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Results for “Membrane Transport Modulators”

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PubMed2004

Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.

Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.

Animals↗

PubMed2002

Mechanism of action of methylphenidate: insights from PET imaging studies.

Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). We have used Positron Emission Tomography (PET) to investigate the mechanism of action of MPH in the human brain. We have shown (a) that oral MPH reaches peak concentration in the brain 60-90 minutes after its administration, (b) that therapeutic doses of MPH block more than 50% of the dopamine transporters (DAT), and (c) that of the two enantiomers that compose MPH, it is d-threo-methylphenidate (d-MPH) and not l-threo-methylphenidate (l-MPH) that binds to the DAT. We have also shown that therapeutic doses of MPH significantly enhance extracellular dopamine (DA) in the basal ganglia, which is an effect that appears to be modulated by the rate of DA release and that is affected by age (older subjects show less effect). Thus, we postulate (a) that MPH's therapeutic effects are in part due to amplification of DA signals, (b) that variability in responses is in part due to differences in DA tone between subjects, and (c) that MPH's effects are context dependent. Because DA enhances task specific neuronal signaling and decreases noise, we also postulate that MPH-induced increases in DA could improve attention and decrease distractibility; and that since DA modulates motivation, the increases in DA would also enhance the saliency of the task facilitating the 'interest it elicits' and thus improving performance.

Adolescent↗

PubMed2002

Interaction of dopamine D1 and NMDA receptors mediates acute clozapine potentiation of glutamate EPSPs in rat prefrontal cortex.

The atypical antipsychotic drug clozapine effectively alleviates both negative and positive symptoms of schizophrenia via unclear cellular mechanisms. Clozapine may modulate both glutamatergic and dopaminergic transmission in the prefrontal cortex (PFC) to achieve part of its therapeutic actions. Using whole cell patch-clamp techniques, current-clamp recordings in layers V-VI pyramidal neurons from rat PFC slices showed that stimulation of local afferents (in 2 microM bicuculline) evoked mixed [AMPA/kainate and N-methyl-D-aspartate (NMDA) receptors] glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs). Clozapine (1 microM) potentiated polysynaptically mediated evoked EPSPs (V(Hold) = -65 mV), or reversed EPSPs (rEPSP, V(Hold) = +20 mV) for >30 min. The potentiated EPSPs or rEPSPs were attenuated by elevating [Ca(2+)](O) (7 mM), by application of NMDA receptor antagonist 2-amino5-phosphonovaleric acid (50 microM), or by pretreatment with dopamine D1/D5 receptor antagonist SCH23390 (1 microM) but could be further enhanced by a dopamine reuptake inhibitor bupropion (1 microM). Clozapine had no significant effect on pharmacologically isolated evoked NMDA-rEPSP or AMPA-rEPSPs but increased spontaneous EPSPs without changing the steady-state resting membrane potential. Under voltage clamp, clozapine (1 microM) enhanced the frequency, and the number of low-amplitude (5-10 pA) AMPA receptor-mediated spontaneous EPSCs, while there was no such changes with the mini-EPSCs (in 1 microM TTX). Taken together these data suggest that acute clozapine can increase spike-dependent presynaptic release of glutamate and dopamine. The glutamate stimulates distal dendritic AMPA receptors to increase spontaneous EPSCs and enabled a voltage-dependent activation of neuronal NMDA receptors. The dopamine released stimulates postsynaptic D1 receptor to modulate a lasting potentiation of the NMDA receptor component of the glutamatergic synaptic responses in the PFC neuronal network. This sequence of early synaptic events induced by acute clozapine may comprise part of the activity that leads to later cognitive improvement in schizophrenia.

Action Potentials↗

PubMed2003

Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD.

