European Journal of Pharmacology (v.430, #2-3)
Science Direct (III).
Inhibitory effect of bepridil on hKv1.5 channel current: comparison with amiodarone and E-4031 by Satoru Kobayashi; Yoshie Reien; Takehiko Ogura; Toshihiro Saito; Yoshiaki Masuda; Haruaki Nakaya (149-157).
Effects of bepridil on the depolarization-activated outward K+ currents (I out) in rat atrial myocytes and the human cardiac K+ (hKv1.5) channel current stably expressed in human embryonic kidney (HEK) 293 cells were examined, and compared with those of amiodarone and N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl] methanesulphonamide dihydrochloride dihydrate (E-4031). Membrane currents were recorded using patch-clamp techniques in enzymatically isolated rat atrial myocytes and HEK 293 cells expressing hKv1.5 channels. Bepridil potently inhibited I out elicited by depolarization pulses and prolonged the action potential in rat atrial cells. Bepridil also inhibited the hKv1.5 channel current with the IC50 value of 6.6 μM. The inhibitory effects of bepridil on the currents in HEK 293 cells were voltage-dependent. Amiodarone weakly inhibited rat atrial I out and hKv1.5 channel current. In contrast, E-4031 at a concentration of 10 μM had little influence on these currents. Thus, bepridil inhibits hKv1.5 channel current and the inhibitory effect may be useful for the treatment of atrial fibrillation.
Keywords: Antiarrhythmic agent; Ion channel; Membrane current; Repolarization;
Fungal metabolites, PF1092 compounds and their derivatives, are nonsteroidal and selective progesterone receptor modulators by Yuji Tabata; Yumiko Iizuka; Junko Kashiwa; Naomi Takei Masuda; Rie Shinei; Ken-ichi Kurihara; Tsuneo Okonogi; Shigeru Hoshiko; Yasushi Kurata (159-165).
The potential of new nonsteroidal progesterone receptor ligands, the derivatives of PF1092C ((4aR,5R,6R,7S)-6,7-dihydroxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) discovered from fungal metabolites, was evaluated. PF1092A ((4aR,5R,6R,7S)-6-acetoxy-7-hydroxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) showed good and moderate affinity for porcine and human progesterone receptors in in vitro receptor binding assays, respectively, and partial agonist activity for the progesterone receptor, as determined in assays of two types of progesterone-dependent enzymes in human mammary carcinoma T47D cells. The derivative of PF1092C, CP8481, ((4aR,5R,6R,7S)-6-(2-furancarbonyloxy)-7-hydroxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) possessed better affinity for both progesterone receptors and showed less cross-reactivity for other steroid receptors, such as rat androgen receptor, human glucocorticoid receptor, and human estrogen receptor, and was a more potent modulator of the progesterone receptor than PF1092A. CP8400 ((4aR,5R,6R,7S)-6,7-diacetoxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one) and CP8401 ((4aR,5R,6R,7S)-6,7-dipropionyloxy-4a,5,6,7-tetrahydro-3,4a,5-trimethylnaphtho[2,3-b]furan-2(4H)-one), other derivatives, were indicated to be progesterone receptor antagonists. These results suggest that PF1092 compounds can serve as a new pharmacophore for potent and specific nonsteroidal progesterone receptor modulators.
Keywords: PF1092; Progesterone receptor modulator; Progesterone receptor antagonist; Progesterone receptor agonist; Nonsteroidal; T47D;
High-affinity inhibition of glutamate release from corticostriatal synapses by ω-agatoxin TK by Jaime Barral; Francisco Poblette; Ernesto Mendoza; Juan C Pineda; Elvira Galarraga; José Bargas (167-173).
To know which Ca2+ channel type is the most important for neurotransmitter release at corticostriatal synapses of the rat, we tested Ca2+ channel antagonists on the paired pulse ratio. ω-Agatoxin TK was the most effective Ca2+ channel antagonist (IC50=127 nM; maximal effect=211% (with >1 μM) and Hill coefficient=1.2), suggesting a single site of action and a Q-type channel profile. Corresponding parameters for Cd2+ were 13 μM, 178% and 1.2. The block of L-type Ca2+ channels had little impact on transmission, but we also tested facilitation of L-type Ca2+ channels. The L-type Ca2+ channel agonist, s-(−)-1,4 dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridine carboxylic acid methyl ester (Bay K 8644 (5 μM)), produced a 45% reduction of the paired pulse ratio, suggesting that even if L-type channels do not participate in the release process, they may participate in its modulation.
Keywords: ω-Agatoxin TK; ω-Conotoxin GVIA; Synaptic transmission; Neostriatum; Ca2+ channel;
Modulation by estrogens and xenoestrogens of recombinant human neuronal nicotinic receptors by Ken Nakazawa; Yasuo Ohno (175-183).
The effects of estrogens and xenoestrogens on human neuronal nicotinic acetylcholine receptor/channels were examined by expressing recombinant channels in Xenopus oocytes. When functional channels were expressed with α3 and β4 subunits, estrogens (17β-estradiol, 17α-estradiol, 17α-ethynylestradiol and diethylstilbestrol) and xenoestrogens (bisphenol A, p-nonylphenol and p-octylphenol) inhibited an ionic current activated by acetylcholine at concentrations up to 100 μM. When the subunit combination was changed to α4β2, diethystilbestrol and the xenoestrogens inhibited the acetylcholine-activated current, but 17β-estradiol or 17α-estradiol did not. For 17α-ethynylestradiol, the current through the α4β2 receptor/channel was inhibited at 1 μM, but it was markedly enhanced at 10 and 100 μM. Tamoxifen (10 μM), an antiestrogen, itself inhibited the acetylcholine-activated current but did not antagonize the current modulations induced by the estrogens and the xenoestrogens. These and additional results suggest that human neuronal nicotinic acetylcholine receptors are the targets of non-genomic actions of estrogens and xenoestrogens.
Keywords: Nicotinic receptor; Estrogen; Xenoestrogen; Non-genomic action;
The effects of cyclopentane and cyclopentene analogues of GABA at recombinant GABAC receptors by Mary Chebib; Rujee K Duke; Robin D Allan; Graham A.R Johnston (185-192).
