Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An uncontrolled clinical study with WIN 27,147-2 was conducted with 10 hospitalized depressed psychiatric patients. There was statistically significant improvement in the total scores of the HAM-D, BPRS and Zung; in the scores of all the factors of the HAM-D and Zung; in the scores of the anxiety/depression and activation factors of the BPRS, and in the scores of 6 of the 18 items of the BPRS. Judged by clinical global impression, 9 of the 10 patients were very much improved and 1 patient much improved. The most frequently occurring adverse effects were dry mouth, sweating, drowsiness and insomnia.
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PMID:WIN 27,147-2 in the treatment of depression. An uncontrolled clinical study. 1 70

Ibogaine (40 mg/kg i.p.), when given 2 hours before an acute injection of cocaine (25 mg/kg s.c.) to C57BL/6 mice, reduced the cocaine-induced locomotor stimulation. Such stimulation was also reduced in the ibogaine-treated mice when a second injection of cocaine was given 24 hr later. Thus, the reduction in locomotor activity was not just the short-term depression of locomotor activity seen after ibogaine administration. When mice were given a daily injection of cocaine for 3 days and ibogaine was given after the cocaine injection on day 3, and again on day 4, cocaine-induced locomotor activity was reduced three hours later on day 4. On days 5 and 9 of the cocaine administration, with no further ibogaine treatment ambulatory counts were still lower in the ibogaine-pretreated mice. Locomotor stimulation induced by amphetamine (10 mg/kg) was not affected by ibogaine. An acute injection of ibogaine resulted in a transient increase in turnover of dopamine, as indicated by the increase in the ratio of metabolites of the dopamine to dopamine, followed by a decrease in the metabolites in striatum and frontal cortex 24 hr later. In vivo treatment with ibogaine did not affect the binding of [3H]WIN 35,248 to the cocaine binding site in striatal tissue measured in vitro. In addition, ibogaine added in vitro had a weak affinity to the WIN 35,248 binding site (IC50 for cocaine = 120 nM and for ibogaine = 1,500 nM). The results suggest that ibogaine may have induced a selective change in the dopaminergic system that results in a decrease in responsiveness to cocaine that persisted for at least 1 week.
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PMID:Ibogaine antagonizes cocaine-induced locomotor stimulation in mice. 155 3

Cocaine potently inhibits the spontaneous activity of dorsal raphe serotonin (5-hydroxytryptamine [5-HT] neurons which possess impulse-modulating receptors of the 5-HT1A subtype. In an investigation of the neuropharmacologic mechanisms underlying this electrophysiologic effect, we have compared cocaine with structurally and functionally similar compounds, attempted to reverse cocaine-induced suppression of 5-HT dorsal raphe nucleus (DRN) neuronal activity, and assessed the effects of 5-HT depletion on the response to cocaine. Extracellular recordings in chloral hydrate-anesthetized rats were obtained using single-unit recording techniques; drugs were infused intravenously IV) in a cumulative dose manner. The active isomer (-)-cocaine (ID50 = 0.5 +/- 0.15 mg/kg) and the phenyltropane analogue WIN 35428 (ID50 = 0.17 +/- 0.03 mg/kg) that share the ability of cocaine to block monoamine uptake also inhibit impulse activity in 5-HT neurons. In contrast, the inactive isomers (+)-cocaine, (+)-pseudococaine and the metabolite benzoylecgonine do not exhibit the same range of potency (maximal 20% to 30% inhibition at a cumulative dose of 8 to 16 mg/kg). A selective inhibitor of uptake for 5-HT (fluoxetine; ID50 = 1.8 +/- 0.5 mg/kg), but not norepinephrine (desipramine) or dopamine (GBR 12909), mimicked cocaine, as did the monoamine releaser amphetamine (ID50 = 2.86 +/- 0.46 mg/kg). The putative 5-HT1A autoreceptor antagonist spiperone reversed the cocaine-induced depression of firing rate in 64% of 5-HT neurons tested whereas receptor antagonists for dopamine D2 (haloperidol), 5-HT2 (ketanserin), gamma-aminobutyric acid (picrotoxin) and 5-HT1/beta-adrenergic (propranolol) were ineffective. Following treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (100 mg/kg/day of the base for 3 days), impulse depression induced by cocaine was significantly attenuated as compared to control, which suggests that the effects of cocaine may be dependent on endogenous 5-HT stores. In summary, these findings support the hypothesis that the inhibitory effects of cocaine on 5-HT DRN neurons are mediated by increased 5-HT available for interaction with 5-HT1A impulse-regulating autoreceptors in the DRN, as a consequence of cocaine-induced blockade of 5-HT reuptake processes. Further studies are required to clarify the relative contribution of cocaine-5-HT interactions to the behavioral and physiologic effects of this psychostimulant.
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PMID:The interaction of cocaine with serotonin dorsal raphe neurons. Single-unit extracellular recording studies. 213 98

