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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of a benzoyl-piperidine drug (BDP) that facilitates AMPA receptor-mediated synaptic responses were tested on the acquisition and retention of long-term memory at dosages that had no detectable effects on a variety of performance measures. BDP-12 produced a dose-dependent suppression of exploratory activity in rats with statistically reliable effects occurring at 50 mg/kg (i.p.). The drug had no effects on balance beam performance at 30 mg/kg but at 45 mg/kg reduced the number of crossings made within a session; it did not, however, affect the time required to perform a traversal. The performance of well-trained rats presented with a familiar pair of odors (correct and incorrect) was not not detectably altered by BDP-12 at 30 mg/kg; however, the number of correct responses made in a five-trial test was reduced at 45 mg/kg. These results indicate that the AMPA receptor modulator at 30 mg/kg has little influence on arousal, motivation, sensori-motor processing, and attention; higher dosages cause a depression of learned and unlearned prepotent responses. The effects of the lower concentration were tested on two-odor discrimination learning in rats that had extensive training on the task. The animals (n = 20) were given three or five acquisition trials with novel odor pairs immediately after an injection of drug or vehicle and then tested 1-3 d later for retention in five unrewarded probe trials. Retention performance was not significantly better than chance 52.6 +/- 4.5% correct) for odors learned on vehicle injection days but was well above chance for odors learned on drug injection days (70.6 +/- 4.2% correct). Within-subject comparisons confirmed the memory enhancing effect of BDP-12 (p < 0.01). Analyses of performance during five training trials indicated that the rats made more correct responses on days on which they were given the drug than on days on which they were injected with vehicle (p < 0.02). Within-subject differences in acquisition were correlated with differences in retention (r = 0.70). There were no evident effects of the drug on response latencies during acquisition. These results suggest that AMPA receptor modulators reduce the amount of training needed for the formation of long-term memory and do so at dosages which have little effect on variables that secondarily influence acquisition. Possible reasons for this selectivity are discussed.
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PMID:Facilitation of olfactory learning by a modulator of AMPA receptors. 861 39

The effect of capsaicin-induced stimulation of afferent neurons on peristalsis and the possible neural mediators involved in this action were examined in the guinea-pig isolated ileum. The intraluminal pressure threshold for eliciting peristaltic waves was used to quantify facilitation (decrease in threshold) or inhibition (increase in threshold) of peristalsis. Capsaicin (0.1-1 microM) caused an initial short-lasting stimulation of peristalsis followed by a prolonged inhibition of peristaltic activity. Capsaicin (1 microM) was ineffective when the gut segments had been pretreated with 3.3 microM capsaicin, which is indicative of an afferent neuron-dependent action of the drug. In contrast, the abolition of peristalsis caused by a high concentration of capsaicin (33 microM) was fully reversible on removal and reproducible on readministration of capsaicin, a feature characteristic of a nonspecific depression of smooth muscle excitability. Baseline peristalsis and the excitatory/inhibitory effect of capsaicin (1 microM) on peristalsis remained unaltered by a combination of the tachykinin NK1 receptor antagonist (+)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenyl piperidine (CP-99,994; 0.3 microM) and the tachykinin NK2 receptor antagonist (L(-)-N-methyl-N[4-acetylamino-4-phenyl-piperidine-2-(3,4- -dichlorophenyl)butyl]-benzamide (SR-48,968; 0.1 microM). Further experiments, performed in the presence of a low concentration of atropine (10 nM) showed that the calcitonin gene-related peptide (CGRP) antagonist human alpha-calcitonin gene-related peptide (8-37) [hCGRP(8-37); 10 microM] attenuated the delayed inhibitory effect of capsaicin on peristalsis, but did not influence baseline peristaltic activity and the capsaicin-induced facilitation of peristalsis. Blockade of nitric oxide (NO) synthesis by NG-nitro-L-arginine methylester (L-NAME, 300 microM) facilitated baseline peristaltic activity and reduced the delayed inhibition of peristalsis caused by capsaicin (1 microM) without affecting the initial peristalsis-stimulating action of capsaicin. The effects of L-NAME were prevented by L-arginine (1 mM). The data of the current study indicate that capsaicin-sensitive afferent neurons do not participate in the neural pathways subserving peristalsis in the guinea-pig small intestine, but modulate peristaltic activity upon stimulation with capsaicin. The initial stimulant action of capsaicin on peristalsis is independent of tachykinins acting via NK1 or NK2 receptors, while the delayed capsaicin-induced depression of peristalsis involves CGRP and NO.
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PMID:The inhibitory modulation of guinea-pig intestinal peristalsis caused by capsaicin involves calcitonin gene-related peptide and nitric oxide. 875 Sep 23