The pharmacological effects of the enantiomers of cis-3-aminocyclopentanecarboxylic acids ((+)- and (−)-CACP), the enantiomers of trans-3-aminocyclopentanecarboxylic acids ((+)- and (−)-TACP), and the enantiomers of 4-aminocyclopent-1-ene-1-carboxylic acids ((+)- and (−)-4-ACPCA) were studied on human homomeric ρ1 and ρ2 GABAC receptors expressed in Xenopus oocytes using two-electrode voltage clamp methods. These compounds are conformationally restricted analogues of γ-aminobutyric acid (GABA) held in a five-membered ring. (+)-TACP (EC50 (ρ1)=2.7±0.2 μM; EC50 (ρ2)=1.45±0.22 μM), (+)-CACP (EC50 (ρ1)=26.1±1.1 μM; EC50 (ρ2)=20.1±2.1 μM) and (−)-CACP (EC50 (ρ1)=78.5±3.5 μM; EC50 (ρ2)=63.8±23.3 μM) were moderately potent partial agonists at ρ1 and ρ2 GABAC receptors, while (−)-TACP (100 μM inhibited 56% and 62% of the current produced by 1 μM GABA at ρ1 and ρ2 receptors, respectively) was a weak partial agonist with low intrinsic activity at these receptors. In contrast, (+)-4-ACPCA (K i (ρ1)=6.0±0.1 μM; K i (ρ2)=4.7±0.3 μM) did not activate GABAC ρ1 and ρ2 receptors but potently inhibited the action of GABA at these receptors, while (−)-4-ACPCA had little effect as either an agonist or an antagonist. The affinity order at both GABAC ρ1 and ρ2 receptors was (+)-TACP>(+)-4-ACPCA≫(+)-CACP>(−)-CACP≫(−)-TACP≫(−)-4-ACPCA. This study shows that the cyclopentane and cyclopentene analogues of GABA affect GABAC receptors in a unique manner, defining a preferred stereochemical orientation of the amine and carboxylic acid groups when binding to GABAC receptors. This is exemplified by the partial agonist, (+)-TACP, and the antagonist, (+)-4-ACPCA.
Keywords: γ-Aminobutyric acid (GABA); GABAC receptor; Structure–activity relationship; Cyclopentane and cyclopentene analogues of GABA; Xenopus oocyte;
Cloning and functional pharmacology of two corticotropin-releasing factor receptors from a teleost fish by Sigrun Pohl; Mark G. Darlison; W.Craig Clarke; Karl Lederis; Dietmar Richter (193-202).
Although it is well established that fish possess corticotropin-releasing factor (CRF) and a CRF-like peptide, urotensin I, comparatively little is known about the pharmacology of their cognate receptors. Here we report the isolation and functional expression of two complementary DNAs (cDNAs), from the chum salmon Oncorhynchus keta, which encode orthologues of the mammalian and amphibian CRF type 1 (CRF1) and type 2 (CRF2) receptors. Radioligand competition binding experiments have revealed that the salmon CRF1 and CRF2 receptors bind urotensin I with ∼8-fold higher affinity than rat/human CRF. These two peptides together with two related CRF-like peptides, namely, sauvagine and urocortin, were also tested in cAMP assays; for cells expressing the salmon CRF1 receptor, EC50 values for the stimulation of cAMP production were between 4.5±1.8 and 15.3±3.1 nM. For the salmon CRF2 receptor, the corresponding values were: rat/human CRF, 9.4±0.4 nM; urotensin I, 21.2±2.1 nM; sauvagine, 0.7±0.1 nM; and urocortin, 2.2±0.7 nM. We have also functionally coupled the O. keta CRF1 receptor, in Xenopus laevis oocytes, to the endogenous Ca2+-activated chloride conductance by co-expression with the G-protein α subunit, Gα16. The EC50 value for channel activation by rat/human CRF (11.2±2.6 nM) agrees well with that obtained in cAMP assays (15.3±3.1 nM). We conclude that although sauvagine is 13- and 30-fold more potent than rat/human CRF and urotensin I, respectively, in activating the salmon CRF2 receptor, neither receptor appears able to discriminate between the native ligands CRF and urotensin I.
Keywords: Adenylate cyclase; Corticotropin-releasing factor receptor; Gα16; Urocortin; Urotensin I; Xenopus oocyte expression;
Activity of diadenosine polyphosphates at P2Y receptors stably expressed in 1321N1 cells by Kalpana Patel; Ashley Barnes; Janet Camacho; Clare Paterson; Robert Boughtflower; Diane Cousens; Fiona Marshall (203-210).
The selectivities of the diadenosine polyphosphates (Ap n As, n=2–6) at the human P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11 receptors stably expressed in 1321N1 human astrocytoma cells was determined using a Fluorescence Imaging Plate Reader (FLIPR) to measure intracellular Ca2+ mobilisation. The rank order of agonist potencies at P2Y1 were: ADP>P1,P3-diadenosine triphosphate (Ap3A)>P1,P3-diadenosine hexaphosphate (Ap6A)=P1,P3-diadenosine diphosphate (Ap2A)≫P1,P3-diadenosine pentaphosphate (Ap5A). P1,P3-diadenosine tetraphosphate (Ap4A) was inactive up to 1 mM. The rank order of agonist potencies at P2Y2 were: UTP>Ap4A≫Ap6A>Ap5A>Ap3A≫Ap2A. The Ap4A concentration response curve appeared to be bi-phasic. At P2Y4 all the Ap n As tested were inactive as agonists. At P2Y6, only Ap3A and Ap5A showed significant agonist activity. At P2Y11, only Ap4A showed significant agonist activity. Ap n As were inactive as antagonists of the P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11 receptors. At P2Y4, however, the Ap n As potentiated the UTP response.
Keywords: Diadenosine polyphosphate; P2Y receptor; FLIPR; G-protein coupled receptor;
Chronic administration of amitriptyline and caffeine in a rat model of neuropathic pain: multiple interactions by Michael J Esser; Teena Chase; Gary V Allen; Jana Sawynok (211-218).
