The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jun 2002
Persistent antagonism of methamphetamine-induced dopamine release in rats pretreated with GBR12909 decanoate.
Methamphetamine abuse is a serious global health problem, and no effective treatments for methamphetamine dependence have been developed. In animals, the addictive properties of methamphetamine are mediated via release of dopamine (DA) from nerve terminals in mesolimbic reward circuits. At the molecular level, methamphetamine promotes DA release by a nonexocytotic diffusion-exchange process involving DA transporter (DAT) proteins. ⋯ Autoradiographic analysis revealed that GBR-decanoate caused long-term decreases in DAT binding in the brain. Our data suggest that GBR-decanoate, or similar agents, may be useful adjuncts in treating methamphetamine dependence. This therapeutic strategy would be especially useful for noncompliant patient populations.
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J. Pharmacol. Exp. Ther. · May 2002
Modulation of cellular expression of glucocorticoid receptor and glucocorticoid response element-DNA binding in rat brain during alcohol drinking and withdrawal.
To define the molecular mechanisms of abnormal hypothalamic pituitary adrenal (HPA) axis during ethanol dependence, we investigated the effect of chronic ethanol treatment (15 days) and its withdrawal (24 h) on the expression of glucocorticoid receptors (GRs) and glucocorticoid response element (GRE)-DNA binding in the rat brain. The effects of chronic mianserin [serotonin (5-HT)(2A/2C) antagonist] treatment on these parameters in various brain structures of control diet-fed and ethanol-fed rats were also investigated. It was found that ethanol treatment and withdrawal significantly decreased the GR protein levels in cortical (cingulate gyrus, frontal, parietal, and piriform cortex) and amygdaloid (central, medial, and basolateral) structures and paraventricular nucleus (PVN) of hypothalamus of rats. ⋯ Furthermore, ethanol treatment and its withdrawal or mianserin treatment had no effect on the neuron-specific nuclear protein levels in the various brain structures. Taken together, these results indicate that interaction of 5-HT(2A/2C) receptors with GRs in cortical, central amygdaloid, and PVN structures may play a role in neural mechanisms of alcohol dependence. It is possible that decreased GR expression in PVN may be responsible for the abnormal HPA axis during ethanol exposure and withdrawal.
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J. Pharmacol. Exp. Ther. · May 2002
The role of superoxide and nuclear factor-kappaB signaling in N-methyl-D-aspartate-induced necrosis and apoptosis.
N-Methyl-D-aspartate (NMDA) receptor-mediated cell death is complex, probably involving elements of necrosis and apoptosis. The mechanisms underlying this phenomenon are incompletely understood but have been suggested to involve reactive oxygen species such as nitric oxide and superoxide anion (O(2)) and nuclear factor-kappaB (NF-kappaB) signaling. In this study, we used a selective nonpeptidyl superoxide dismutase mimetic (M40403) and SN50, a peptide inhibitor of NF-kappaB translocation, to investigate the role of O(2) and the potential downstream signaling molecules in cell death induced by activation of the NMDA receptor. ⋯ SN50 was also able to block NMDA-induced cell death as well as the increased Bax/Bcl-X(L) ratio. Time course studies and experiments with SN50 and M40403 suggest that O(2) production and NF-kappaB translocation may be involved in necrosis and apoptosis, but the latter also requires an increased expression of Bax. The ability of M40403 to prevent NMDA-induced cell death relatively early in this cascade suggests its potential therapeutic utility in central nervous systems diseases such as stroke that are associated with increased NMDA receptor-mediated production of O(2).
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J. Pharmacol. Exp. Ther. · Mar 2002
Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity.
Administration of a high-dose regimen of methamphetamine (METH) rapidly and profoundly decreases plasmalemmal and vesicular dopamine (DA) transport in the striatum, as assessed in synaptosomes and purified vesicles, respectively. To determine whether these responses were common to other amphetamines of abuse, effects of methylenedioxymethamphetamine (MDMA) on the plasmalemmal DA transporter (DAT) and vesicular monoamine transporter-2 (VMAT-2) were assessed. Similar to effects of METH reported previously, multiple high-dose MDMA administrations rapidly (within 1 h) decreased plasmalemmal DA uptake, as assessed ex vivo in synaptosomes prepared from treated rats. ⋯ In addition to affecting DAT function, MDMA rapidly decreased vesicular DA transport as assessed in striatal vesicles prepared from treated rats. Unlike effects of multiple METH injections reported previously, this decrease partially recovered by 24 h after drug treatment. Taken together, these results reveal several differences between effects of MDMA and previously reported METH on DAT and VMAT-2; differences that may underlie the dissimilar neurotoxic profile of these agents.
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J. Pharmacol. Exp. Ther. · Mar 2002
Effects of mu-opioid agonists on cocaine- and food-maintained responding and cocaine discrimination in rhesus monkeys: role of mu-agonist efficacy.
Mu-opioid agonists decrease cocaine self-administration in laboratory studies and cocaine use by many cocaine- and opioid-dependent polydrug abusers. To assess the role of mu-agonist efficacy as a determinant of these effects, this study evaluated cocaine- and food-maintained responding by rhesus monkeys (Macaca mulatta) during chronic treatment with saline or the high-efficacy mu-agonist fentanyl (0.001-0.01 mg/kg/h), the intermediate-efficacy mu-agonist morphine (0.032-0.32 mg/kg/h), or the low-efficacy mu-agonists nalbuphine (0.1-1.0 mg/kg/h) and butorphanol (0.0032-0.032 mg/kg/h). Responding was maintained by cocaine and food under a second order schedule of reinforcement during multiple daily sessions of cocaine and food availability. ⋯ Morphine and fentanyl produced smaller decreases in cocaine self-administration, and undesirable effects precluded evaluation of higher fentanyl and morphine doses. Decreases in cocaine self-administration produced by nalbuphine and butorphanol probably did not reflect a general blockade of cocaine's abuse-related effects, because nalbuphine and butorphanol did not block the discriminative stimulus effects of cocaine in monkeys trained to discriminate 0.4 mg/kg cocaine from saline in a food-reinforced drug discrimination procedure. These results suggest that low-efficacy mu-agonists may decrease cocaine self-administration to a greater degree and with fewer undesirable effects than high-efficacy mu-agonists.