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Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans. Systemic immunity against gene therapy vectors has been shown to hamper therapeutic efficacy; however, helper-dependent high-capacity adenovirus (HC-Ad) vectors elicit sustained transgene expression, even in the presence of systemic anti-adenoviral immunity. We engineered HC-Ads encoding the conditional cytotoxic herpes simplex type 1 thymidine kinase (TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Flt3L). Flt3L expression is under the control of the regulatable Tet-ON system. In anticipation of a phase I clinical trial for GBM, we assessed the therapeutic efficacy, biodistribution, and clinical and neurotoxicity with escalating doses of HC-Ad-TetOn-Flt3L + HC-Ad-TK in rats. Intratumoral administration of these therapeutic HC-Ads in rats bearing large intracranial GBMs led to long-term survival in approximately 70% of the animals and development of antiglioma immunological memory without signs of neuropathology or systemic toxicity. Systemic anti-adenoviral immunity did not affect therapeutic efficacy. These data support the idea that it would be useful to develop HC-Ad vectors further as a therapeutic gene-delivery platform to implement GBM phase I clinical trials.

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The purpose of the present study was to compare the effects of contingent and noncontingent cocaine administration on plasma levels of corticosterone in rats. Male rats were trained to self-administer cocaine under a fixed-ratio 5 schedule. The rats were yoked such that the delivery of cocaine (0.25 mg/kg/infusion) to one rat (contingent cocaine) produced the simultaneous noncontingent delivery of the same dose of cocaine (noncontingent cocaine) or saline (noncontingent saline) to other rats. Although saline administration had no effect, plasma corticosterone levels were significantly higher in rat receiving contingent cocaine compared to those receiving noncontingent cocaine. These results demonstrate that the active vs. passive administration of cocaine can differentially affect this neuroendocrine response.

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Extant data, mostly from studies in vitro, suggest that coumarin and nicotine are both metabolized by CYP2A6, a cytochrome P450 isozyme. In order to investigate this issue further, the activity of this enzyme in vivo was measured in 37 non-smokers and 37 smokers using coumarin (2.0 mg, PO) as the metabolic probe. The percentage of coumarin metabolized to 7-hydroxycoumarin in 8 h was measured in urine by high-pressure liquid chromatography. There was more than 10-fold variability in coumarin metabolism in both groups. Coumarin metabolism was significantly reduced in smokers (46.6 +/- 4.4%) as compared to non-smokers (66.4 +/- 3.5%; p < or = .001). The results support previous in vitro findings that both coumarin and nicotine are metabolized, at least in part, by a common pathway, which most likely is CYP2A6.

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The present study examined the persistent functional consequences associated with exposure to single and multiple doses of (+/-) 3,4-methylenedioxymethamphetamine (MDMA) as reflected by the neuroendocrine responses to d,l-fenfluramine (FEN). Adult male rats were administered a single dose of MDMA (20 mg/kg, s.c.) and challenged 2 weeks later with saline or FEN (2, 4, 6 and 8 mg/kg, s.c.). The corticotropin (ACTH) response to FEN (6 and 8 mg/kg) was blunted and the prolactin response to FEN (4 and 6 mg/kg) was enhanced in MDMA pre-treated rats. The ACTH and prolactin responses to FEN (6 mg/kg, s.c.) were then evaluated 4, 8 and 12 months after exposure to single and multiple doses MDMA (20 mg/kg, s.c. and 20 mg/kg, s.c., bid, x 4 days, respectively). The ACTH response to FEN was significantly reduced at 4 and 8 months in both MDMA treatment groups, and at 12 months in the multiple dose group only. In contrast, the prolactin response to FEN was enhanced in both groups of MDMA treated rats at 4 months, but only in the multiple dose group at 8 months. By 12 months, the prolactin response to FEN had normalized. Following multiple doses of MDMA, 5-HT concentrations were reduced significantly in the frontal cortex at 4 and 12 months. The results indicate that exposure to single or multiple doses of MDMA can produce functional alterations which can persist for months, whereas the biochemical sequelae were less robust and shorter lived.

