimulatory effect of estrogen on the activity of TIDA neurons is mediated by prolactin.

3,4-Dihydroxyphenylacetic Acid↗