This study was designed to determine (1) whether chronic amitriptyline administration was effective in alleviating symptoms of neuropathic pain in a rat model of spinal nerve injury, and (2) whether the effect of amitriptyline involved manipulation of endogenous adenosine, by determining the effect of caffeine, a non-selective adenosine A1 and A2 receptor antagonist, on its actions. Nerve injury was produced by unilateral spinal nerve ligation of the fifth and sixth lumbar nerves distal to the dorsal root ganglion, and this resulted in stimulus-evoked thermal hyperalgesia and static tactile mechanical allodynia. Animals received pre- and post-surgical intraperitoneal doses of amitriptyline (10 mg/kg) and caffeine (7.5 mg/kg), alone or in combination, and following surgery, were administered amitriptyline (15–18 mg/kg/day) and caffeine (6–8 mg/kg/day), alone or in combination, in the drinking water. Rats were tested for thermal reaction latencies and static tactile thresholds at 7, 14 and 21 days following surgery. In the paw ipsilateral to the nerve ligation, chronic amitriptyline administration consistently decreased the thermal hyperalgesia produced by spinal nerve ligation over a 3-week period, and this effect was blocked by concomitant caffeine administration at all time intervals. In the contralateral paw, thermal withdrawal latencies were more variable, with the most reproducible finding being a reduction in thermal thresholds in the amitriptyline–caffeine combination group. There was no effect by either drug or the drug combination on the static tactile allodynia produced by spinal nerve ligation in the ipsilateral paw. However, chronic amitriptyline administration induced a tactile hyperaesthesia in the contralateral paw at all time intervals, and this effect was exacerbated by concomitant chronic caffeine administration. The results of this study indicate that chronic administration of amitriptyline is effective in alleviating thermal hyperalgesia, but not static tactile allodynia, in the hindpaw ipsilateral to nerve injury, and the block of this effect by caffeine suggests that this effect is partially achieved through manipulation of endogenous adenosine systems. Additionally, chronic amitriptyline administration induces contralateral hyperaesthetic responses that are augmented by caffeine. Both the symptom-specific effect, and adenosine involvement in amitriptyline action may be important considerations governing its use in neuropathic pain.
Keywords: Amitriptyline; Caffeine; Adenosine; Neuropathic pain; Chronic administration;
GV196771A, an NMDA receptor/glycine site antagonist, attenuates mechanical allodynia in neuropathic rats and reduces tolerance induced by morphine in mice by Mauro Quartaroli; Nicola Fasdelli; Letizia Bettelini; Gabriella Maraia; Mauro Corsi (219-227).
The effects of the N-methyl-d-aspartate (NMDA) receptor/glycine site antagonist, GV196771A (E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid sodium salt), on mechanical allodynia and on tolerance to the antinociceptive effects induced by morphine were evaluated. Its antiallodynic properties were studied in a model of chronic constriction injury applied to rat sciatic nerve. GV196771A (0.3–10 mg/kg, p.o.) dose-dependently inhibited established mechanical allodynia when tested 14 or 21 days after nerve ligation. In the formalin test in mice, GV196771A (10 or 20 mg/kg, p.o.), administered for 8 days together with morphine 10 mg/kg, i.p. inhibited morphine tolerance development in both early and late phases of the test. This finding reinforces the key role of the NMDA receptors in the plastic event, such as allodynia, which develops in some conditions of painful neuropathy. Moreover, the capability to strongly reduce morphine-induced tolerance suggests that GV196771A could be an alternative agent for the treatment of difficult pain states not only when given alone, but also in combination, in order to prolong the analgesic effects of the opiates.
Keywords: NMDA receptor/glycine site antagonist; Chronic constrictive injury; Mechanical allodynia; Opioid; Tolerance; GV196771A;
Antinociceptive effect of the novel compound OT-7100 in a diabetic neuropathy model by Shinya Miki; Norihiro Yoshinaga; Takeshi Iwamoto; Tsuneo Yasuda; Seiji Sato (229-234).
We previously reported that OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-α]pyrimidine) had antinociceptive potency in various animal models. To further characterize this compound, the present study examined the effects of OT-7100 on mechanical hyperalgesia and motor nerve conduction velocity in streptozotocin-induced diabetic rats. OT-7100 significantly increased the nociceptive threshold in the diabetic rat in a dose-dependent manner. Gabapentin (anticonvulsant agent) and insulin strongly increased the nociceptive threshold but gabapentin increased it above normal levels. An aldose reductase inhibitor slightly increased the nociceptive threshold at a high dose. We also measured glucose levels and motor nerve conduction velocity in OT-7100-treated rats. Insulin decreased glucose levels but OT-7100 had no effect on glucose levels or on motor nerve conduction velocity. These results suggest that OT-7100 alleviates hyperalgesia in a diabetic neuropathy model in a different manner from gabapentin or aldose reductase inhibitor and may be a new treatment for the pain associated with peripheral nerve injury.
Keywords: OT-7100; Pain; Diabetic neuropathy; Streptozotocin;
(−)-d-Deprenyl attenuates apoptosis in experimental brain ischaemia by László Simon; Géza Szilágyi; Zoltán Bori; Péter Orbay; Zoltán Nagy (235-241).
(−)-d-Deprenyl protects neurons from oxidative damage and helps to maintain the mitochondrial membrane potential by influencing intracellular anti-apoptotic oncoproteins, such as Bcl-2. The cellular rescue in the penumbra region by (−)-d-deprenyl administration was examined after permanent middle cerebral artery occlusion in rats. (−)-d-Deprenyl was given continuously following permanent middle cerebral artery occlusion. Two days later, the rats were killed and their infarct volumes were determined. Coronal brain sections were stained with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate deoxyribonucleic acid (DNA) nick-end labelling (TUNEL) and caspase-3, TUNEL and anti-neuronal nuclei (NeuN) double labelling. Neural plasticity was characterized by growth-associated protein-43 (GAP-43) immunohistochemistry. A 1000×1000-μm region was sampled at both cortical margins of the TUNEL-positive area at its borders. The numbers of TUNEL-labelled and TUNEL–caspase-3-labelled cells decreased significantly. (−)-d-Deprenyl treatment increased the number of GAP-43-positive cells. We conclude that (−)-d-deprenyl reduced the number of affected cells and induced neuronal plasticity.
Keywords: (−)-d-Deprenyl; Middle cerebral artery occlusion; Apoptosis; TUNEL;
Ovariectomy aggravates convulsions and hippocampal γ-aminobutyric acid inhibition induced by cyclosporin A in rats by Koji Tominaga; Atsushi Yamauchi; Hideki Shuto; Midori Niizeki; Kazutaka Makino; Ryozo Oishi; Yasufumi Kataoka (243-249).