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The role of the sigma receptor in prolonged pain was examined by assessing the effects of 1,3,di-o-tolylguanidine (DTG), a selective sigma receptor ligand, on the formalin test in mice. Formalin injected subcutaneously into the hindpaw produces a biphasic pain response: an acute phase of short duration followed by a longer-lasting tonic phase. DTG (10 mg/kg, i.p.) potently reduced pain behavior in the acute phase but increased pain behavior in the tonic phase. Rimcazole (5 and 10 mg/kg, i.p.), a selective sigma receptor antagonist, blocked both the DTG-induced decrease and increase in pain behavior observed in the acute and tonic phases, respectively. These data support previous findings indicating a modulatory role for the sigma receptor in nociceptive processes, and suggest that this receptor differentially modulates acute vs. tonic pain.

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The role of sigma receptors in antinociceptive processes remains equivocal, because previous sigma drugs also bind to PCP/NMDA and opiate receptors. The present study examined the antinociceptive effects of the high-affinity, sigma-selective ligand 1,3-di-o-tolylguanidine (DTG; 10, 15, and 20 mg/kg, IP) on tail-withdrawal latencies in mice. DTG produced significant but short-lived increases in withdrawal latencies at all dose levels. DTG also produced hypothermia, but this effect was dissociable from antinociception. The highly selective sigma ligand rimcazole (10 and 25 mg/kg, IP) antagonized DTG antinociception in a dose-dependent manner. The opiate antagonist naloxone and the PCP/NMDA antagonist MK-801 were, however, without effect. Haloperidol, which also binds to sigma receptors, increased withdrawal latencies but did not alter DTG antinociception. These data implicate sigma receptors as the site of DTG antinociception, and more generally support the distinction between sigma, opiate, and PCP/NMDA receptors.

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The present study characterized the response of the hypothalamo-pituitary-adrenal axis after the acute administration of enantiomeric pairs of drugs that bind to phencyclidine (PCP) and sigma receptors. Rats were injected with the enantiomers of 1-(1-phenylcyclohexyl)-3-methylpiperidine (PCMP), N-allylnormetazocine (SKF 10,047), dioxadrol (dexoxadrol and levoxadrol) or pentazocine, and plasma levels of adrenocorticotropin (ACTH) and corticosterone were determined by radioimmunoassay. The effects of the enantiomers of PCMP and dioxadrol showed stereospecificity as both (+)-PCMP and dexoxadrol increased plasma levels of ACTH and corticosterone but (-)-PCMP and levoxadrol had no effect. Whereas (-)-pentazocine produced greater responses than (+)-pentazocine, the two enantiomers of SKF 10,047 did not show stereoselectivity. Although the potency of the enantiomers of PCMP and dioxadrol parallel their affinity for binding to PCP receptors, the potency of the enantiomers of pentazocine did not. These results suggest that although the stimulation of the hypothalamo-pituitary-adrenal axis by PCP and drugs with PCP-like activity might be due to interactions with PCP receptors, the effects of pentazocine also involve interactions at other sites.

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The purpose of the present study was to compare the acute and repeated administration of MK-801 (dizocilpine) on body temperature and behavior in the rat, and to determine whether there is cross-tolerance and/or cross-sensitization to phencyclidine (PCP) after repeated administration of MK-801. The acute administration of MK-801 increased body temperature, and this response was enhanced after repeated drug administration. PCP had little effect on body temperature in control rats, but produced increases in body temperature in rats treated daily with MK-801. The acute administration of MK-801 produced ataxia, locomotion, sniffing, and head-weaving, and after repeated drug administration both ataxia and head-weaving were reduced. PCP-induced ataxia, backpedalling, head-weaving, and turning behaviors were decreased in rats treated daily with MK-801, but PCP-induced locomotion and rearing were increased. These results indicate that there is cross-sensitization to the hyperthermic and locomotor effects of MK-801 and PCP, but there is cross-tolerance to some of the other behavioral effects of the drugs.

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The authors present an innovative approach for providing freshman and sophomore medical students with their initial exposure to the problems of alcohol and other drug abuse. Students in small interactive group seminars teach each other about the major areas of substance abuse: treatment, prevention/education, research, and law enforcement. They are aided by group moderators, by resource professionals, and by recovery teachers as they make field trips, attend 12-step meetings, and get background material. They utilize audiovisuals, role-plays, and programmed patients in a report/debate format. Effects of this seminar on their attitudes have been measured and are presented.

