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N R Zahniser

Publications and source records attributed to N R Zahniser.

At least 19 recordsLinked to original sources
PubMed2001

Chronic and acute regulation of Na+/Cl- -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems.

Na+/Cl- -dependent neurotransmitter transporters, which constitute a gene superfamily, are crucial for limiting neurotransmitter activity. Thus, it is critical to understand their regulation. This review focuses primarily on the norepinephrine transporter, the dopamine transporter, the serotonin transporter, and the gamma-aminobutyric acid transporter GAT1. Chronic administration of drugs that alter neurotransmitter release or inhibit transporter activity can produce persistent compensatory changes in brain transporter number and activity. However, regulation has not been universally observed. Transient alterations in norepinephrine transporter, dopamine transporter, serotonin transporter, and GAT1 function and/or number occur in response to more acute manipulations, including membrane potential changes, substrate exposure, ethanol exposure, and presynaptic receptor activation/inhibition. In many cases, acute regulation has been shown to result from a rapid redistribution of the transporter between the cell surface and intracellular sites. Second messenger systems involved in this rapid regulation include protein kinases and phosphatases, of which protein kinase C has been the best characterized. These signaling systems share the common characteristic of altering maximal transport velocity and/or cell surface expression, consistent with regulation of transporter trafficking. Although less well characterized, arachidonic acid, reactive oxygen species, and nitric oxide also alter transporter function. In addition to post-translational modifications, cytoskeleton interactions and transporter oligomerization regulate transporter activity and trafficking. Furthermore, promoter regions involved in transporter transcriptional regulation have begun to be identified. Together, these findings suggest that Na+/Cl- -dependent neurotransmitter transporters are regulated both long-term and in a more dynamic manner, thereby providing several distinct mechanisms for altering synaptic neurotransmitter concentrations and neurotransmission.

Animals↗
PubMed2001

Ethanol potentiates the function of the human dopamine transporter expressed in Xenopus oocytes.

Ethanol alters a variety of properties of brain dopaminergic neurons including firing rate, synthesis, release, and metabolism. Recent studies suggest that ethanol's action on central dopamine systems may also involve modulation of dopamine transporter (DAT) activity. The human DAT was expressed in Xenopus oocytes to examine directly the effects of ethanol on transporter function. [3H]Dopamine (100 nM) accumulation into DAT-expressing oocytes increased significantly in response to ethanol (10 min; 10-100 mM). In two-electrode voltage-clamp experiments, DAT-mediated currents were also enhanced significantly by ethanol (10-100 mM). The magnitude of the ethanol-induced potentiation of DAT function depended on ethanol exposure time and substrate concentration. Cell surface DAT binding ([3H]WIN 35,428; 4 nM) also increased as a function of ethanol exposure time. Thus, the increase in dopamine uptake was associated with a parallel increase in the number of DAT molecules expressed at the cell surface. These experiments demonstrate that DAT-mediated substrate translocation and substrate-associated ionic conductances are sensitive to intoxicating concentrations of ethanol and suggest that DAT may represent an important site of action for ethanol's effects on central dopaminergic transmission. A potential mechanism by which ethanol acts to enhance DAT function may involve regulation of DAT expression on the cell surface.

Animals↗
PubMed2001

Dopamine D2 receptor regulation of the dopamine transporter expressed in Xenopus laevis oocytes is voltage-independent.

Presynaptic dopamine D2 receptors (D2Rs) regulate dopamine transporter (DAT) activity in the brain. A potential mechanism was suggested by the observations that somatodendritic D2R activation produces hyperpolarization and the velocity of DAT expressed in Xenopus laevis oocytes varies with changes in membrane potential. To investigate whether D2R regulation of DAT function is voltage-dependent, we coexpressed the long isoform of the human (h) D2R and the hDAT in oocytes. Most DAT substrates fully activate D2Rs at concentrations used to measure uptake. Thus, DAT function was compared under conditions of maximal D2R activation (0.1-10 microM DA) or maximal D2R blockade (DA + 1 microM (-)-sulpiride). D2R activation significantly increased [3H]DA uptake into unclamped oocytes expressing relatively lower velocities. Uptake measured with a saturating concentration of DA suggested a D2R-induced increase in Vmax. The D2R-mediated enhancement of DA uptake was not associated with changes in resting membrane potential and was abolished by pertussis toxin pretreatment. Furthermore, in voltage-clamped oocytes, D2R activation enhanced both DA uptake and DAT-mediated steady-state currents by as much as 70%. Activation of D2Rs resulted in a 59% increase in cell surface binding of the cocaine analog [3H]WIN 35,428; this effect was also abolished by pertussis toxin pretreatment. Saturation experiments confirmed that D2R activation was associated with an increased Bmax and unchanged Ki for [3H]WIN 35,428. These results suggest that D2R-induced up-regulation of DAT activity occurs via a voltage-independent mechanism that depends on G(i/o) activation and a rapid increase in expression of functional DAT molecules at the cell surface.