The possible cyclosporin A application for rheumatoid arthritis that develops preferentially in middle-aged women raises concerns about adverse effects of cyclosporin A, including neurotoxicity in patients with climacterium. The present study was aimed at elucidating the effect of cyclosporin A on the convulsive activity and γ-aminobutyric acid (GABA) neural activity of the hippocampus in ovariectomized rats, as a menopause/climacterium model. Ovariectomy markedly aggravated the effect of repeated administration of cyclosporin A (40 mg/kg, once a day for 5 or 6 days), convulsions and reduction of the basal GABA levels and aminooxyacetic acid-evoked GABA accumulation. These aggravations were blocked by estradiol replacement. The present findings demonstrated that ovariectomy increased the susceptibility to cyclosporin A-induced convulsions by accelerating an inhibitory action of cyclosporin A on GABA neural activity in the hippocampus, this being blocked by estrogen replacement. Menopause/climacterium is, therefore, included in the risk factors for cyclosporin A-induced neurotoxicity and this risk is lowered by estrogen replacement therapy.
Keywords: Cyclosporin A; Ovariectomy; Convulsion; γ-Aminobutyric acid (GABA); Menopause; Climacterium;
AMPA and GABAB receptor antagonists and their interaction in rats with a genetic form of absence epilepsy by Rafał M Kamiński; Clementina M Van Rijn; Waldemar A Turski; Stanisław J Czuczwar; Gilles Van Luijtelaar (251-259).
The effects of combined and single administration of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 7,8-methylenedioxy-1-(4-aminophenyl)-4-methyl-3-acetyl-4,5-dihydro-2,3-benzodiazepine (LY 300164), and of the GABAB receptor antagonist γ-aminopropyl-n-butyl-phosphinic acid (CGP 36742), on spontaneously occurring spike-wave discharges were investigated in WAG/Rij rats. LY 300164 had minor effects; only the highest dose (16 mg/kg) reduced the number of spike-wave discharges in a short time window. CGP 36742 was more effective as it significantly reduced the number of spike-wave discharges and shortened their duration at the doses of 25 and 100 mg/kg. The ED50 values for the inhibition of spike-wave discharges by LY 300164 and CGP 36742 in a time window 30–60 min after injection were 15.5 and 16.6 mg/kg, respectively. The ED50 of CGP 36742 was reduced to 8.0 mg/kg when this antagonist was administered in combination with LY 300164 (6 mg/kg). The interaction between the two antagonists appeared to be additive according to isobolographic analysis. Importantly, CGP 36742 and LY 300164 administered either alone or in combination had no apparent effects on behavior. These results may provide information for a rational approach to polytherapy for the treatment of generalized absence epilepsy.
Keywords: CGP 36742; LY 300164; AMPA/kainate receptor; GABAB receptor; Absence epilepsy; WAG/Rij; Isobologram;
γ-Hydroxybutyric acid and baclofen decrease extracellular acetylcholine levels in the hippocampus via GABAB receptors by Felice Nava; Giovanna Carta; Marco Bortolato; Gian Luigi Gessa (261-263).
The effect of γ-hydroxybutyric acid (GHB) and baclofen, a GABAB receptor agonist, on extracellular hippocampal acetylcholine levels was studied in freely moving rats by microdialysis. GHB (200 and 500 mg/kg, i.p.) reduced in a dose-dependent manner, extracellular hippocampal acetylcholine concentrations and this effect was prevented by the GABAB receptor antagonist (2S)(+)-5,5-Dimethyl-2-morpholineacetic acid (SCH 50911), at the dose of 20 mg/kg (i.p.), while the putative GHB receptor antagonist 6,7,8,9-Tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS 382) was ineffective. Similar to GHB, the GABAB agonist baclofen (10 and 20 mg/kg, i.p.) produced a dose-related reduction in extracellular acetylcholine concentrations which was prevented by SCH 50911. These findings indicate that GHB-induced reduction of hippocampal acetylcholine release is mediated by GABAB receptors and support a possible involvement of hippocampal GABAB receptors in the control of cognitive processes and in the claimed amnesic effect of GHB intoxication.
Keywords: Microdialysis; Baclofen; GHB (γ-hydroxybutyric acid); SCH 50911; Acetylcholine; Hippocampus; GABAB receptor;
Involvement of serotonergic and dopaminergic mechanisms in hyperthermia induced by a serotonin-releasing drug, p-chloroamphetamine in mice by Yumi Sugimoto; Minako Ohkura; Kiyo Inoue; Jun Yamada (265-268).
Serotonergic and dopaminergic involvement in hyperthermia induced by a serotonin (5-hydroxytryptamine, 5-HT)-releasing drug, p-chloroamphetamine, was investigated in mice. Neither the 5-HT transporter inhibitor fluoxetine nor the 5-HT depleter p-chlorophenylalanine affected p-chloroamphetamine-induced hyperthermia. The dopamine depleter α-methyl-p-tyrosine significantly reduced p-chloroamphetamine-induced hyperthermia. The dopamine D1 receptor antagonist 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) antagonized p-chloroamphetamine-induced hyperthermia, although the dopamine D2 receptor antagonist sulpiride was without effect. These results indicate that p-chloroamphetamine-induced hyperthermia in mice is mediated by dopamine release followed by activation of the dopamine D1 receptor.
Keywords: p-Chloroamphetamine; Hyperthermia; 5-HT (5-hydroxytryptamine, serotonin); Dopamine; Dopamine D1 receptor; Dopamine D2 receptor; (Mouse);
Effects of cocaine- and amphetamine-regulated transcript peptide, leptin and orexins on hypothalamic serotonin release by Giustino Orlando; Luigi Brunetti; Chiara Di Nisio; Barbara Michelotto; Lucia Recinella; Giovanni Ciabattoni; Michele Vacca (269-272).
We have studied the effects of cocaine- and amphetamine-regulated transcript (CART) peptide-(55–102), leptin, orexin-A and orexin-B on basal and depolarization (K+ 15 mM)-induced serotonin (5-hydroxytryptamine, 5-HT) release from rat hypothalamic neuronal endings (synaptosomes) in vitro. We have found that leptin and CART peptide-(55–102) have no effect on 5-HT release, while orexin-A and orexin-B inhibit depolarization-stimulated serotonin release. We can conclude that leptin and CART peptide-(55–102), which play a physiological role as feeding inhibitors, do not acutely affect 5-HT release from hypothalamic synaptosomes; on the other hand, feeding induced by orexin-A and orexin-B could be partially explained by decreased 5-HT release.
