S R Childers

Wake Forest School of Medicine, Winston-Salem, NC, United States

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Publications (153)564.44 Total impact

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    ABSTRACT: Concurrent use of cocaine and heroin (speedball) has been shown to exert synergistic effects on dopamine neurotransmission in the nucleus accumbens (NAc), as observed by significant increases in extracellular dopamine levels and compensatory elevations in the maximal reuptake rate (Vmax ) of dopamine. The present studies were undertaken to determine whether chronic self-administration of cocaine, heroin or a combination of cocaine:heroin led to compensatory changes in the abundance and/or affinity of high- and low-affinity DAT binding sites. Saturation binding of the cocaine analog [(125) I] 3β-(4-iodophenyl)tropan-2β-carboxylic acid methyl ester ([(125) I]RTI-55) in rat NAc membranes resulted in binding curves that were best fit to two-site binding models, allowing calculation of dissociation constant (Kd ) and binding density (Bmax ) values corresponding to high- and low-affinity DAT binding sites. Scatchard analysis of the saturation binding curves clearly demonstrate the presence of high- and low- affinity binding sites in the NAc, with low-affinity sites comprising 85 to 94% of the binding sites. DAT binding analyses revealed that self-administration of cocaine and a cocaine:heroin combination increased the affinity of the low-affinity site for the cocaine congener RTI-55 compared to saline. These results indicate that the alterations observed following chronic speedball self-administration are likely due to the cocaine component alone; thus further studies are necessary to elaborate upon the synergistic effect of cocaine:heroin combinations on the dopamine system in the NAc. Synapse, 2014. © 2014 Wiley Periodicals, Inc.
    Synapse 06/2014; · 2.31 Impact Factor
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    ABSTRACT: Although biochemical and physiological evidence suggests a strong interaction between striatal CB(1) cannabinoid (CB(1) R) and D(2) dopamine (D(2) R) receptors, the mechanisms are poorly understood. We targeted medium spiny neurons (MSNs) of the indirect pathway using shRNA to knockdown either CB(1) R or D(2) R. Chronic reduction in either receptor resulted in deficits in gene and protein expression for the alternative receptor and concomitantly increased expression of the cannabinoid receptor interacting protein 1a (CRIP1a), suggesting a novel role for CRIP1a in dopaminergic systems. Both CB(1) R and D(2) R knockdown reduced striatal dopaminergic-stimulated [(35) S]GTPγS binding, and D(2) R knockdown reduced pallidal WIN55212-2-stimulated [(35) S]GTPγS binding. Decreased D(2) R and CB(1) R activity was associated with decreased striatal phosphoERK. A decrease in mRNA for opioid peptide precursors pDYN and pENK accompanied knockdown of CB(1) Rs or D(2) Rs, and over-expression of CRIP1a. Down-regulation in opioid peptide mRNAs was followed in time by increased DOR1 but not MOR expression, leading to increased DPDPE-stimulated [(35) S]GTPγS binding in the striatum. We conclude that mechanisms intrinsic to striatal MSNs or extrinsic via the indirect pathway adjust for changes in CB(1) R or D(2) R levels by modifying the expression and signaling capabilities of the alternative receptor as well as CRIP1a and the opioid system. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12139.
    Journal of Neurochemistry 01/2013; · 3.97 Impact Factor
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    ABSTRACT: Behavioral flexibility, the ability to modify responses due to changing task demands, is detrimentally affected by aging with a shift towards increased cognitive rigidity. The neurobiological basis of this cognitive deficit is not clear although striatal cholinergic neurotransmission has been implicated. To investigate the possible association between striatal acetylcholine signaling with age-related changes in behavioral flexibility, young, middle-aged, and aged F344 X Brown Norway F1 rats were assessed using an attentional set-shifting task that includes two tests of behavioral flexibility: reversal learning and an extra-dimensional shift. Rats were also assessed in the Morris water maze to compare potential fronto-striatal-dependent deficits with hippocampal-dependent deficits. Behaviorally characterized rats were then assessed for acetylcholine muscarinic signaling within the striatum using oxotremorine-M-stimulated [(35)S]GTPγS binding and [(3)H]AFDX-384 receptor binding autoradiography. The results showed that by old age, cognitive deficits were pronounced across cognitive domains, suggesting deterioration of both hippocampal and fronto-striatal regions. A significant decline in oxotremorine-M-stimulated [(35)S]GTPγS binding was limited to the dorsomedial striatum of aged rats when compared to young and middle-aged rats. There was no effect of age on striatal [(3)H]AFDX-384 receptor binding. These results suggest that a decrease in M2/M4 muscarinic receptor coupling is involved in the age-associated decline in behavioral flexibility.