Animals↗
PubMed2001

Protein tyrosine kinase inhibitors alter human dopamine transporter activity in Xenopus oocytes.

The dopamine (DA) transporter (DAT) regulates dopaminergic synaptic transmission by controlling extracellular levels of DA. Thus, understanding signaling mechanisms that alter DAT function is critical for understanding dopaminergic neurotransmission. We have expressed the human DAT (hDAT) in Xenopus laevis oocytes to test the hypothesis that protein tyrosine kinases (PTKs) acutely regulate DAT function by altering cell surface expression of the transporter. Using a relatively high concentration of DA (10 microM), we found that several PTK inhibitors, namely, genistein, lavendustin A, and tyrphostin 25 (10 microM), decreased DA uptake velocity by 58, 41, and 30% of control, respectively. Furthermore, genistein potently inhibited DA uptake with a K(i) = 68 nM. Kinetic analysis confirmed that genistein decreased the V(max) of the DAT, with no change in K(m). The effects of PTK inhibition on hDAT-associated currents were also measured. All three PTK inhibitors attenuated substrate transport-associated currents to similar extents as DA uptake. In contrast, the potent Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) did not significantly inhibit either DA uptake or transport-associated currents. PTK inhibitors decreased hDAT-associated leak currents, however in a more variable manner than for uptake and transport-associated currents. Genistein also decreased cell surface binding of [(3)H]WIN 35,428 to hDAT by 48% of control. Together, these data provide several lines of evidence suggesting that PTK inhibition rapidly reduces hDAT activity via redistribution of the transporter away from the cell surface. Thus, PTKs likely represent another component of cellular signaling cascades that acutely regulate neurotransmitter transporters.

Animals↗
PubMed2000

Functional uncoupling of adenosine A(2A) receptors and reduced responseto caffeine in mice lacking dopamine D2 receptors.

Dopamine D(2) receptors (Rs) and adenosine A(2A)Rs are coexpressed on striatopallidal neurons, where they mediate opposing actions. In agreement with the idea that D(2)Rs tonically inhibit GABA release from these neurons, stimulation-evoked GABA release was significantly greater from striatal/pallidal slices from D(2)R null mutant (D(2)R(-/-)) than from wild-type (D(2)R(+/+)) mice. Release from heterozygous (D(2)R(+/-)) slices was intermediate. However, contrary to predictions that A(2A)R effects would be enhanced in D(2)R-deficient mice, the A(2A)R agonist CGS 21680 significantly increased GABA release only from D(2)R(+/+) slices. CGS 21680 modulation was observed when D(2)Rs were antagonized by raclopride, suggesting that an acute absence of D(2)Rs cannot explain the results. The lack of CGS 21680 modulation in the D(2)R-deficient mice was also not caused by a compensatory downregulation of A(2A)Rs in the striatum or globus pallidus. However, CGS 21680 significantly stimulated cAMP production only in D(2)R(+/+) striatal/pallidal slices. This functional uncoupling of A(2A)Rs in the D(2)R-deficient mice was not explained by reduced expression of G(s), G(olf), or type VI adenylyl cyclase. Locomotor activity induced by the adenosine receptor antagonist caffeine was significantly less pronounced in D(2)R(-/-) mice than in D(2)R(+/+) and D(2)R(+/-) mice, further supporting the idea that D(2)Rs are required for caffeine activation. Caffeine increased c-fos only in D(2)R(-/-) globus pallidus. The present results show that a targeted disruption of the D(2)R reduces coupling of A(2A)Rs on striatopallidal neurons and thereby responses to drugs that act on adenosine receptors. They also reinforce the ideas that D(2)Rs and A(2A)Rs are functionally opposed and that D(2)R-mediated effects normally predominate.

Animals↗
PubMed2000

N-methyl-D-aspartate receptor responses are differentially modulated by noncompetitive receptor antagonists and ethanol in inbred long-sleep and short-sleep mice: behavior and electrophysiology.