Keywords: CART (cocaine- and amphetamine-regulated transcript); Leptin; Orexin; Fenfluramine; Hypothalamus; 5-HT (5-hydroxytryptamine, serotonin);
The neuropeptide FF analogue, 1DMe, acts as a functional opioid autoreceptor antagonist in the rat spinal cord by Annie Mauborgne; Sylvie Bourgoin; Harry Poliénor; Michel Roumy; Guy Simonnet; Jean-Marie Zajac; François Cesselin (273-276).
We assessed the possible influence of a neuropeptide FF analogue, 1DMe ([d-Tyr1,(NMe)Phe3]neuropeptide FF), on the inhibitory action of endogenous and exogenous ∂-opioid receptor agonists on K+-evoked [Met5]-enkephalin release from superfused rat spinal cord slices. 1DMe (0.1–10 μM) dose-dependently enhanced the increase in superfusate [Met5]-enkephalin content due to the peptidase inhibitors thiorphan (1 μM) and bestatin (20 μM), and prevented the reduction in [Met5]-enkephalin release due to stimulation of ∂ receptors by 1 μM deltorphin I. Because it had the same effects as ∂-opioid receptor antagonists, 1DMe might act through the functional blockade of presynaptically located ∂-opioid autoreceptors.
Keywords: [Met5] enkephalin; In vitro release; Neuropeptide FF; Spinal cord; Opioid receptor ligand; Peptidase inhibitor;
Involvement of corticotropin-releasing factor receptor subtype 1 in morphine withdrawal regulation of the brain noradrenergic system by Masahiko Funada; Chiaki Hara; Kiyoshi Wada (277-281).
Effects of pretreatment with the selective corticotropin-releasing factor (CRF) subtype 1 (CRF1) receptor antagonist, 2-(N-(2-methylthio-4-isopropylphenyl)-N-ethyl-amino-4-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine (CRA1000) on the behavioral and biochemical changes after naloxone-precipitated morphine withdrawal were examined in ICR mice. Mice were chronically treated with morphine (8–45 mg/kg) for 5 days. Naloxone (3 mg/kg, s.c.) precipitated jumping, diarrhea, and body weight loss in morphine-dependent mice. In addition, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and noradrenaline turnover (MHPG/noradrenaline) levels in the cerebral cortex were increased following naloxone challenge in morphine-dependent mice. However, 5-hydroxytriptamine turnover did not alter the increase following naloxone challenge in morphine-dependent mice. Pretreatment with CRA1000 (20 mg/kg, i.p.) attenuated the incidence of withdrawal signs and naloxone-precipitated increases in noradrenaline turnover. These results suggest that the activation of CRF1 receptor may play an important role in the elevation of noradrenaline transmission, but not in 5-hydroxytriptamine transmission, in the cerebral cortex, which projects from the locus coeruleus during morphine withdrawal.
Keywords: Corticotropin-releasing factor (CRF); Dependence; Morphine; Noradrenaline;
Involvement of cholinergic and glutamatergic functions in working memory impairment induced by interleukin-1β in rats by Yuji Matsumoto; Mayuki Yoshida; Shigenori Watanabe; Tsuneyuki Yamamoto (283-288).
Interleukin-1β at doses of 32 and 100 ng/side, injected bilaterally into the dorsal hippocampus of rats, significantly increased the working memory errors in a three-panel runway setup, whereas interleukin-1β at doses affecting working memory errors had no effect on the number of errors in the first trial or the latency. The increase in working memory errors induced by intrahippocampal administration of 100 ng/side interleukin-1β was significantly decreased by concurrent injection (300 ng/side) of the interleukin-1 receptor antagonist. The cholinesterase inhibitor physostigmine at a dose of 3.2 μg/side and d-cycloserine (1.0 and 10 μg/side), which is a partial agonist acting at the glycine binding site of the NMDA receptor/channel complex, reduced the increase in working memory errors induced by 100 ng/side interleukin-1β. These results suggest that interleukin-1β causes disruptions of septohippocampal cholinergic and glutamatergic transmission via its high-affinity receptor, which underlie the impairment of working memory.
Keywords: Interleukin-1β; Working memory; Acetylcholine; N-methyl-d-aspartate receptor; Hippocampus;
Effects of adenosine receptor agonists and antagonists on pentylenetetrazole-induced amnesia by Houman Homayoun; Simin Khavandgar; Mohammad Reza Zarrindast (289-294).
The effect of adenosine agents on amnesia induced by pentylenetetrazole was examined in mice. Post-training administration of pentylenetetrazole (50 and 60 mg/kg) disrupted 24-h retention of a single-trial passive avoidance task. The adenosine receptor antagonists, theophylline (2.5–25 mg/kg) and 8-phenyltheophylline (0.5–2 mg/kg), administered 30 min before and just after training at doses which did not affect retention, reduced the amnestic effect of pentylenetetrazole in a dose-dependent manner. Post-training administration of the adenosine A1 receptor agonists, N 6-cyclohexyladenosine (CHA, 0.1 and 0.5 mg/kg) and N 6-phenylisopropyladenosine (R-PIA, 0.03 and 0.1 mg/kg), but not the adenosine A2 receptor agonist, 5′-N-ethylcarboxamidoadenosine (NECA, 0.01 and 0.001 mg/kg), impaired retention. Nonamnestic doses of CHA and R-PIA potentiated the disruption induced by a lower dose of pentylenetetrazole (40 mg/kg). NECA did not induce any response in this respect. It is suggested that an adenosine A1 receptor mechanism is involved in amnesia induced by pentylenetetrazole.
Keywords: Adenosine; Pentylenetetrazole; Passive avoidance; Amnesia; (Mouse);
Possible involvement of prostaglandins in haloperidol-induced orofacial dyskinesia in rats by Pattipati S Naidu; Shrinivas K Kulkarni (295-298).