    Behavioural brain research 11/2011; 227(1):258-64. · 3.22 Impact Factor
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    ABSTRACT: This review evaluates the cellular mechanisms of constitutive activity of the cannabinoid (CB) receptors, its reversal by inverse agonists, and discusses the pitfalls and problems in the interpretation of the research data. The notion is presented that endogenously produced anandamide (AEA) and 2-arachidonoylglycerol (2-AG) serve as autocrine or paracrine stimulators of the CB receptors, giving the appearance of constitutive activity. It is proposed that one cannot interpret inverse agonist studies without inference to the receptors' environment vis-à-vis the endocannabinoid agonists which themselves are highly lipophilic compounds with a preference for membranes. The endocannabinoid tone is governed by a combination of synthetic pathways and inactivation involving transport and degradation. The synthesis and degradation of 2-AG is well characterized, and 2-AG has been strongly implicated in retrograde signalling in neurons. Data implicating endocannabinoids in paracrine regulation have been described. Endocannabinoid ligands can traverse the cell's interior and potentially be stored on fatty acid-binding proteins (FABPs). Molecular modelling predicts that the endocannabinoids derived from membrane phospholipids can laterally diffuse to enter the CB receptor from the lipid bilayer. Considering that endocannabinoid signalling to CB receptors is a much more likely scenario than is receptor activation in the absence of agonist ligands, researchers are advised to refrain from assuming constitutive activity except for experimental models known to be devoid of endocannabinoid ligands.
    British Journal of Pharmacology 03/2011; 163(7):1329-43. · 5.07 Impact Factor
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    ABSTRACT: Neuropathic pain alters opioid self-administration in rats. The brain regions altered in the presence of neuropathic pain mediating these differences have not been identified, but likely involve ascending pain pathways interacting with the limbic system. The amygdala is a brain region that integrates noxious stimulation with limbic activity. μ-Opioid receptors were blocked in the amygdala using the irreversible antagonist, β-funaltrexamine, and the antiallodynic and reinforcing effects of heroin were determined in spinal nerve-ligated rats. In addition, the effect of β-funaltrexamine was determined on heroin self-administration in sham-operated rats. β-Funaltrexamine decreased functional activity of μ-opioid receptors by 60 ± 5% (mean ± SD). Irreversible inhibition of μ-opioid receptors in the amygdala significantly attenuated the ability of doses of heroin up to 100 μg/kg to reverse hypersensitivity after spinal nerve ligation. Heroin intake by self-administration in spinal nerve-ligated rats was increased from 5.0 ± 0.3 to 9.9 ± 2.1 infusions/h after administration of 2.5 nmol of β-funaltrexamine in the lateral amygdala, while having no effect in sham-operated animals (5.8 ± 1.6 before, 6.7 ± 0.9 after). The antiallodynic effects of 60 μg/kg heroin were decreased up to 4 days, but self-administration was affected for up to 14 days. μ-Opioid receptors in the lateral amygdala partially meditate heroin's antiallodynic effects and self-administration after peripheral nerve injury. The lack of effect of β-funaltrexamine on heroin self-administration in sham-operated subjects suggests that opioids maintain self-administration through a distinct mechanism in the presence of pain.
    Anesthesiology 03/2011; 114(3):633-42. · 5.16 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 33(30).
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 27(39).
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    ABSTRACT: A series of enantiomerically pure 1-naphthyl and 4-indolyl arylalkylamines were prepared and evaluated for their binding affinities to the monoamine transporters. The two series of enantiomers displayed considerable differences in binding selectivity between the monoamine transporters, leading to the design of (S)-4-(3,4-dichlorophenyl)-4-(1H-indol-4-yl)-N-methylbutan-1-amine as a potent inhibitor for the dopamine and serotonin transporters.