OBJECTIVE: Methylphenidate, the most common treatment for attention deficit hyperactivity disorder (ADHD), increases extracellular dopamine in the brain, which is associated with its reinforcing as well as its therapeutic effects. The authors evaluated variables that distinguish these two properties. METHOD: The brain imaging and clinical literatures were analyzed to identify variables that contribute to the abuse liability as well as to the clinical efficacy of methylphenidate. RESULTS: Four variables were identified. 1) Dose--there is a threshold for methylphenidate-induced dopamine increases to be perceived as reinforcing and to produce therapeutic effects. 2) Pharmacokinetics--the reinforcing effects of methylphenidate are associated with rapid changes in serum concentrations and presumably fast dopamine increases (as achieved with intravenous injection or insufflation), whereas the therapeutic effects are associated with slowly ascending serum concentrations and presumably smoothly rising dopamine levels (as achieved with oral administration). 3) Individual differences--sensitivity to methylphenidate varies across individuals and sets a threshold for blood and brain levels required for reinforcing effects (drug liking) and for therapeutic effects (symptom reduction). 4) Context--the effects of methylphenidate are modulated by different settings in abuse (rituals of self-administration and powerful conditioning) and in clinical use (external demands of low activity and focused attention). CONCLUSIONS: Reinforcing effects occur when methylphenidate elicits large and fast dopamine increases that mimic those of phasic dopamine cell firing, whereas therapeutic effects occur when methylphenidate elicits slow, steady-state dopamine increases that mimic those of tonic firing. Thus, the characteristics of clinical use (low doses administered orally and titrated for therapeutic effects) constrain methylphenidate's abuse.

Attention Deficit Disorder with Hyperactivity↗

PubMed2004

Interleukin-1beta represses MRP2 gene expression through inactivation of interferon regulatory factor 3 in HepG2 cells.

The human multidrug resistance protein 2 (MRP2/ABCC2), expressed on the bile canalicular membrane, mediates the multispecific efflux of several organic anions, including conjugates of glucuronate, sulfate, and glutathione. Expression of MRP2 can be altered in response to environmental stimuli such as cholestasis and jaundice. We previously reported that MRP2 mRNA expression levels are decreased in the nontumorous part of hepatitis C virus-infected human liver tissues, and that inflammatory cytokines inhibit MRP2 expression in human hepatic (HepG2) cells. We investigated the molecular mechanisms by which inflammatory cytokines modulate MRP2 gene expression in hepatic cells. Treatment of human hepatic cells with interleukin-1beta (IL-1beta) or tumor necrosis factor alpha resulted in a decrease in the protein and mRNA levels of MRP2. IL-1beta inhibited the transcriptional activity of MRP2 promoter constructs by 40%, and this inhibition of MRP2 promoter activity was mediated through the interferon stimulatory response element (ISRE). Electrophoretic mobility shift assays with IL-1beta-treated nuclear extracts showed a decrease in the formation of DNA protein complexes, specifically those including interferon regulatory factor 3 (IRF3). Expression of recombinant human IRF3 increased MRP2 promoter activity. Treatment with a specific extracellular signal-regulated kinase inhibitor relieved IL-1beta-induced MRP2 mRNA downregulation and abrogated the binding of IRF3 to the ISRE element. In conclusion, IL-1beta induces downregulation of the MRP2 gene by inactivating IRF3 binding to ISRE on the MRP2 promoter in human hepatic cells; this inactivation is accomplished via interference with the extracellular signal-regulated kinase pathway.

DNA-Binding Proteins↗

PubMed2002

SecB modulates the nucleotide-bound state of SecA and stimulates ATPase activity.

In Escherichia coli, the formation of SecA-SecB complexes has a direct effect on SecA ATPase activity. The mechanism of this interaction was evaluated and defined using controlled trypsinolysis, equilibrium dialysis at low temperature, and kinetic analyses of the SecA ATPase reaction. The proteolysis data indicate that SecB and the nonhydrolyzable ATP analogue AMP-P-C-P induce similar conformational changes in SecA which result in a more open or extended structure that is suggestive of the ATP-bound form. The effect is synergistic and concentration-dependent, and requires the occupation of both the high- and low-affinity nucleotide binding sites for maximum effect. The equilibrium dialysis experiments and kinetic data support the observation that the SecB-enhanced SecA ATPase activity is the result of an increased rate of ATP hydrolysis rather than an increase in the affinity of ATP for SecA and that the high-affinity nucleotide binding site is conformationally regulated by SecB. It appears that SecB may function as an intermolecular regulator of ATP hydrolysis by promoting the ATP-bound state of SecA. The inhibition of SecA ATPase activity by sodium azide in the presence of IMVs and a functional signal peptide further indicates that SecB promotes the ATP-bound form of SecA.