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The current study investigated the effects of the acute s.c. and i.c.v. administration of 1,3-di-o-tolylguanidine (DTG) on body temperature in rats. The effects of putative sigma receptor antagonists BMY 14802 and rimcazole on DTG-induced changes in body temperature also were evaluated. The acute s.c. administration of DTG (10.0 and 20.0 mg/kg) produced hypothermia but no observable behavioral effects. Similarly, the acute i.c.v. administration of DTG (12.0-100.0 micrograms/rat) produced hypothermia, but ataxia occurred after this route of administration. The s.c. administration of BMY 14802 alone (25.0 mg/kg) decreased body temperature and enhanced the DTG-induced hypothermia, whereas the administration of rimcazole (25.0 mg/kg) neither altered body temperature nor affected the hypothermia produced by DTG. Neither BMY 14802 nor rimcazole produced any behavioral effects when administered alone. The inability of the putative sigma receptor antagonists BMY 14802 and rimcazole to antagonize DTG-induced hypothermia suggests that either these compounds at the dose used have little sigma receptor antagonist activity, or that the DTG-induced hypothermia is not due to specific interactions with sigma receptors.

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The characterization of the sigma receptor has been hampered by the lack of a functional bioassay system. Drugs that bind to sigma receptors have been reported to inhibit carbachol-induced phosphatidylinositol turnover in rat brain; however, these drugs might directly affect muscarinic acetylcholine receptors. The purpose of the present study was to determine the affinity for muscarinic receptors and the antimuscarinic activity of sigma and phencyclidine receptor ligands. All of the drugs tested inhibited the binding of [3H]N-methylscopolamine to guinea pig cerebral cortical membranes with KI values in the micromolar range and also inhibited carbachol-induced contractions in the guinea pig ileum. These results demonstrate that these compounds have substantial antimuscarinic activity which might limit the use of the inhibition of carbachol-induced phosphatidylinositol turnover as a functional assay system for studying sigma ligands. Furthermore, this antimuscarinic activity must be considered when evaluating the effects of these compounds after in vivo administration.

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Phencyclidine (PCP) markedly stimulates the pituitary-adrenal axis in the rat, inducing the release of adrenocorticotropin (ACTH) and corticosterone. However, the site or sites where PCP produces these effects is not known. This study sequentially examined the effects of PCP on the different components of the central nervous system-pituitary-adrenal axis. PCP did not produce corticosterone release in dispersed adrenal cells in vitro, nor did it stimulate the release of corticosterone in hypophysectomized rats, showing that PCP-induced corticosterone release in intact animals is secondary to the release of ACTH from the pituitary. PCP failed to alter either the basal or the corticotropin releasing factor-induced release of ACTH from superfused pituitaries in vitro, indicating that PCP does not act directly at the level of the pituitary. PCP increased plasma levels of ACTH in adrenalectomized rats, demonstrating that PCP does not stimulate the release of ACTH only by blocking glucocorticoid negative feedback mechanisms. PCP stimulated the release of both ACTH and corticosterone when given by injection directly into brain via the lateral cerebral ventricles. These results indicate that PCP activates the pituitary-adrenal axis by acting at a site or sites within the central nervous system, leading to the subsequent release of ACTH from the pituitary.

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The current study investigated the effects of acute and chronic administration of (+)-SKF 10,047 on body temperature in rats. The effect of phencyclidine on body temperature in chronically (+)-SKF 10,047-treated rats was also investigated. The acute administration of (+)-SKF 10,047 at doses of 5 to 40 mg/kg s.c. did not alter body temperature; however, 80 mg/kg produced hypothermia. In contrast, chronic administration of (+)-SKF 10,047 (5-20 mg/kg) produced dose-dependent hyperthermia when tested on day 7 and 10 of chronic treatment. Moreover, sensitization to the hyperthermic effects occurred as the degree of hyperthermia was greater on day 10 compared to day 7. Phencyclidine (20 mg/kg s.c.) produced hypothermia in rats chronically treated with saline for 13 days, but hyperthermia in rats chronically treated with 20 mg/kg of (+)-SKF 10,047 for the same duration. The hyperthermic effect of chronic (+)-SKF 10,047 treatment is similar to the previously reported dose-dependent hyperthermia in chronically phencyclidine-treated animals. The cross-sensitization of chronically (+)-SKF 10,047-treated rats to the hyperthermic effects of phencyclidine supports the hypothesis that there may be common mechanisms underlying the chronic effects of these drugs on body temperature.