    Bioorganic & medicinal chemistry letters 12/2008; 19(1):58-61. · 2.65 Impact Factor
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    ABSTRACT: The present study was designed to reveal the relationship between cocaine-induced dopamine uptake changes and patterns of cocaine self-administration observed under a fixed-ratio schedule. Cocaine was intravenously infused into anesthetized rats, according to inter-infusion intervals obtained from self-administering animals, and dopamine uptake changes (apparent K(m)) were assessed in the nucleus accumbens using voltammetry. The data demonstrate that cocaine-induced dopamine transporter (DAT) inhibition accounts for the accumbal dopamine fluctuations, which are associated with the cyclic regularity of cocaine intake observed during self-administration. Specifically, the inter-infusion intervals that are maintained during cocaine self-administration correlate with the maintenance of a rapidly changing level of dopamine uptake inhibition, which appears to be tightly regulated. Furthermore, this maintained level of dopamine uptake inhibition was found to shift upward using intervals from animals that had shown an escalation in the rate of cocaine self-administration. Although no significant change in the apparent K(m) was revealed in animals that exhibited an escalation in the rate of cocaine intake, an increased dopamine uptake rate was found suggesting an upregulation of DAT number in response to a history of high cocaine intake. This is the first demonstration of the tight correlation that exists between the level of dopamine uptake inhibition and rates of cocaine self-administration. Moreover, a new mathematical model was created that quantitatively describes the changes in cocaine-induced dopamine uptake and correctly predicts the level of dopamine uptake inhibition. This model permits a computational interpretation of cocaine-induced dopamine uptake changes during cocaine self-administration.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2008; 34(5):1174-84. · 8.68 Impact Factor
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    ABSTRACT: Previous studies have shown that the phenylisothiocyanate tropane analog 2-beta-propanoyl-3-beta-(2-naphthyl)-8-[4-isothiocyanato)benzyl]nortropane (HD-205) binds covalently to dopamine and serotonin transporters (DAT and SERT, respectively) in rat brain membranes (Biochem Pharmacol 74:336-344, 2007). The present study evaluated the irreversible effects of HD-205 in vivo in rats after intracranial injection. Rats were implanted with unilateral cannulae in rat striatum, and HD-205 (0.001-3 nmol) was administered by intrastriatal injection. In vitro autoradiography of DAT binding with [125I]2-carbomethoxy-3-(4-iodophenyl)tropane (RTI-55) on brain sections obtained 24 h after injection showed a highly localized blockade of binding in striatum, with maximal blockade of binding by 1 to 3 nmol HD-205. Similar blockade of SERT binding (using [3H]-citalopram) was observed in the same area. No blockade of DAT or SERT binding was observed after intrastriatal injections of the reversible analog 2-beta-propanoyl-3-beta-(2-naphthyl)-8-benzyl nortropane (HD-206), and HD-205 treatment had no effect on D(2)- and mu-opioid-stimulated guanosine 5'-O-(3-[35S]thio)-triphosphate binding in sections from the same animals. In a time course study, rats administered with 1 nmol HD-205 showed recovery of 50% DAT binding after 3 to 4 days postinjection, and full recovery after 6 weeks. Rats implanted with bilateral cannulae were tested for cocaine-induced locomotor activity. Two days after intrastriatal injection of 1 nmol of HD-205, systemic (20 mg/kg i.p.) cocaine-induced locomotor activity was not affected; however, locomotor activity induced by intrastriatal administration of cocaine (6 nmol) was eliminated. This strategy of site-specific chemical blockade of transporters could serve as a valuable tool to evaluate the neuroanatomical basis of DAT-mediated cocaine effects.
    Journal of Pharmacology and Experimental Therapeutics 09/2008; 326(2):587-95. · 3.89 Impact Factor
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    ABSTRACT: Irreversible tropane analogs have been useful in identifying binding sites of cocaine on biogenic amine transporters, including transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET). The present study characterizes the properties of the novel phenylisothiocyanate tropane HD-205, synthesized from the highly potent 2-napthyl tropane analog WF-23. In radioligand binding studies in brain membranes, direct IC(50) values of HD-205 were 4.1, 14 and 280nM at DAT, SERT and NET, respectively. Wash-resistant binding was characterized by preincubation of HD-205 with brain membranes, followed by extensive washing before performing transporter radioligand binding. Results for HD-205 showed wash-resistant IC(50) values of 191, 230 and 840nM at DAT, SERT and NET, respectively. Saturation binding studies with [(125)I]RTI-55 in membranes pretreated with 100nM HD-205 showed that HD-205 significantly decreased the B(max) but not K(D) of DAT and SERT binding. To further characterize its irreversible binding, an iodinated analog of HD-205, HD-244, was prepared from a trimethylsilyl precursor. The direct IC(50) of HD-244 at DAT was 20nM. [(125)I]HD-244 was synthesized with chloramine-T, purified on HPLC, reacted with rat striatal membranes, and proteins were separated by SDS-PAGE. Results showed several non-specific labeled bands, but only a single specific band of radioactivity co-migrating with an immunoreactive DAT band at approx. 80 kilodaltons was detected, suggesting that [(125)I]HD-244 covalently labeled DAT protein in striatal membranes. These results demonstrate that phenylisothiocyanate analogs of WF-23 can be used as potential ligands to map distinct binding sites of cocaine analogs at DAT.