Several fentanyl analogs (Bagley et al., 1989, J. Med. Chem. 32, 663) were compared to fentanyl and morphine for their effects on respiratory depression as determined by arterial blood gas (pH, pCO2 and pO2) measurements. Fentanyl (0.1 mg/kg), morphine (10 mg/kg), #16 (1-phenethyl-4-[N-(pyridin-2-yl)-N-(methoxymethylcarbonyl)amino] piperidine, 1 mg/kg), #17 (1-phenethyl-4-[N-(pyridin-2-yl) -N-(2-furoyl)amino]piperidine, 0.5 mg/kg) and #29 (1-phenethyl-4-[N- (pyrimidin-2-yl)-N-(methoxy-methylcarbonyl) amino]piperidine, 10 mg/kg) produced significant respiratory depression in rats. Pretreatment with the mu1-opioid receptor selective antagonist, naloxonazine (10 mg/kg), blocked the respiratory effect of fentanyl and its analogs, but not that of morphine. The results suggest that the mu1-opioid receptor plays an important role in the respiratory effects of fentanyl and its analogs. Hence, the mechanism of fentanyl-induced respiratory depression appears to be distinct from that produced by morphine. The most likely explanation for this difference is the possible contribution of muscle rigidity and catalepsy to the observed changes in blood gas parameters caused by the fentanyl analogs, while the respiratory depression of morphine, measured by these same parameters, appears to be independent of its effect on muscle rigidity.
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PMID:Evidence for mu1-opioid receptor involvement in fentanyl-mediated respiratory depression. 889 2

(+/-)-Tramadol is a synthetic 4-phenyl-piperidine analogue of codeine. It is a central analgesic with a low affinity for opioid receptors. Its selectivity for mu receptors has recently been demonstrated, and the M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug. The rate of production of this M1 derivative (O-demethyl tramadol), is influenced by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6). Nevertheless, this affinity for mu receptors of the CNS remains low, being 6000 times lower than that of morphine. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This was demonstrated by the discovery of a monoaminergic activity that inhibits noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level. (+/-)-Tramadol is a racemic mixture of 2 enantiomers, each one displaying differing affinities for various receptors. (+/-)-Tramadol is a selective agonist of mu receptors and preferentially inhibits serotonin reuptake, whereas (-)-tramadol mainly inhibits noradrenaline reuptake. The action of these 2 enantiomers is both complementary and synergistic and results in the analgesic effect of (+/-)-tramadol. After oral administration, tramadol demonstrates 68% bioavailability, with peak serum concentrations reached within 2 hours. The elimination kinetics can be described as 2-compartmental, with a half-life of 5.1 hours for tramadol and 9 hours for the M1 derivative after a single oral dose of 100mg. This explains the approximately 2-fold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol. The recommended daily dose of tramadol is between 50 and 100mg every 4 to 6 hours, with a maximum dose of 400 mg/day; the duration of the analgesic effect after a single oral dose of tramadol 100mg is about 6 hours. Adverse effects, and nausea in particular, are dose-dependent and therefore considerably more likely to appear if the loading dose is high. The reduction of this dose during the first days of treatment is an important factor in improving tolerability. Other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria and constipation. Tramadol can be administered concomitantly with other analgesics, particularly those with peripheral action, while drugs that depress CNS function may enhance the sedative effect of tramadol. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and administration with tricyclic antidepressant drugs should also be avoided. Tramadol has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence. This was confirmed by various controlled studies and postmarketing surveillance studies, which reported an extremely small number of patients developing tolerance or instances of tramadol abuse. Tramadol is a central acting analgesic which has been shown to be effective and well tolerated, and likely to be of value for treating several pain conditions (step II of the World Health Organization ladder) where treatment with strong opioids is not required.
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PMID:[Pharmacology of tramadol]. 919 Mar 21