Adenosine Triphosphatases↗

PubMed2006

Post-translational regulation of EAAT2 function by co-expressed ubiquitin ligase Nedd4-2 is impacted by SGK kinases.

The human excitatory amino acid transporter (EAAT)2 is the major glutamate carrier in the mammalian CNS. Defective expression of the transporter results in neuroexcitotoxicity that may contribute to neuronal disorders such as amyotrophic lateral sclerosis (ALS). The serum and glucocorticoid inducible kinase (SGK) 1 is expressed in the brain and is known to interact with the ubiquitin ligase Nedd4-2 to modulate membrane transporters and ion channels. The present study aimed to investigate whether SGK isoforms and the related kinase, protein kinase B (PKB), regulate EAAT2. Expression studies in Xenopus oocytes demonstrated that glutamate-induced inward current (IGLU) was stimulated by co-expression of SGK1, SGK2, SGK3 or PKB. IGLU is virtually abolished by Nedd4-2, an effect abrogated by additional co-expression of either kinase. The kinases diminish the effect through Nedd4-2 phosphorylation without altering Nedd4-2 protein abundance. SGKs increase the transporter maximal velocity without significantly affecting substrate affinity. Similar to glutamate-induced currents, [3H] glutamate uptake and cell surface abundance of the transporter were increased by the SGK isoforms and down-regulated by the ubiquitin ligase Nedd4-2. In conclusion, all three SGK isoforms and PKB increase EAAT2 activity and plasma membrane expression and thus, may participate in the regulation of neuroexcitability.

Animals↗

PubMed1995

Rat kidney papilla contains abundant synaptobrevin protein that participates in the fusion of antidiuretic hormone-regulated water channel-containing endosomes in vitro.

Antidiuretic hormone (ADH) regulates renal water excretion by altering the permeability of the collecting duct to water. ADH-responsive epithelial cells are the major cell type lining kidney tubules in the inner medulla and papilla. ADH modulates apical membrane water permeability by the insertion and removal of vesicles containing aquaporin collecting duct water channel protein (now termed AQP-2). To identify and characterize proteins responsible for trafficking of AQP-2-containing vesicles, we utilized antibody and cDNA probes to synaptobrevin b (also termed VAMP-2, for vesicle-associated membrane protein 2), a protein that mediates synaptic vesicle exocytosis in the brain and whose structural homologs are now considered to be components of a complex responsible for intracellular vesicle fusion in all cells. We now report that rat kidney inner medulla and papilla contain abundant synaptobrevin protein. Only light endosomes, one of two types of purified papillary AQP-2-containing endosomes, possess synaptobrevin. Light endosomes fuse in vitro by means of an ATP-dependent process that is significantly inhibited when endosomes are preincubated with either anti-synaptobrevin antibody or tetanus toxin. These data define a functional role for a synaptobrevin protein in the fusion of endosomes in vitro. The presence of abundant synaptobrevin proteins in endosomes containing AQP-2 water channels, as well as insulin-sensitive glucose transporters [Cain, C. C., Trimble, W. S. & Lienhard, G. E. (1992) J. Biol. Chem. 267, 11681-11684], and in cells of Malpighian tubules responsible for urine formation in insects [Chin, A. S., Burgess, R. W., Wong, B. R., Schwartz, T. L. & Scheller, R. H. (1993) Gene 131, 175-181] suggests a specialized role for synaptobrevin in vesicle-mediated membrane transport modulated by peptide hormones.

Animals↗

PubMed1989

A rapid and sensitive flow cytometric method for the detection of multidrug-resistant cells.

Multidrug-resistant (MDR) cells are characterized by a defect in drug accumulation caused by activity of an energy-dependent rapid drug efflux pump. The action of this drug pump can be inhibited by specific agents, referred to as membrane transport modulating agents (MTMAs), resulting in a restoration of the intracellular drug accumulation. This paper presents a flow cytometric assay for the detection of MDR cells, which is based on the ability of these cells to respond to MTMAs. Daunorubicin net-uptake kinetics were measured of anthracycline-sensitive (A2780/S) and -resistant (A2780/R) human ovarian carcinoma cells in vitro. A2780/R cells accumulated significantly less (about a factor of 5) daunorubicin as compared to A2780/S cells. Addition of verapamil or cyclosporin A to A2780/R cells at steady-state daunorubicin uptake led to a dose-dependent increase in cellular daunorubicin accumulation. The sensitivity of the assay was determined by testing mixtures of A2780/S and A2780/R cells. Analysis of A2780/S cells contaminated with A2780/R cells showed that as few as 2.5% MDR cells could readily be detected in the mixture. In conclusion, this functional assay enables the detection of MDR cells in a heterogeneous cell suspension and is ideally suited for the study of the occurrence of typical MDR in human cancer.