BACKGROUND: Short-sleep (SS) mice exhibit higher locomotor activity than do long-sleep (LS) mice when injected with low doses of ethanol or the noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 (dizocilpine). SS mice also have higher densities of brain NMDARs. However, two strains of LS X SS recombinant inbred (RI) mice also show differential activation to ethanol and MK-801, but have similar numbers of NMDARs. Here we used inbred LS (ILS) and SS (ISS) mice to investigate further the relationship between NMDARs and sensitivity to the stimulant effects of low doses of ethanol. METHODS: Open field activity and spontaneous alternations were measured after saline or drug injection. [3H]MK-801 binding parameters were determined in hippocampus, cortex, striatum, and nucleus accumbens. Extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region of hippocampal slices. RESULTS: Systemic injection of either ethanol or MK-801 increased locomotor activity to a greater extent in ISS mice than in ILS mice. The competitive NMDAR antagonist 2-carboxypiperazin-4-yl-propyl-1-lphosphonic acid (+/- CPP) depressed activity of ILS, but not ISS, mice. No strain differences were observed in spontaneous alternations or in the number or affinity of NMDARs in the brain regions examined. Likewise, the magnitudes of hippocampal NMDAR-mediated fEPSPs were similar in ILS and ISS mice and were inhibited to the same extent by a competitive NMDAR antagonist. However, both ethanol and the NMDAR NR2B receptor antagonist ifenprodil inhibited the late component of hippocampal NMDAR fEPSPs to a greater extent in ISS, than in ILS, mice. CONCLUSIONS: Differential ethanol- and MK-801-induced behavioral activation in ILS and ISS mice was not associated with differences in NMDAR number. Nonetheless, pharmacological differences in hippocampal NMDAR responsiveness suggest that ISS mice express NMDARs that have a greater sensitivity to noncompetitive, but not competitive, NMDAR antagonists. These differences, which may reflect differences in NMDAR subunit composition, could underlie the differential responsiveness to low doses of ethanol in ILS and ISS mice.

Animals↗
PubMed1999

Modulation of endogenous GABA release by an antagonistic adenosine A1/dopamineD1 receptor interaction in rat brain limbic regions but not basal ganglia.

Behavioral and biochemical studies suggest that a negative interaction exists between adenosine A(1) and dopamine D(1) receptors in the brain and that this may contribute to the psychomotor effects of adenosine receptor agonists and antagonists. We examined the functional significance of A(1) and D(1) receptor subtypes in modulating electrically evoked endogenous GABA release from slices/punches of rat basal ganglia (striatum, globus pallidus, striatum containing globus pallidus, and substantia nigra reticulata) and limbic regions (ventral pallidum and nucleus accumbens). In basal ganglia, stimulation of A(1) receptors with the selective agonist R-PIA (1-100 nM) resulted in a concentration-dependent decrease in GABA release. The selective A(1) antagonist DPCPX (10-100 nM) increased GABA release, suggesting that endogenous adenosine tonically inhibits GABA release. However, in basal ganglia, consistent dopamine D(1) receptor modulation of GABA, release was not observed in response to either D(1) agonists or antagonists. Furthermore, the A(1) receptor-mediated inhibition of GABA release was not changed by concurrent activation of D(1) receptors, thus confirming the lack of D(1) receptor modulation under these conditions. In contrast, in ventral pallidum and nucleus accumbens, stimulation of D(1) receptors with SKF-82958 (1 microM) increased GABA release significantly. The D(1) receptor-mediated increase in GABA release was attenuated by concurrent activation of adenosine A(1) receptors. These results are consistent with the hypothesis that an antagonistic A(1)/D(1) receptor interaction may be important in modulating GABA release in limbic regions.

Adenosine↗
PubMed1999

Methodology for coupling local application of dopamine and other chemicals with rapid in vivo electrochemical recordings in freely-moving rats.