1. Climbing fibre-mediated excitatory postsynaptic potentials (CF-EPSPs) or currents (CF-EPSCs) were recorded from Purkinje cells in rat cerebellar slices using the whole-cell recording technique. 2. Climbing fibre responses displayed prominent paired-pulse depression (PPD). In the current-clamp recording mode, PPD resulted in a decreased number of spikelets in the second complex spike of the pair, and depression of the after-depolarization and after-hyperpolarization. 3. The mechanism of PPD was examined under voltage clamp. Manipulations that reduce transmitter release significantly affected PPD. These included lowering extracellular Ca2+ concentration and bath application of baclofen or adenosine. 4. Changing the number of stimulated climbing fibres, equivalent to changing the number of release sites, had no effect on PPD. 5. Selective manipulations of postsynaptic responsiveness had no effect on PPD. These included partial blockade of CF-EPSCs by a non-NMDA receptor antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and changing the holding potential. 6. A rapidly dissociating AMPA receptor antagonist, 2,3-cis-piperidine dicarboxylic acid, inhibited the second CF-EPSC of the pair proportionately more than the first, suggesting that presynaptic release by the second pulse is decreased. 7. PPD at interstimulus intervals of 50 ms or longer (up to 3000 ms) was not significantly affected by manipulations that change postsynaptic glutamate receptor desensitization. 8. Blockade of metabotropic glutamate, GABAB and adenosine receptors had no effect on PPD, suggesting that presynaptic autoreceptors do not contribute to PPD. 9. These results indicate that decreased transmitter release is a major cause of PPD at cerebellar climbing fibre-Purkinje cell synapses.
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PMID:Presynaptic origin of paired-pulse depression at climbing fibre-Purkinje cell synapses in the rat cerebellum. 949 Aug 67

The novel tachykinin receptor antagonist CGP49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-(quinolin-4-y lmethylamino)piperidine) has been compared with three other selective non-peptide tachykinin NK1 receptor antagonists. The drugs were tested as antagonists of the depolarization of spinal motoneurones induced by bath application of the selective tachykinin NK1 receptor agonist septide-(6-11) (300 nM) for 120 s at 15 min intervals. The antagonists were bath applied and the depolarizations were recorded from lumbar ventral roots of 7 to 12 day old rat and gerbil hemisected spinal cords in vitro. The gerbil preparation is considered to model the human species variant of the tachykinin NK1 receptor. With the exception of SR140333 ((S)-1-[2-[3-(3,4-dichlorophenyl)-1-[[3-(1-methylethoxy)phenyl]ace tyl]-3-piperidinyl]ethyl]-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride), the antagonists were approximately thirty-fold more potent on gerbil preparations. The respective mean IC50 values from gerbil preparations produced by CP96345 ((2S-cis)-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicy clo[2.2.2]octan-3-amine), CGP49823, SR140333 and CP99994 ((2S-cis)-N-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine) were, in microM +/- S.E. (n) 0.10 +/- 0.02 (6), 0.22 +/- 0.03 (6), 0.30 +/- 0.10 (5) and 0.38 +/- 0.02 (5) and the corresponding values from the rat preparations were 3.7 +/- 0.4 (5), 7.8 + 1.3 (5), 1.06 +/- 0.16 (6) and 10.5 +/- 2.2 (7). Dominance of tachykinin NK1 receptor activity in the measured responses was confirmed by low potency of the tachykinin NK2-selective antagonist SR48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl] benzamide) which yielded an IC50 value of 12.0 +/- 2.8 (5) on gerbil preparations and produced less than 50% depression of septide-induced depolarization of rat motoneurones at the highest concentration (100 microM) tested.
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PMID:The potency of the novel tachykinin receptor antagonist CGP49823 at rat and gerbil motoneurones in vitro. 954 86