Antibiotics, Antineoplastic↗

PubMed1989

Effects of cyclosporin A and verapamil on the intracellular daunorubicin accumulation in Chinese hamster ovary cells with increasing levels of drug-resistance.

Multidrug-resistance (MDR) is characterized by the presence of a 170 kDa glycoprotein (P-glycoprotein) in the plasma membrane. P-glycoprotein is thought to act as an efflux pump, leading to reduced drug accumulation in MDR cells. This defect in drug accumulation can be overcome by membrane transport modulating agents (MTMAs). We determined the concentration of MTMA needed for maximal restoration of daunorubicin content in 4 Chinese hamster ovary cell lines with increasing levels of drug-resistance using flow cytometry. Stimulation of daunorubicin accumulation occurred in a dose-dependent manner. The required level of MTMA needed for maximal drug accumulation increased with the level of drug-resistance. CHrA3 cells, which have a level of resistance comparable to clinical samples, needed relatively low concentrations of MTMA for maximal restoration of drug accumulation. This indicates that, in trial combining drugs and MTMAs, low dosages of MTMAs could be sufficient for optimal potentiation of cytotoxicity.

Animals↗

PubMed2003

Modulators of membrane drug transporters potentiate the activity of the DMI fungicide oxpoconazole against Botrytis cinerea.

Modulators known to reduce multidrug resistance in tumour cells were tested for their potency to synergize the fungitoxic activity of the fungicide oxpoconazole, a sterol demethylation inhibitor (DMI), against Botrytis cinerea Pers. Chlorpromazine, a phenothiazine compound known as a calmodulin antagonist, appeared the most potent compound. Tacrolimus, a macrolide compound with immunosuppressive activity, was also active. The synergism of chlorpromazine negatively correlated with the sensitivity of the parent strain and mutants of B. cinerea. The synergism was highest in a mutant that overexpressed the ATP-binding cassette transporter BcatrD, known to transport DMI fungicides such as oxpoconazole. The synergism of chlorpromazine positively correlated with its potency to enhance the accumulation of oxpoconazole in BcatrD mutants. These results indicate that chlorpromazine is a modulator of BcatrD activity in B. cinerea and suggest that mixtures of DMI fungicides with modulators may represent a perspective for the development of new resistance management strategies.

Botrytis↗

PubMed2001

Membrane cholesterol modulates serotonin transporter activity.

The synaptic actions of the neurotransmitter serotonin are terminated by a selective high-affinity reuptake mediated by the serotonin transporter (SERT). To gain insight into the modulation of the functional properties of this integral membrane protein by cholesterol, a main component of the lipid bilayer, we stably expressed the rat SERT in human embryonic kidney 293 cells and, upon altering the cholesterol content of these cells by different means, analyzed SERT activity. Depletion of the level of membrane cholesterol by treatment with either the cholesterol chelating agent methyl-beta-cyclodextrin (MbetaCD), cholesterol oxidase, or the cholesterol-binding fluorochrome filipin resulted in a decrease in SERT activity due to both a loss of affinity of substrate and ligand binding and a concomitant reduction of the maximal transport rate. In cholesterol-depleted membranes, cholesterol levels could be restored to those found in untreated membranes by incubation of the membranes with an MbetaCD-cholesterol complex, which correlated with a reversal of the cholesterol depletion-mediated decrease in the level of high-affinity binding. This was not the case when other steroids, such as ergosterol, 5-cholestene, or pregnenolone, were substituted into cholesterol-depleted membranes. These results suggest that membrane cholesterol modulates the functional properties of the SERT by specific molecular interactions which are needed to stabilize the transporter in its optimally active form.

Carrier Proteins↗

PubMed1990

Hormonal modulation of hepatic plasma membrane lactate transport in cultured rat hepatocytes.