Methodology is presented for constructing and using an electrode/microcannulae assembly that allows in vivo electrochemical measurements coupled with local application of dopamine (DA) and other chemicals in the unanesthetized freely-moving rat. Rats were implanted with a voltammetric electrode constructed of a carbon fiber sealed in fused silica tubing attached to a pair of stainless steel guide cannulae, into which fused silica injection cannulae were inserted for local application of DA and other chemicals. Precise delivery of nanoliter volumes was accomplished using a syringe drive combined with a fluid swivel to deliver the solutions to the injection cannulae. A newly-designed miniature potentiostat connected to a commutator via a modular telephone jack assembly allowed for high-speed chronoamperometric electrochemical recordings in freely-moving rats. Initial experiments characterized the in vitro electrochemical recording characteristics of the voltammetric electrode. In vivo studies were also carried out to study clearance of locally-applied DA and of potassium-evoked endogenous DA in the striatum and nucleus accumbens of freely-moving rats. In addition, the effects of chloral hydrate anesthesia on DA clearance signals in the nucleus accumbens were investigated. Moreover, the stability and reproducibility of this recording technique for measuring exogenous DA clearance was verified over a period of 5 days. Finally, the concurrent effects of systemic cocaine injection on DA uptake in nucleus accumbens and locomotor activity were examined. These studies support the conclusion that the methodology described herein allows for rapid chronoamperometric electrochemical recordings in freely-moving rats with precise microapplications of DA and other chemicals combined with concurrent measures of animal behavior.

Anesthesia↗
PubMed1999

Voltage-dependency of the dopamine transporter in the rat substantia nigra.

The possible voltage-dependence of the dopamine transporter (DAT) was investigated using electrophysiological and electrochemical recordings in rat brain slices containing the substantia nigra (SN). Whole-cell patch clamp recordings of DA neurons, revealed that addition of 15 mM KCl rapidly depolarized the membrane potential by approximately 20 mV, whereas these cells were hyperpolarized approximately 10 mV by DA (10 microM) and approximately 14 mV by the GABAB-receptor agonist baclofen (30 microM). High-speed chronoamperometric recordings were used to monitor clearance properties of exogenously applied DA signals during similar manipulations. Superfusion of slices with 15 mM KCl significantly increased the time course of the DA signal, consistent with inhibition of DAT activity. Application of the D2 DA-receptor antagonist sulpiride (50 microM) also significantly increased the time course, suggesting that DA-induced hyperpolarization enhances DAT activity. Baclofen reversed the effects of sulpiride on DA clearance. These results demonstrate that changes in DA cell membrane potential can modulate DAT activity.

Animals↗
PubMed1999

Dopamine D2 receptor-deficient mice exhibit decreased dopamine transporter function but no changes in dopamine release in dorsal striatum.

Presynaptic D2 dopamine (DA) autoreceptors, which are well known to modulate DA release, have recently been shown to regulate DA transporter (DAT) activity. To examine the effects of D2 DA receptor deficiency on DA release and DAT activity in dorsal striatum, we used mice genetically engineered to have two (D2+/+), one (D2+/-), or no (D2-/-) functional copies of the gene coding for the D2 DA receptor. In vivo microdialysis studies demonstrated that basal and K+-evoked extracellular DA concentrations were similar in all three genotypes. However, using in vivo electrochemistry, the D2-/- mice were found to have decreased DAT function, i.e., clearance of locally applied DA was decreased by 50% relative to that in D2+/+ mice. In D2+/+ mice, but not D2-/- mice, local application of the D2-like receptor antagonist raclopride increased DA signal amplitude, indicating decreased DA clearance. Binding assays with the cocaine analogue [3H]WIN 35,428 showed no genotypic differences in either density or affinity of DAT binding sites in striatum or substantia nigra, indicating that the differences seen in DAT activity were not a result of decreased DAT expression. These results further strengthen the idea that the D2 DA receptor subtype modulates activity of the striatal DAT.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Lack of an effect of age on beta-adrenoceptor-mediated lipolysis in isolated human adipocytes.

We examined the effect of age on the beta-adrenoceptor response in adipocytes that contain both beta 1- and beta 2-adrenoceptors. Twelve healthy young and 12 old subjects on a 150 mEq/24 h sodium diet underwent gluteal fat biopsies. Isolated adipocytes from all the subjects were stimulated with increasing concentrations of isoproterenol for glycerol release. In 13 of the subjects (7 young and 6 old), we also performed beta-adrenoceptor binding studies on adipocyte membranes. In addition in eight subjects (four young and four old), we also utilized a competitive binding assay to calculate the percent of beta-adrenoceptors that were of the beta 1 subtype. Our data showed that old subjects, when treated under identical conditions as the young subjects prior to fat biopsy, did not demonstrate any differences in the beta-adrenoceptor stimulated lipolysis. The Vmax of lipolysis was 10.6 +/- 1.4 nmoles glycerol/mg lipid/2 h in the young group and 9.9 +/- 1.1 in the old group. The concentrations of isoproterenol that resulted in Vmax and 1/2 Vmax were also the same in the two age groups. The addition of 8-cyclopentyl-1,3-dimethylxanthine (CPT), a specific A1-adenosine receptor antagonist, resulted in mild but equivalent enhancement of glycerol release in both age groups. The beta-adrenoceptor numbers and affinities from adipocyte membranes did not demonstrate age-related differences either (Bmax 106 +/- 17 fmol/mg of protein in the young, and 137 +/- 27 in the old; Kd 79.6 +/- 21.3 pM in the young and 81.9 +/- 16.6 in the old). The percent of beta 1-adrenoceptors on the adipocyte membranes was also similar in the two age groups (35.2 +/- 2.6% in the young; 37.1 +/- 4.5% in the old). In conclusion, we could not demonstrate any differences in the beta-adrenoceptor responses from peripheral adipocytes that contain both beta 1- and beta 2-adrenoceptors, in a group of healthy elderly and young subjects who were subjected to identical dietary and orthostatic conditions prior to the biopsy. These data suggest that neither beta 1- nor beta 2-adrenoceptor responses in human adipocytes show significant changes due to aging.