    Biochemical Pharmacology 08/2007; 74(2):336-44. · 4.58 Impact Factor
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    ABSTRACT: Cholinesterase inhibitors which reach the central nervous system produce pain relief but are poorly tolerated because of gastrointestinal side effects. Here, the authors tested whether donepezil, a central nervous system penetrant cholinesterase inhibitor with a low incidence of gastrointestinal side effects, would relieve hypersensitivity in an animal model of neuropathic pain. Male rats were anesthetized, and the L5 and L6 spinal nerves were ligated unilaterally. Hypersensitivity was measured by withdrawal threshold to von Frey filament application to the hind paw after oral donepezil, and antagonists administered centrally and peripherally. Efficacy of chronic oral donepezil to relieve hypersensitivity was tested, and activation of G proteins by M(2) muscarinic receptors was determined by carbachol-stimulated [(35)S]guanosine triphosphate (gamma)S autoradiography in brain and spinal cord. Spinal nerve ligation resulted in hypersensitivity that was more severe ipsilateral than contralateral to surgery. Oral donepezil reduced hypersensitivity bilaterally in a dose-dependent manner for 2 h, and this effect was blocked by spinal but not supraspinal or peripheral muscarinic receptor antagonism. Oral donepezil maintained efficacy over 2 weeks of twice daily administration, and this treatment did not lead to desensitization of muscarinic receptor-coupled G proteins in brain or spinal cord. Donepezil, a well-tolerated cholinesterase inhibitor used in the treatment of Alzheimer dementia, reduces hypersensitivity in this rat model of neuropathic pain by actions on muscarinic receptors in the spinal cord. Lack of tolerance to this effect, in contrast to rapid tolerance to direct receptor agonists, suggests that cholinesterase inhibition may be useful in the treatment of neuropathic pain.
    Anesthesiology 06/2007; 106(5):1019-25. · 5.16 Impact Factor
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    ABSTRACT: Methadone maintenance therapy has been the mainstay of treatment for heroin addiction since the 1970s. Recent studies indicate that methadone is of greater relative intrinsic efficacy than the active metabolites of heroin at mu-opioid receptors and that the extent of mu-opioid receptor desensitization is dependent upon agonist efficacy. Regional differences have been found for mu-opioid receptor desensitization with chronic heroin self-administration, and a similar paradigm was employed to compare regional differences between the effects of heroin and methadone. Rats were trained to self-administer heroin i.v., and the dose available was increased incrementally to a terminal value of 6 mg/kg for each infusion. Half of these rats were allowed to continue to self-administer heroin, while dependence was maintained in the others by hourly infusions of 3 mg/kg of methadone. A separate group of animals was kept on a low dose of heroin. Activation of G-proteins by the high efficacy agonist DAMGO was decreased to a greater extent in animals treated chronically with methadone compared with those allowed to self-administer heroin in amygdala, periaqueductal gray, and subicular nucleus. Activation of G-proteins by the partial agonist endomorphin was decreased in striatum, thalamus, and amygdala in rats from all drug treatment groups, but to a greater extent in the striatum in methadone treated rats compared with the heroin groups. Elucidating the mechanisms by which methadone induces differential desensitization of mu-opioid receptors across brain regions compared with heroin could provide insights to improve the pharmacotherapy of heroin addiction.
    Synapse 04/2007; 61(3):176-84. · 2.31 Impact Factor
  • Annals of the New York Academy of Sciences 12/2006; 654(1):33 - 51. · 4.38 Impact Factor
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    ABSTRACT: Spinally administered adenosine reduces hypersensitivity in animals and humans with nerve injury, but also causes transient pain in humans and reduces tonic inhibition in spinal neurons. Nerve injury results in increased tonic spinal cord adenosine A1 receptor activation, consistent with a role for adenosine to generate hypersensitivity. Here, we demonstrate that chronic intrathecal adenosine induces hypersensitivity in normal animals and that chronic blockade of spinal adenosine A1 receptors by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine partially prevents nerve injury-induced hypersensitivity. In contrast, chronic blockade of spinal adenosine A1 receptors failed to reduce increased tonic G-protein signaling in the spinal cord after nerve injury. These data support a role for chronic adenosine A1 receptor stimulation after nerve injury to result in hypersensitivity.