Hormonal modulation of hepatic plasma membrane lactate transport was studied in primary cultures of isolated hepatocytes from fed rats to examine the mechanism for the known enhancement of lactate transport in starvation and diabetes. Total cellular lactate entry was increased by 14% in the presence of dexamethasone; this was accounted for by an approximately 40% increase in the carrier-mediated component of entry with no effect on diffusion. A trend of similar magnitude was evident with glucagon. The effects of dexamethasone and glucagon on lactate transport constitute an additional potential mechanism for enhancement of gluconeogenesis by these hormones.

Animals↗

PubMed2003

Regulation of dopamine transporter function and plasma membrane expression by dopamine, amphetamine, and cocaine.

Pharmacological alterations in dopamine transporter (DAT) function not only modulate dopamine reuptake, but they can induce rapid changes in the plasmalemmal expression of the transporter. By modifying transporter membrane expression, drugs may alter the maximum rate of neurotransmitter clearance, shifting cellular transport capacity and disrupting normal receptor stimulation. DAT-interacting drugs include the illicit and highly abused psychostimulants amphetamine and cocaine. Regulation of transporter activity and plasma membrane expression by these drugs has been implicated in the long-term processes of reward and addiction. This review summarizes the regulation of DAT by transporter substrates and blockers with particular emphasis on the modulation of DAT cell surface expression by acute exposure to amphetamine and cocaine.

Amphetamine↗

PubMed2001

Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters.

1. Previous data demonstrate that the tricyclic antidepressant, desipramine, induces glucocorticoid receptor (GR) translocation from the cytoplasm to the nucleus in L929 cells and increases dexamethasone-induced GR-mediated gene transcription in L929 cells stably transfected with the mouse mammary tumour virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter gene (LMCAT cells) (Pariante et al., 1997). 2. To extend these findings, the present study has investigated the effects of 24 h coincubation of LMCAT cells with dexamethasone and amitriptyline, clomipramine, paroxetine, citalopram or fluoxetine. 3. All antidepressants, except fluoxetine, enhanced GR-mediated gene transcription, with clomipramine having the greatest effect (10 fold increase). Twenty-four hours coincubation of cells with desipramine, clomipramine or paroxetine, also enhanced GR function in the presence of cortisol, but not of corticosterone. 4. It is proposed that these effects are due to the antidepressants inhibiting the L929 membrane steroid transporter, which actively extrudes dexamethasone and cortisol from the cell, but not corticosterone. This is further confirmed by the fact that clomipramine failed to enhance GR-mediated gene transcription in the presence of dexamethasone when the membrane steroid transporter was blocked by verapamil. 5. The membrane steroid transporters that regulate access of glucocorticoids to the brain in vivo, like the multiple drug resistance p-glycoprotein, could be a fundamental target for antidepressant action.

Animals↗

PubMed2005

Subtype-specific GABA transporter antagonists synergistically modulate phasic and tonic GABAA conductances in rat neocortex.

GABAergic inhibition in the brain can be classified as either phasic or tonic. gamma-Aminobutyric acid (GABA) uptake by GABA transporters (GATs) can limit the time course of phasic currents arising from endogenous and exogenous GABA, as well as decrease a tonically active GABA current. GABA transporter subtypes 1 and 3 (GAT-1 and GAT-3) are the most heavily expressed of the four known GAT subtypes. The role of GATs in shaping GABA currents in the neocortex has not been explored. We obtained patch-clamp recordings from layer II/III pyramidal cells and layer I interneurons in rat sensorimotor cortex. We found that selective GAT-1 inhibition with NO711 decreased the amplitude and increased the decay time of evoked inhibitory postsynaptic currents (IPSCs) but had no effect on the tonic current or spontaneous IPSCs (sIPSCs). GAT-2/3 inhibition with SNAP-5114 had no effect on IPSCs or the tonic current. Coapplication of NO711 and SNAP-5114 substantially increased tonic currents and synergistically decreased IPSC amplitudes and increased IPSC decay times. sIPSCs were not resolvable with coapplication of NO711 and SNAP-5114. The effects of the nonselective GAT antagonist nipecotic acid were similar to those of NO711 and SNAP-5114 together. We conclude that synaptic GABA levels in neocortical neurons are controlled primarily by GAT-1, but that GAT-1 and GAT-2/3 work together extrasynaptically to limit tonic currents. Inhibition of any one GAT subtype does not increase the tonic current, presumably as a result of increased activity of the remaining transporters. Thus neocortical GAT-1 and GAT-2/3 have distinct but overlapping roles in modulating GABA conductances.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2005

Assays for measuring extracellular GABA levels and cell migration rate in acute slices.