Adipocytes↗
PubMed1999

Age-related reductions in [3H]WIN 35,428 binding to the dopamine transporter in nigrostriatal and mesolimbic brain regions of the fischer 344 rat.

In the present study, we used the potent cocaine analog [3H]WIN 35, 428 to map and quantify binding to the dopamine transporter (DAT) within the dorsal striatum, nucleus accumbens, substantia nigra, and ventral tegmental area in young (6-month-old), middle-aged (12-month-old), and aged (18- and 24-month-old) Fischer 344 rats. Quantitative autoradiographic analysis of indirect [3H]WIN 35,428 saturation curves revealed two-site binding for all four brain regions in every age group. The percentage of binding to the high- or low-affinity sites did not differ with age or region and was approximately 50%. However, significant age-related decreases in the overall density (Bmax) of [3H]WIN 35,428-binding sites were observed in the striatum, nucleus accumbens, substantia nigra, and ventral tegmental area. The Bmax within all brain regions declined by more than 15% every 6 months, with the Bmax in the aged (24-month-old) group being approximately half that measured in the young adult (6-month-old) group. Competition experiments indicated that nomifensine also exhibited two-site binding to the DAT in Fischer 344 rats. No consistent age-related differences in binding affinities were noted with either [3H]WIN 35,428 or nomifensine. Taken together, these results support the hypothesis that functional DATs within the nigrostriatal and mesolimbic systems are down-regulated with age, without changing their affinity for ligands.

Age Factors↗
PubMed1999

In vivo dopamine clearance rate in rat striatum: regulation by extracellular dopamine concentration and dopamine transporter inhibitors.

Dopamine transporter (DAT) inhibitors are expected to decrease dopamine (DA) clearance from the extracellular space of the brain. However, mazindol and cocaine have been reported to "anomalously" increase DA clearance rate. To better understand in vivo DAT activity both in the absence and presence of DAT inhibitors, clearance of exogenously applied DA was measured in dorsal striata of urethane-anesthetized rats using high-speed chronoamperometry. As higher amounts of DA were ejected, DA signal amplitudes, but not time courses, increased. Clearance rates increased until near maximal rates of 0.3 to 0.5 microM/s were attained. Provided baseline clearance rates were relatively low (< 0.1 microM/s), local application of either nomifensine or cocaine markedly increased exogenous DA signal amplitudes and time courses. Relative to the low baseline group, locally applied nomifensine decreased clearance rate when baseline clearance was high ( approximately 0.4 microM/s). However, even when baseline clearance rates were high, systemic injection of nomifensine, mazindol, GBR 12909, or benztropine increased DA signal amplitudes to a greater extent than time courses, consistent with the observed increases in clearance rates. In contrast, despite low baseline clearance rates, systemic injection of cocaine, WIN 35,428, or d-amphetamine preferentially increased DA signal time course, consistent with the observed decreases in clearance rates. Our results emphasize that as extracellular DA concentrations increase, DAT velocity increases to a maximum, partially explaining the ability of DAT inhibitors to increase DA clearance rates. However, by itself, kinetic activation is not sufficient to explain the ability of certain systemically administered DAT inhibitors to anomalously increase DA clearance.

Animals↗
PubMed1999

MK-801-induced locomotor activity in long-sleep x short-sleep recombinant inbred mouse strains: correlational analysis with low-dose ethanol and provisional quantitative trait loci.