    Neuroreport 11/2006; 17(15):1619-22. · 1.40 Impact Factor
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    Steven R Childers
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    ABSTRACT: The biological response to cannabinoid agonist begins when the agonist-bound receptor activates G-protein G(alpha) subunits, thus initiating a cascade of signal transduction pathways. For this reason, information about cannabinoid receptors/G-protein coupling is critical to understand both the acute and chronic actions of cannabinoids. This review focuses on these mechanisms, predominantly examining the ability of cannabinoid agonists to activate G-proteins in brain with agonist-stimulated [(35)S]guanylyl-5'-O-(gamma-thio)-triphosphate ([(35)S]GTPgammaS) binding. Acute efficacies of cannabinoid agonists at the level of G-protein activation depend not only on the ability of the agonist to induce a high affinity state in G(alpha) for GTP, but also to induce a low affinity for GDP. When several agonists are compared, it is clear that cannabinoid agonists differ considerably in their efficacy. Both WIN 55212-2 and levonantradol are full agonists, while Delta(9)-tetrahydrocannabinol is a weak partial agonist. Of interest, anandamide and its stable analog methanandamide are partial agonists. Chronic treatment in vivo with cannabinoids produces significant tolerance to the physiological and behavioral effects of these drugs, and several studies have shown that this is accompanied by a significant loss in the ability of cannabinoid receptors to couple to G-proteins in brain. These effects vary across different brain regions and are usually (but not always) accompanied by loss of cannabinoid receptor binding. Although the relationship between cannabinoid receptor desensitization and tolerance has not yet been established, these mechanisms may represent events that lead to a loss of cannabinoid agonist response and development of tolerance.
    The AAPS Journal 02/2006; 8(1):E112-7. · 4.39 Impact Factor
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    ABSTRACT: The synthesis of potent 4-aryl methoxypiperidinol inhibitors of the dopamine transporter is described. Symmetrical para substituents of the benzene rings are important for high potency in binding to the dopamine transporter. 4-[Bis(4-fluorophenyl) methoxy]-1-methylpiperidine has an IC50 of 22.1+/-5.73 nM and increases locomotor activity in mice.
    Bioorganic & Medicinal Chemistry Letters 12/2005; 15(22):4915-8. · 2.34 Impact Factor
  • Catherine E Maher, Thomas J Martin, Steven R Childers
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    ABSTRACT: Previous studies have shown that chronic opiate treatment decreases mu opioid-stimulated [35S]GTPgammaS binding in specific brain regions. To extend these findings, the present study investigated DAMGO-stimulated [35S]GTPgammaS binding in membrane homogenates and coronal sections from rats non-contingently administered heroin. Rats were administered saline or increasing doses of heroin i.v. hourly up to 288 mg/kg/day over 40 days. In brain sections, chronic heroin administration decreased DAMGO-stimulated [35S]GTPgammaS binding in medial thalamus and amygdala, with no effect in cingulate cortex or nucleus accumbens. Chronic heroin administration also reduced [35S]GTPgammaS binding stimulated by the principal metabolite of heroin, 6-monoacetylmorphine. In contrast, no significant changes in mu opioid receptor binding were observed in amygdala or thalamus using [3H]DAMGO autoradiography. In membranes from amygdala and thalamus, chronic heroin treatment decreased the maximal effect of DAMGO in stimulating [35S]GTPgammaS binding, with no effect on DAMGO potency. GTPgammaS saturation analysis showed that chronic heroin treatment decreased the Bmax, and increased the K(D), of DAMGO-stimulated [35S]GTPgammaS binding. These data suggest potential mechanisms by which chronic agonist treatment produces opioid receptor/G-protein desensitization in brain.