The postnatal subventricular zone (SVZ) contains the largest pool of dividing and migrating neural precursors in the adult rodent brain. Neuronal precursors migrate throughout the SVZ and along the rostral migratory stream (RMS) towards the olfactory bulb where they differentiate into interneurons. To facilitate the investigation of cell migration in the SVZ and RMS, an inexpensive migration assay was developed for use in acute brain slices. Acute sagittal slices were kept at 37 degrees C in 5% O2/95% CO2-saturated solution and migrating cells in the SVZ and RMS were visualized using an upright infrared-differential interference contrast microscope. Time-lapse movies were acquired to identify the direction and measure the speed of cell migration. The neurotransmitter GABA and inhibitors of GABA receptors or transporters can be bath applied to determine the function of endogenous GABA on the direction and speed of cell migration. In parallel, the levels of endogenous GABA released from acute SVZ or RMS explants were measured with mass spectrometry. Additional techniques such as electrophysiology and immunohistochemistry confirmed the identity of cells as neuronal precursors and characterized the expression of GABA receptors and transporters. This report describes how modulations in the direction and speed of neuronal precursor migration can be accurately monitored and how changes in local GABA levels can be measured. The described techniques can be used to identify the endogenous factors that regulate cell migration. Identifying such factors is essential for the future therapeutic use of SVZ cells to replace damaged or lost cells.

Animals↗

PubMed2003

Substance P and cholecystokinin regulate neurochemical responses to cocaine and methamphetamine in the striatum.

The mechanism of action of drugs of abuse like cocaine and amphetamines has been studied extensively in the dopamine terminal field areas of the caudate-putamen (CPu) and the nucleus accumbens (NAc) of the rodent brain. These brain regions contain several neuropeptides that must play important roles in the normal physiological functions of these brain regions. The study of neuropeptide physiology in the context of the neurobiological responses to drugs of abuse may shed some light on the intrinsic mechanism of action of neuropeptides of the CPu and the NAc. The neuropeptides substance P (SP) and cholecystokinin (CCK) are present in the striatum where they could play an important role regulating the effects of psychostimulants like cocaine and amphetamines (methamphetamine [METH] is a long acting derivative of d-amphetamine). These highly addictive agents induce the release of dopamine (DA) (and other catecholamines) from dopaminergic terminals of the striatum. The excessive release of DA in the striatum and the NAc has been implicated in the habit-forming properties of these drugs. In order to study the contribution of SP and CCK in the striatum during psychostimulant treatment, we employed selective non-peptide neurokinin-1 (NK-1) and cholecystokinin-2 (CCK-2) receptor antagonists that readily cross the blood brain barrier. We infused the neurokinin-1 receptor (NK-1R) antagonist, L-733,060, into the striatum of freely moving rats via a microdialysis probe in order to assess the effects of SP on cocaine-induced DA overflow in the striatum. Infusion of the NK-1R antagonist prior to a systemic injection of cocaine (10 mg/kg i.p.) significantly attenuated DA overflow in the striatum. Conversely, infusion of a CCK-2 receptor (CCK-2R) antagonist, L-369,293, through the microdialysis probe evoked DA overflow in the striatum in the absence of cocaine and potentiated DA overflow after a single injection of cocaine (10 mg/kg i.p.). Exposure to METH (10 mg/kg 4x at two-hour intervals) produced deficits of dopamine transporters (DAT) in mice striatum that are detectable three days after the treatment and are long lasting. Pre-treatment (i.p. injections) with the NK-1R antagonist, WIN-51,708 30 minutes before the 1st and 4th injections of METH prevented the loss of DAT in the striatum. Moreover, pre-treatment with the NK-1R antagonist prevents METH-induced cell death. Taken together, these results demonstrate that the NK-1R and the CCK-2R are important modulators of the actions of the psychostimulants cocaine and METH. Neuropeptide receptors represent an important control point mediating the effects of the neurotransmitter DA in the striatum of the rodent brain.

Animals↗