Dopaminergic abnormality is one of the pathological mechanisms involved in the pathophysiology of tardive dyskinesia, a late complication of neuroleptic treatment. Prostaglandins modulate the dopamine release in the striatum, the principle area involved in the pathophysiology of tardive dyskinesia. Rats were chronically treated with haloperidol (HPD) (1.5 mg/kg) for a period of 21 days, to induce orofacial dyskinesia. Behavioural assessment of orofacial dyskinesia was done 24 h after the last dose of haloperidol. Catalepsy was induced in rats by acute treatment with haloperidol (1 mg/kg), and catalepsy was scored for the next 4 h. Chronic haloperidol treatment induced profound vacuous chewing movements in rats. Indomethacin, a nonselective cyclooxygenase inhibitor dose-dependently (5–20 mg/kg) suppressed the vacuous chewing movements count in haloperidol-treated animals. In conclusion, the results of the present study infer that prostaglandins might play a significant role in the haloperidol-induced vacuous chewing movements, and prostaglandin synthesis inhibitors can serve as novel drug candidates for the treatment of tardive dyskinesia.
Keywords: Tardive dyskinesia; Dopamine; Indomethacin; Prostaglandin; Vacuous chewing movement;
FK506 does not affect cardiac contractility and adrenergic response in vitro by Hendrik Milting; Paul M.L Janssen; Thekla Wangemann; Harald Kögler; Erik Domeier; Tim Seidler; Kavous Hakim; Martin Grapow; Oliver Zeitz; Jürgen Prestle; Hans-Reinhard Zerkowski (299-304).
FK506 (tacrolimus) is a new immunosuppressant being used in cardiac allograft transplantation. While cyclosporine A has been shown to exert an acute negative inotropic effect on isolated heart muscle preparations, little is known of the inotropic influence of FK506. The Ca2+ release channel of human skeletal muscle and cardiac muscle is associated with FK506 binding proteins (FKBP), FKBP12 and FKBP12.6, respectively. FKBPs can be dissociated by treatment with FK506. As a consequence of FK506 exposure, isolated skeletal muscle and cardiac muscle ryanodine receptors show altered gating characteristics. Therefore, we analyzed the direct inotropic effect of FK506 exposure to isolated, intact heart muscle preparations from the human and rabbits. Experiments were performed on isolated, electrically stimulated right atrial auricular muscle strips obtained from human myocardium during elective open heart surgery and on intact right ventricular trabeculae from rabbit hearts. The human preparations were exposed to concentrations of 8×10−9, 8×10−8 and 8×10−6 M FK506 followed by a cumulative dose–response curve with isoprenaline as a non-selective β-adrenoceptor agonist. Our data suggest that FK506 does not exert any positive or negative inotropic effect in either human or rabbit myocardium.
Keywords: FK506; Immunophilin; Ryanodine receptor; Excitation–contraction coupling; FK506 binding protein (FKBP);
Absence of mast cell involvement in active systemic anaphylaxis in rats by Yancai Guo; Per Hedqvist; Lars E Gustafsson (305-310).
This study investigates the role of mast cells in the hypotension induced by antigen-mediated anaphylaxis, compound 48/80 and dextran in mast cell-deficient white spotting (Ws/Ws) and normal wild type (+/+) rats. Rats were sensitized with 10 μg of intraperitoneal ovalbumin in saline or saline alone (sham-sensitized). Sensitized rats, both Ws/Ws and +/+ but not sham-sensitized rats, challenged intravenously with ovalbumin exhibited hypotensive responses. There was no evidence of mast cell activation in rat mesentery 20 min after intravenous antigen challenge in sensitized +/+ rats. Hypotension induced by intravenous injection of dextran (Dextran-162, 6%, 2 ml kg−1) or compound 48/80 (1 mg kg−1) occurred in +/+ rats, but not in Ws/Ws rats, and was inhibited by pretreatment with a combination of chlorpheniramine and cimetidine. Taken together, these data indicate that the hypotensive response induced by antigen-mediated anaphylaxis is independent of mast cell activation, whereas mast cell amines play the main role in the hypotensive response induced by dextran or compound 48/80.
Keywords: Anaphylaxis; Histamine; Mast cell-deficient (Ws/Ws), rat;
Comparison of responses to novel nitric oxide donors in the feline pulmonary vascular bed by Bracken J De Witt; James R Marrone; Alan D Kaye; Larry K Keefer; Philip J Kadowitz (311-315).
Pulmonary vascular responses to the novel diazeniumdiolate nitric oxide (NO) donors diethylamine/NO, diethylenetriamine/NO, spermine/NO, sulfite/NO, and angeli's salt, were investigated and compared in the intact-chest cat. Under conditions of controlled blood flow, when tone in the pulmonary vascular bed had been raised to a high steady level, intralobar injections of diethylamine/NO (0.3–10 μg), diethylenetriamine/NO (10–30 μg), spermine/NO (10–30 μg), sulfite/NO (10–30 μg), and angeli's salt (10–30 μg) caused dose-related decreases in lobar arterial pressure without changing left atrial pressure. In terms of relative vasodilator activity in the pulmonary vascular bed, the dose of the compounds that decreased lobar arterial pressure 4 mm Hg (ED4 mm Hg) was significantly lower for diethylamine/NO compared to S-nitroso-N-acetylpenicillamine which was significantly less than diethylenetriamine/NO, spermine/NO, sulfite/NO, and angeli's salt. The half-life of the vasodilator responses, as measured by 50% response recovery time, to diethylamine/NO, diethylenetriamine/NO, spermine/NO, sulfite/NO, and angeli's salt was similar for doses with similar magnitudes of vasodilation, while the half-life to S-nitroso-N-acetylpenicillamine was significantly less than the diazeniumdiolate NO donors. The present data demonstrate that the diazeniumdiolate NO donors diethylamine/NO, diethylenetriamine/NO, spermine/NO, sulfite/NO, and angeli's salt have potent but relatively short-lasting vasodilator activity in the pulmonary vascular bed of the cat.
Keywords: Cat; Circulation; Diazeniumdiolate; Diethylamine/NO; Diethylenetriamine/NO; Spermine/NO; Sulfite/NO; Angeli's salt;
Protective effects of nitroglycerin-induced preconditioning mediated by calcitonin gene-related peptide in rat small intestine by Ying Dun; Yi-Bin Hao; Yu-Xiu Wu; Yi Zhang; Rong-Rui Zhao (317-324).