    Life Sciences 08/2005; 77(10):1140-54. · 2.56 Impact Factor
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    Steven R Childers, Xinhui Li, Ruoyu Xiao, James C Eisenach
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    ABSTRACT: 2-Amino-4,5,6,7-tetrahydrobenzo(beta)thiophen-3-yl 4-chlorophenylmethanone (T62) is a member of a group of allosteric modulators of adenosine A1 receptors tested in animal models of neuropathic pain to increase the efficacy of adenosine. To determine its mechanisms at the level of receptor-G-protein activation, the present studies examined the effect of T62 on A1-stimulated [35S]guanosine-5'-O-(gamma-thio)-triphosphate ([35S]GTPgammaS) binding in brain membranes, and by [35S]GTPgammaS autoradiography using the A1 agonist, phenylisopropyladenosine (PIA), to activate G-proteins. In hippocampal membranes, T62 increased both basal and PIA-stimulated [35S]GTPgammaS binding. The effect of T62 was non-competitive in nature, since it increased the maximal effect of PIA, with no effect on agonist potency. GTPgammaS saturation analysis showed that T62 increased the number of G-proteins activated by agonist but had no effect on the affinity of activated G-proteins for GTPgammaS. [35S]GTPgammaS autoradiography showed that the neuroanatomical localization of T62-stimulated [35S]GTPgammaS binding was identical to that of PIA-stimulated activity. The increase in PIA-stimulated activity by T62 varied between brain regions, with areas of lower A1 activation producing the largest percent modulation by T62. These results suggest a mechanism of allosteric modulators to increase the number of activated G-proteins per receptor, and provide a neuroanatomical basis for understanding potential therapeutic effects of such drugs.
    Journal of Neurochemistry 06/2005; 93(3):715-23. · 3.97 Impact Factor
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    ABSTRACT: The potent tropane analog, WF-23 [2beta-propanoyl-3beta-(2-naphthyl) tropane], blocks dopamine, serotonin, and norepinephrine transporters with high affinity in vitro and blocks transporters for at least 2 days following a single in vivo administration. Previous studies demonstrated desensitization of monoamine receptor-coupled G-proteins in brain following chronic treatment of rats with WF-23. The current study sought to determine the time course of this desensitization and the behavioral effects of receptor desensitization. Rats were treated with 1 mg/kg WF-23 and injected i.p. every 48 h for 1 to 21 days. Receptor activation of G-proteins was determined by guanosine 5'-O-(3-[(35)S]thiotriphosphate) ([(35)S]GTPgammaS) binding in brain sections for monoamine receptors, as well as mu opioid receptors as a nonmonoamine receptor control. Chronic treatment with WF-23 produced significant reductions in D(2), 5-hydroxytryptamine 1A, and alpha(2)-adrenergic receptor-stimulated [(35)S]GTPgammaS binding; however, the time course of desensitization varied with different receptors. There was no effect of WF-23 treatment on mu opioid-stimulated [(35)S]GTPgammaS binding at any time point. Consistent with previous studies, there was no effect of WF-23 treatment on D(2) receptor binding, as determined by [(3)H]spiperone autoradiography. Locomotor activity was significantly increased for up to 48 h following acute administration of WF-23, demonstrated by increased photocell beam interruptions. WF-23-induced increases in locomotor activity occurred following repeated administration, as above, for up to 7 days. Following 7 days of treatment, there was a significant decrease in WF-23-increased locomotor activity. This reduction occurred at the same time point as the decrease in D(2) receptor/G-protein coupling, suggesting a role of D(2) desensitization in producing tolerance to WF-23-mediated behavior.
    Journal of Pharmacology and Experimental Therapeutics 06/2005; 313(2):510-7. · 3.89 Impact Factor

Publication Stats

4k Citations
564.44 Total Impact Points

Institutions

  • 1997–2011
    • Wake Forest School of Medicine
      • • Department of Anesthesiology
      • • Department of Physiology and Pharmacology
      Winston-Salem, NC, United States
  • 1996–2010
    • University at Buffalo, The State University of New York
      • Department of Chemistry
      Buffalo, New York, United States
  • 1992–2008
    • Wake Forest University
      • • Department of Physiology and Pharmacology
      • • Department of Chemistry
      Winston-Salem, NC, United States
  • 2004
    • Campbell University
      • Department of Pharmaceutical Science
      Buies Creek, NC, United States
  • 1999–2002
    • Virginia Commonwealth University
      • Department of Pharmacology and Toxicology
      Richmond, VA, United States
  • 2000
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 1989
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 1983
    • University of Florida
      • College of Medicine
      Gainesville, FL, United States