The behavioral profile of a range of adenosine receptor ligands was examined in rats using a locomotor activity model. Adenosine receptor agonists, including the selective A1 receptor agonist, N6-cyclopentyladenosine (CPA) and the A2A agonist, 2-[(2-aminoethylamino)carbonylethyl-phenylethylamino]- 5'-ethylcarboxa midoadenosine (APEC), reduced spontaneous motor activity in a dose-dependent manner. CPA-induced locomotor depression was attenuated by adenosine A1 receptor selective antagonists, such as 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), (R)-1-[(E)-3-(2-phenylpyrazolo[1, 5-a]pyridin-3-yl)-acryloyl]-2-piperidine ethanol (FK453), and (R)-1-[(E)-3-(2-phenylpyrazolo[1, 5-a]pyridin-3-yl)-acryloyl]-piperidin-2-yl acetic acid (FK352), but not by the A2A receptor antagonist, (E)-1,3-dipropyl-8-(3, 4-dimethoxystyryl)-7-methylxanthine (KF17837). By contrast, APEC-induced hypolocomotion was attenuated by KF17837 but not by DPCPX, confirming that adenosine A1 and A2A receptor activation mediates locomotor output independently. It was found that two peripheral adenosine receptor antagonists, 8-(p-sulphophenyl)-1, 3-dipropylxanthine (DPSPX) and 8-(p-sulphophenyl)-1, 3-dimethylxanthine (8-PST), did not alter CPA-induced hypolocomotion. This confirmed that pharmacological reversal of the adenosine A1 receptor-mediated response involved a central site of drug action. The relationship between occupancy of central adenosine A1 receptors and behavioral effect was therefore assessed. Regression analysis on log transformed data confirmed associations between antagonist affinity for brain [3H]DPCPX binding sites and, in order of increasing significance, the equivalent behavioral dose (EBD) for reversal of CPA-induced hypolocomotion (r2 = 0.32), the serum concentration of drug (r2 = 0.65), and most significantly with the brain concentration of drug detected 20 min after administration of the (EBD) (r2 = 0.95). These data suggest that competition between agonists and antagonists, for occupancy of central adenosine A1 receptors, is intrinsic to the pharmacological reversal of CPA-induced hypolocomotion. The validity of the model as a simple predictive screen for the blood/brain barrier permeability of adenosine A1 receptor antagonists was thereby confirmed.
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PMID:Pharmacological characterization of a simple behavioral response mediated selectively by central adenosine A1 receptors, using in vivo and in vitro techniques. 961 4

The aim of this study was to characterize the modulation of synaptic transmission in the glutamatergic corticostriatal pathway by cholinergic and adrenergic receptors. In coronal slices of mouse brain, negative-going field potentials were recorded in the dorsal striatum in response to stimulation of the overlying white matter, and their susceptibility to various pharmacological manipulations was studied. The responses were mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors, since they were augmented by aniracetam (0.5-1.5 mM), a positive modulator of AMPA-type glutamate receptors, and blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (> or = 10 microM), a selective antagonist of AMPA receptors. Carbachol (10 microM), a muscarinic agonist, reduced the size of responses and abolished paired-pulse depression; these effects being consistent with previous studies indicating that muscarinic activation inhibits release of glutamate in the corticostriatal pathway. Muscarinic antagonists could block the effect of carbachol. Their rank order was: 10 microM scopolamine (a non-selective muscarinic antagonist) > or = 1 microM 4-diphenylacetoxy-N-methyl-piperidine (M3/M1 antagonist)>1 microM pirenzepine (M1 antagonist)>10 microM methoctramine (M2 antagonist). McN-A-343 (1-10 microM), an M1 muscarinic agonist, was ineffective in this preparation. In contrast, isoproterenol (10-30 microM), a beta-adrenergic agonist, slightly increased the synaptic responses, but it did not affect paired-pulse depression. None of alpha-adrenergic agents (30 nM-1.0 microM dexmedetomidine, an alpha2-adrenergic agonist, 0.3 microM atipamezole, an alpha2-adrenergic antagonist or 30 microM phenylephrine, an alpha1-adrenergic agonist) influenced the size of the responses; neither did these drugs alter paired-pulse depression. These results indicate that the activation of striatal M3-like muscarinic receptors and beta-adrenoceptors, but not M2-like muscarinic receptors and alpha-adrenoceptors, modulates directly corticostriatal glutamatergic neurotransmission.
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PMID:Activation of muscarinic M3-like receptors and beta-adrenoceptors, but not M2-like muscarinic receptors or alpha-adrenoceptors, directly modulates corticostriatal neurotransmission in vitro. 1018 37