BACKGROUND: Low doses of the N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 (dizocilpine) or ethanol increase locomotor activity to a lesser extent in long-sleep (LS), than in short-sleep (SS), mice. LS mice also have fewer brain [3H]MK-801 binding sites than SS mice. In this study, LSXSS recombinant inbred (RI) mice were used to investigate whether different NMDAR densities contribute to differential MK-801 activation and whether common genes are involved in initial sensitivity to MK-801-and ethanol-induced activation. METHODS: Locomotor activity was measured for 90 min after saline or MK-801 injection. Quantitative autoradiographic analysis of [3H]MK-801 binding was used to measure densities of NMDARs in seven brain regions. The ethanol (1-2 g/kg) activation scores from Erwin and colleagues (1997) were used for correlational analysis, as was their method for quantitative trait loci (QTL) analysis. RESULTS: Both saline and MK-801 (0.3 mg/kg, given intraperitoneally) induced a continuum of locomotor responses across the LSXSS RI strains. There was a 4-fold range of MK-801 difference scores (MK-801 score-saline baseline), with the RI 9 and RI 4 strains representing low and high responders, respectively. Dose-response experiments with these two strains confirmed that 0.3 mg/kg MK-801 produced significant activation, similar to previous results with LS and SS mice. However, unlike previous LS/SS results, lower densities of NMDARs were not observed in the RI 9 than in the RI 4 mouse brains. No significant genetic correlations were observed between MK-801-induced and ethanol-induced responses in the LSXSS RI mice. Two provisional MK-801 activation QTLs were identified (p < 0.01) on chromosomes 11 and 19, neither in common with those mapped for ethanol activation. CONCLUSIONS: Different densities of brain NMDARs are unlikely to account for the differential activation of LSXSS RI mice by MK-801. Additionally, in the RI mice either separate sets of genes regulate low dose MK-801- and ethanol-induced locomotor responses or the overlapping subset of genes controlling these two behaviors is small (< or =10%).

Animals↗
PubMed1998

Maintenance of late-phase LTP is accompanied by PKA-dependent increase in AMPA receptor synthesis.

Long-term potentiation (LTP) is a form of synaptic plasticity that has been extensively studied as a putative mechanism underlying learning and memory. A late phase of LTP occurring 3-5 hours after stimulation and depending on transcription, protein synthesis and cyclic-AMP-dependent protein kinase (protein kinase A, or PKA) has been described, but it is not known whether transcription of presynaptic and/or postsynaptic genes is required to support late-phase LTP. Here we show that late-phase LTP can be obtained in rat hippocampal CA1 mini-slices in which the cell bodies of presynaptic Schaffer collateral/commissural fibres are removed. Thus, transcription of presynaptic genes is not necessary to support maintenance of late-phase LTP. The AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor is the predominant mediator of the ionotropic response to synaptically released glutamate in the hippocampus and it has been implicated in LTP maintenance. We find that synthesis of AMPA receptor subunits is increased three hours after LTP induction: this effect on the synthesis of the AMPA receptor is blocked by inhibitors of PKA and of transcription. Our results support the idea of a postsynaptic mechanism maintaining late-phase LTP, in which AMPA receptor synthesis is increased as a result of PKA-dependent gene transcription.

Animals↗
PubMed1998

In vivo electrochemical studies of dopamine clearance in subregions of rat nucleus accumbens: differential properties of the core and shell.

The dopamine (DA) uptake/clearance properties of the DA transporter (DAT) in the core and shell of the nucleus accumbens were measured using in vivo electrochemical recordings. Calibrated amounts of a DA solution were pressure-ejected from a micropipette/electrode assembly placed in the core or shell of the nucleus accumbens in anesthetized male Fischer 344 rats. Initial studies in the two brain regions revealed that the core and shell have different DA clearance properties as measured by the extracellular DA signal amplitudes, clearance times, and clearance rates. Although the same number of picomoles of DA were applied, DA clearance signals recorded in shell had significantly greater amplitudes but faster clearance rates than those recorded in the core. Systemic administration of 20 mg/kg cocaine, a monoamine transporter inhibitor, greatly increased the signal amplitude from the locally applied DA in both the core and shell. Signal amplitudes were increased to a greater extent in the shell, compared with the core, after cocaine administration. However, cocaine affected the clearance time of DA only in the core and the DA clearance rate only in the shell. Taken together with previously reported data, these studies further support differential activity of the DAT in the core versus shell subregions of the nucleus accumbens. In addition, these data indicate that DATs are more sensitive to the effects of psychomotor stimulants, such as cocaine, in the shell of the nucleus accumbens.

Animals↗