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Phencyclidine (PCP) is a widely used drug of abuse; however, little is known of its effects on neuroendocrine function. The present study characterized the effects of the acute and chronic administration of PCP on the release of adrenocorticotropin, corticosterone and prolactin in the rat. For the acute studies, PCP hydrochloride (0.5-10.0 mg/kg s.c.) was administered and the subjects were sacrificed 15 to 300 min later. The acute administration of PCP produced rapid and long-lasting increases in plasma levels of adrenocorticotropin and corticosterone but decreased plasma levels of prolactin. For the chronic studies, PCP (1.0-20.0 mg/kg/day s.c.) was injected daily and the subjects sacrificed 60 min after injection on day 15. PCP continued to stimulate the pituitary-adrenal axis after chronic administration; however, there was a decrease in the magnitude of response, indicating the development of some degree of tolerance. In contrast, none of the doses of PCP tested decreased plasma prolactin levels in chronically treated subjects. There were no differences in plasma or brain levels of PCP in the chronically PCP-treated rats, indicating that tolerance was not due to changes in the biodisposition of PCP. These results indicate that PCP disrupts neuroendocrine function markedly in the rat. The differential development of tolerance to the effects of PCP on the pituitary-adrenal axis and prolactin release may indicate that different neurochemical substrates underlie the effects of PCP on different endocrine systems.

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Some of the dioxolanes produce pharmacological effects that have much in common with phencyclidine and phencyclidine-like drugs. Dioxadrol can be resolved into two enantiomers, dexoxadrol and levoxadrol. Dexoxadrol has an affinity for phencyclidine receptors that is much greater than that of levoxadrol, but dexoxadrol and levoxadrol have nearly equal affinities for sigma receptors. The systematic analysis of the relative potencies of dexoxadrol and levoxadrol can be used as an approach to define effects mediated by phencyclidine vs sigma receptors. Compounds that act on phencyclidine receptors, as well as affecting behavior, alter body temperature in the rat. The purpose of the present study was to compare and contrast the effects of the acute administration of dexoxadrol, levoxadrol, MK-801 and phencyclidine on body temperature in the rat. Dexoxadrol and levoxadrol (5.0, 10.0, 20.0 or 40.0 mg/kg), MK-801 (0.12, 0.6 or 1.2 mg/kg) or phencyclidine (5.0, 10.0 or 20.0 mg/kg) were administered subcutaneously and body temperature was measured. Both dexoxadrol and MK-801 produced hyperthermia but levoxadrol did not affect body temperature. In contrast to the hyperthermic effects of dexoxadrol and MK-801, phencyclidine produced hypothermia. These findings indicate that hypothermia induced by phencyclidine is not due to interactions with phencyclidine receptors and, while dexoxadrol, MK-801 and phencyclidine may share some similar receptor binding and behavioral characteristics, they can be differentiated on the basis of their effects on body temperature.

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The role of metabolism in the in vivo actions of phencyclidine (PCP) was examined by comparing deuterium-substituted drug with drug of normal isotopic abundance. PCP elicits two responses that differ in their time course, ataxia, which is observable immediately after dosage, and hypothermia, which peaks approximately 90 to 120 min after drug administration. The role of metabolism in these responses was determined by comparing bioavailabilities of deuterium enriched (d10) and normal (d0) PCP with the two responses. Plasma concentration was determined after the i.v. and i.p. administration of d10 and d0 drug and the bioavailability of the d10 was found to be 1.3 to 1.5 times the d0. The clearance of the d10 was also smaller than the d0. The d10, which is pharmacologically equivalent in vitro, is metabolized more slowly than the d0 in vitro. The pharmacokinetic and pharmacodynamic bioavailabilities exhibited comparable isotope effects, indicating that both responses are due to the actions of the parent drug.

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