As part of our research program toward new, potential antidepressants, a series of unsymmetrical ureas has been prepared and evaluated as 5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activities. The design of these compounds was based on coupling of various indole derivatives, previously shown to inhibit 5-HT reuptake, to three different aniline moieties, which are part of known 5-HT(1B/1D) ligands. Binding experiments in rat frontal cortex using [(125)I]iodocyanopindolol, in calf striatum using [(3)H]5-HT, and in rat hippocampus using [(3)H]8-OH-DPAT as radioligands, respectively, revealed significantly higher affinity at the 5-HT(1B) receptor as compared to the affinities for the 5-HT(1A) and 5-HT(1D) receptors for a number of compounds, among them 4-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (5), the corresponding 4-fluoro-1H-indol-3-yl analogue 21a, and the corresponding 6-fluoro-1H-indol-3-yl analogue 21b. Conformational restriction of the aniline moiety in 5 only slightly enhanced the 5-HT(1B) affinity, whereas introduction of an aniline moiety with higher conformational flexibility resulted in a less potent 5-HT(1B) receptor ligand as compared to 5. The functional 5-HT(1B/1D) antagonistic activity was investigated using the rabbit saphenous vein model as well as the [(3)H]5-HT release from guinea pig cortical slices. All new compounds tested in the rabbit saphenous vein model were shown to antagonize the sumatriptan-evoked contractile responses with pA(2) values ranging from 7.3 to 8.7. These observations were consistent with the results of the cortical slice model, in which the ureas were found to block the sumatriptan-induced inhibition of potassium-evoked [(3)H]5-HT release. The 5-HT reuptake inhibition of the ureas determined in rat brain synaptosomes was found to be either increased or decreased as compared to the uncoupled indole derivatives indicating that the reuptake inhibition shown by the ureas is not only due to the indole part but also affected by the aniline moiety of the molecule. Among this series of compounds described the ureas 5, 21a, and 21b seem to be the most interesting candidates showing both 5-HT reuptake inhibition and 5-HT(1B/1D) antagonism in vitro. This dual pharmacological profile should in theory lead to a pronounced enhancement in serotonergic neurotransmission and consequently to a more efficient treatment of depression.
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PMID:5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activity: a new approach toward efficient antidepressants. 1073 47

The selective sigma2 (sigma2) ligand Lu 28-179, or 1'-[4[1-(4-fluorophenyl)-1H-indol-3-yl]-l-butyl]spiro[isobenzofuran++ +-1(3H),4'-piperidine], was studied in the chronic mild stress (CMS) model of depression. The CMS test procedure consists of sequential exposures to a variety of mild stressors for a prolonged period of time and results in behavioural hedonic deficits, which can be measured as decreased consumption of a palatable sucrose solution. In rats, exposure to CMS treatment with citalopram or imipramine for 2 or 4 weeks, respectively, normalized the sucrose intake. Similarly, Lu 28-179 (1.0 mg/kg subcutaneously per day) normalized sucrose intake in rats exposed to CMS. This effect was found in two separate experiments and was achieved after 3 and 4 weeks of treatment, respectively. This suggests an antidepressant potential for Lu 28-179. Doses of 0.01 and 0.1 mg/kg were inactive. Groups exposed to CMS and treated with 0.5, 2.0 or 3.0 mg/kg showed a significantly increased sucrose intake compared with vehicle-treated stressed animals at week 5. However, this effect was confounded by decreased intake in the vehicle controls. Lu 28-179 did not affect sucrose intake in non-stressed rats at any of the doses tested.
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PMID:The selective sigma2 ligand Lu 28-179 has an antidepressant-like profile in the rat chronic mild stress model of depression. 1087 16


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