Previous studies of myocardium have shown that ischemic preconditioning could be mimicked by nitroglycerin through stimulating the release of calcitonin gene-related peptide (CGRP). The present study examined whether nitroglycerin could also provide a preconditioning stimulus in the peripheral vascular bed (the anse intestinalis of rat), and whether endogenous CGRP is involved in this process. The model of in situ perfusion was prepared with rat small intestine. One hour of ischemia and 15 min of reperfusion caused a significant impairment of intestinal morphology and an increase in the release of both lactate dehydrogenase and malondialdehyde. Pretreatment with nitroglycerin, 10−7, 3×10−7, 10−6 M for 5 min produced a significant improvement of intestinal tissue morphology and a decrease in the release of both lactate dehydrogenase and malondialdehyde. However, the protection afforded by nitroglycerin was abolished by CGRP-(8-37), a selective CGRP acceptor antagonist. Pretreatment with capsaicin, which specifically depletes the transmitter content of sensory nerves, also abolished the protection by nitroglycerin. In addition, the content of CGRP-like immunoreactivity in the effluent was increased during nitroglycerin perfusion. On the other hand, the results from the in vivo experiment showed that nitroglycerin (i.v. 0.13 mg/kg) injected 5 min before prolonged ischemia could provide significant protection against the injury caused by 30-min ischemia and 1-h reperfusion in the rat small intestine, but would also cause a significant increase in the levels of CGRP in the plasma. All these findings suggest that nitroglycerin-induced preconditioning is related to stimulation of CGRP release in the rat small intestine.
Keywords: Nitroglycerin; Preconditioning; CGRP (calcitonin gene-related peptide); CGRP-(8-37); Capsaicin; Small intestine;
Relaxation and modulation of cyclic AMP production in response to atrial natriuretic peptides in guinea pig tracheal smooth muscle by Philippe Devillier; Emmanuelle Corompt; Didier Bréant; Françoise Caron; Germain Bessard (325-333).
Relaxation and modulation of cyclic AMP production in response to atrial natriuretic peptides were investigated in epithelium-denuded guinea pig tracheal rings, treated with indomethacin (5 μM) and phosphoramidon (1 μM) and contracted with histamine (3 μM). Atrial natriuretic peptide (ANP) was a more potent relaxant than C-type natriuretic peptide whereas ANP-(4–23) was inactive suggesting the involvement of ANPA receptors in the relaxant effect of ANP. ODQ (1H-[1,2,4]oxadiazolo[4,3-A]quinoxalin-1-one, 10 μM), a selective inhibitor of soluble guanylyl cyclase, markedly inhibited the relaxant response to sodium nitroprusside. The relaxant response to ANP was not altered by ODQ demonstrating the involvement of particulate guanylyl cyclase. ANP-induced relaxations, as well as sodium nitroprusside-induced relaxations, were similarly potentiated by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one, 3 μM), a type IV phosphodiesterase inhibitor, and by zaprinast (2-(2-propyloxyphenyl)-8-azapurin-6-one, 10 μM), a type V phosphodiesterase inhibitor. ANP-mediated response was unaffected by glibenclamide (10 μM), a selective blocker of ATP-sensitive K+ channels, and by apamin (1 μM), a selective blocker of small-conductance Ca2+-activated K+ channels. Iberiotoxin (100 nM) extensively prevented the relaxant effect of ANP suggesting the activation of large-conductance Ca2+-activated K+ channels. In addition, ANP (10 nM) and ANP-(4–23) (100 nM) significantly reduced forskolin (1 μM)-stimulated cAMP accumulation suggesting, for the first time, the presence of functional ANPC receptors in guinea pig airway smooth muscle. However, relaxations to forskolin and to isoproterenol were not altered in the presence of ANP-(4–23) or ANP demonstrating that the inhibitory effect of ANP-(4–23) and ANP on adenylyl cyclase was not sufficient to alter the functional response induced by these two activators of adenylyl cyclase.
Keywords: Airway; Smooth muscle; Trachea; ANP (atrial natriuretic peptide); ANP receptor; Guanylyl cyclase; Adenylyl cyclase; K+ channel; Phosphodiesterase inhibitor;
Bronchodilating properties of the VIP receptor agonist Ro 25-1553 compared to those of formoterol on the guinea-pig isolated trachea by Britt-Louise Källström; Bertil Waldeck (335-340).
Ro 25-1553 is a 31-amino acid analogue of vasoactive intestinal peptide (VIP) and has recently been shown to be highly selective for the VPAC2-receptor. The bronchodilating property of this compound was evaluated in vitro on preparations of guinea-pig trachea, with the long-acting β2-adrenoceptor selective agonist, formoterol, as a reference. In strip-preparations precontracted with carbachol, Ro 25-1553 caused a concentration-dependent and complete relaxation of the tracheal smooth muscle. Ro 25-1553 was 3–7 times less potent than formoterol on a molar basis, but the efficacy was comparable with that of formoterol. Both compounds showed a rapid onset of action and a similar durability of effect. Ro 25-1553 appeared to interact with formoterol as well as with salmeterol in an additive way. In vagus nerve-trachea tube preparations, when added to the external medium, Ro 25-1553 concentration-dependently and completely inhibited nerve-induced contractions. This occurred in the same concentration range as needed for relaxation of precontracted strips. Ro 25-1553 was active also when administered into the tracheal lumen albeit the concentration had to be increased. The present study supports and extends previous results suggesting that Ro 25-1553 may be a powerful alternative to the β2-adrenoceptor agonists which prevail today.
Keywords: Ro 25-1553; Formoterol; Salmeterol; Bronchodilator; Trachea; (Guinea-pig); In vitro;
Potent antagonism of 5-HT3 and 5-HT6 receptors by olanzapine by Frank P Bymaster; Julie F Falcone; Delbert Bauzon; John S Kennedy; Kathryn Schenck; Neil W DeLapp; Marlene L Cohen (341-349).
The interaction of the psychotropic agent olanzapine with serotonin 5-HT3 and 5-HT6 receptors was investigated. Olanzapine did not contract the isolated guinea pig ileum, but blocked contractions induced by the 5-HT3 receptor agonist 2-methyl serotonin (2-CH3 5-HT) with a pK B value of 6.38±0.03, close to the affinity of the 5-HT3 receptor antagonist ondansetron. The atypical antipsychotic risperidone (1 μM) did not significantly inhibit 2-CH3 5-HT-induced contractions. Olanzapine had high affinity (pK i=8.30±0.06) for human 5-HT6 receptors in radioligand binding studies. Olanzapine did not stimulate [35S]guanosine-5′-O-(3-thio)triphosphate ([35S]GTPγS) binding to the G protein Gs in cells containing human 5-HT6 receptors, but inhibited 5-HT-stimulated [35S]GTPγS binding (pK B=7.38±0.16). Among other antipsychotics investigated, clozapine antagonized 5-HT6 receptors with a pK B=7.42±0.15, ziprasidone was three-fold less potent, and risperidone, quetiapine and haloperidol were weak antagonists. Thus, olanzapine was not an agonist, but was a potent antagonist at 5-HT6 receptors and had marked antagonism at 5-HT3 receptors.
Keywords: Olanzapine; Risperidone; Quetiapine; Ziprasidone; 5-HT3 receptor; 5-HT6 receptor;
Melatonin and N-acetylserotonin inhibit leukocyte rolling and adhesion to rat microcirculation by Celina M.C Lotufo; Cristiane Lopes; Margarita L Dubocovich; Sandra H.P Farsky; Regina P Markus (351-357).
The hormone melatonin produced by the pineal gland during the daily dark phase regulates a variety of biological processes in mammals. The aim of this study was to determine the effect of melatonin and its precursor N-acetylserotonin on the microcirculation during acute inflammation. Arteriolar diameter, blood flow rate, leukocyte rolling and adhesion were measured in the rat microcirculation in situ by intravital microscopy. Melatonin alone or together with noradrenaline did not affect the arteriolar diameter or blood flow rate. Melatonin inhibited both leukocyte rolling and leukotriene B4 induced adhesion while its precursor N-acetylserotonin inhibits only leukocyte adhesion. The rank order of potency of agonists and antagonist receptor selective ligands suggested that the activation of MT2 and MT3 melatonin binding sites receptors modulate leukocyte rolling and adhesion, respectively. The effect of melatonin and N-acetylserotonin herein described were observed with concentrations in the range of the nocturnal surge, providing the first evidence for a possible physiological role of these hormones in acute inflammation.
Keywords: Inflammation; Microcirculation; Melatonin; Melatonin receptor; N-acetylserotonin;
Effects of losartan in combination with or without exercise on insulin resistance in Otsuka Long–Evans Tokushima Fatty rats by Keisuke Ishizawa; Masanori Yoshizumi; Koichiro Tsuchiya; Eiko Takishita; Yutaka Nakaya; Kazuhiro Kishi; Yousuke Ebina; Hitoshi Houchi; Kazuo Minakuchi; Toshiaki Tamaki (359-367).
Hypertension often complicates type 2 diabetes mellitus, and angiotensin converting enzyme inhibitor treatment has been shown to improve insulin resistance in such cases. However, the effect of angiotensin II type-1 (AT1) receptor antagonists on insulin resistance is still controversial. To gain further information on this effect, we examined the effect of losartan on insulin resistance in Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus. Losartan administration alone lowered systolic blood pressure, but did not improve oral glucose tolerance test or insulin resistance in OLETF rats. However, the administration of losartan with exercise significantly improved both systolic blood pressure and insulin resistance relative to control OLETF rats. On the other hand, losartan treatment, regardless of exercise, increased glucose uptake in excised soleus muscle and fat cells. To explore the beneficial effect of losartan on skeletal muscle glucose uptake, we examined intracellular signaling of soleus muscle. Although Akt activity and glucose transporter type 4 (GLUT4) expressions were not affected by losartan with or without exercise, extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein (MAP) kinase activities were increased by both interventions. These results indicate that angiotensin AT1 receptor antagonist improved local insulin resistance, but not systemic insulin resistance. These findings may explain the controversy over the effect of angiotensin AT1 receptor antagonists on insulin resistance in clinical use. The enhancing effect of angiotensin AT1 receptor antagonist on skeletal muscle glucose uptake may be attributable to MAP kinase activation or other mechanisms rather than phosphatidylinositol 3-kinase activation.
Keywords: Insulin resistance; Angiotensin; MAP (mitogen-activated protein) kinase; OLETF (Otsuka Long–Evans Tokushima Fatty);
The cannabinoid receptor antagonist SR 141716 prevents acquisition of drinking behavior in alcohol-preferring rats by Salvatore Serra; Mauro A.M Carai; Giuliana Brunetti; Raquel Gomez; Samuele Melis; Giovanni Vacca; Giancarlo Colombo; Gian Luigi Gessa (369-371).
The cannabinoid CB1 receptor antagonist, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide) (SR 141716); 0.3–3 mg/kg, i.p., twice daily for 10 days), prevented the acquisition of alcohol drinking behavior in rats genetically selected for alcohol preference (Sardinian alcohol-preferring (sP) rats), having the free choice between alcohol (10%, v/v) and water. The results suggest that activation of cannabinoid CB1 receptors is essential for the acquisition of alcohol drinking behavior in animals with a genetically determined alcohol preference.
Keywords: Cannabinoid CB1 receptor antagonist; Alcohol intake; Sardinian alcohol-preferring (sP) rat;
Treatment with dehydroepiandrosterone sulfate increases NMDA receptors in hippocampus and cortex by Shao Wen; Kai Dong; Jean Philippe Onolfo; Monique Vincens (373-374).
Our aim was to investigate if the memory-enhancing effects reported for dehydroepiandrosterone sulfate in rodents could be mediated through modulation of NMDA receptors. Using autoradiography we studied the effect of dehydroepiandrosterone sulfate, administered for 5 days (30 mg/kg, i.p. twice a day), on NMDA binding sites labelled with [3H]dizocilpine ([3H]MK801) in rat brain. Dehydroepiandrosterone sulfate treatment significantly increased the [3H]MK801 binding sites in hippocampal areas (field CA1, CA3, dentate gyrus lateral blade and medial blade) and in cortex layer IV as compared to the control group. These results demonstrate for the first time the ability of dehydroepiandrosterone sulfate to increase the number of NMDA binding sites in rat brain, an action that could be of interest for therapeutic application.
Keywords: Dehydroepiandrosterone sulfate; NMDA receptor; Brain; (Rat);
Author index (375-378).
Keyword index (379-386).