The effects of U50488H, a kappa agonist, and WIN 44441-3, a kappa antagonist, and their modification of the effects of ethanol, on the behavior of rats in a modified open field apparatus, was examined. Crossover activity was increased by U50488H. Headpoke activity was decreased by WIN 44441-3 and increased by U50488H. Rearing activity was increased by WIN 44441-3 but was not affected by U50488H. The effect of both drugs was dose related, with the largest doses having no effect. Ethanol (0.5 g/kg) stimulated crossover activity while it depressed rearing, headpoke and corner activities; except for crossover activity the 2.0 g/kg dose of ethanol depressed these activities. Pretreatment with WIN 44441-3 (0.5 mg/kg) potentiated the stimulant effect of ethanol on crossover activity and partially reversed the depressant effect of ethanol on rearing and headpoke activities. U50488H potentiated the ethanol-induced depression of headpoke and reversed the depression of corner activity. Pretreatment with U50488H had no effect on ethanol's action on crossover and rearing behaviors. Our results indicate that kappa opiate receptors may mediate some behaviors exhibited by rats in a modified open field apparatus. Activation of these receptors increases locomotor and headpoke activity but had no effect on rearing activity. Furthermore, the 0.5 g/kg dose of ethanol has differential effects on different measures of open field behavior, while the 2.0 g/kg dose was largely depressant. Our data suggest that some of these effects of ethanol may be mediated via kappa opioid receptors.
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PMID:Effects of ethanol in an open field apparatus: modification by U50488H and WIN 44441-3. 254 20

We examined the influence of chronic cocaine exposure, in an unlimited access self-administration paradigm, on density of the dopamine transporter (3H-WIN 35,428 and 3H-GBR 12,935 binding) and concentration of monoamine (dopamine, serotonin, noradrenaline and metabolites) neurotransmitters in rat brain. In normal rodent striatum 3H-WIN 35,428 and 3H-GBR 12,935 binding to the dopamine transporter, although generally similar, showed different subregional rostrocaudal and mediolateral gradients, suggesting that the two ligands might bind to different subtypes or states of the dopamine transporter. Following chronic, unlimited access cocaine self-administration, binding of 3H-WIN 35,428 was significantly elevated in whole nucleus accumbens (+69%, p < 0.001) and striatum (+65%, p < 0.001) on the last day of cocaine exposure ("on-cocaine group"); whereas in the 3 week withdrawn animals ("cocaine-withdrawn group"), levels were either normal (striatum) or reduced (-30%, p < 0.05, nucleus accumbens). Although similar changes in 3H-GBR 12,935 binding were observed, this dopamine transporter ligand showed a smaller and highly subregionally dependent increase in binding in striatal subdivision of the on-cocaine group, but a more marked binding reduction in the cocaine-withdrawn animals. As compared with the controls, mean dopamine levels were reduced in striatum (-15%, p < 0.05) of the on-cocaine group and in nucleus accumbens (-40%, p < 0.05) of the cocaine-withdrawn group. These data provide additional support to the hypothesis that some of the long-term effects of cocaine exposure (drug craving, depression) could be consequent to reduced nucleus accumbens dopamine function. Our data also suggest that dopamine transporter concentration, and perhaps function, might undergo up- or downregulation, either as a direct effect of cocaine, or indirectly as part of a homeostatic response to altered synaptic dopamine levels, and therefore might participate in the neuronal events underlying cocaine-induced behavioral changes.
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PMID:Heterogeneous subregional binding patterns of 3H-WIN 35,428 and 3H-GBR 12,935 are differentially regulated by chronic cocaine self-administration. 818 52

Animal studies suggest that chronic cocaine exposure may increase the function and/or synthesis of the dopamine transporter (DAT) under certain conditions, but the literature is complex. In order to test the hypothesis that cocaine exposure alters the DAT in humans, preliminary studies were done characterizing [3H]WIN 35428 binding in human striatum from normal controls. Following these experiments, the effects of chronic cocaine were examined in post mortem striatal specimens from 7 cocaine users and 7 controls matched for age and post mortem interval, employing quantitative autoradiography. Initial saturation experiments indicated that a one-site model was preferred with a Kd of 11 +/- 4 nM. [3H]WIN 35420 binding was then examined in cocaine users and controls at 0.5, 5, 10, and 50 nM radioligand concentrations. At each concentration of [3H]WIN 35420, optical densities for cocaine-exposed subjects were increased in caudate, putamen, and accumbens. The results suggest that total numbers of binding sites were increased in cocaine users. Based on the present and previous results, it appears that the regulation of the DAT is fairly plastic, and is highly sensitive to cocaine dosing regimes and withdrawal intervals. Chronic adaptations induced by cocaine in the DAT could contribute to the symptoms of binging, withdrawal depression, and/or craving.
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PMID:Cocaine use increases [3H]WIN 35428 binding sites in human striatum. 831 44

In depressive states, theories concerning serotonin and norepinephrine have been dominating, but there are several lines of evidence indicating the involvement of the dopamine system as well, especially in suicidal depression. In this post-mortem study, the binding of the ligand [3H]WIN 35,428 to dopamine uptake sites in the caudate nucleus was investigated in 13 depressed suicide victims and 19 controls. There were no differences in Bmax or Kd between the suicide group and controls. Subdividing the suicide group into subgroups regarding the presence of major depression, antidepressant medication and suicide method, respectively, did not yield any differences. Previous findings regarding reduced CSF HVA in suicidal depression and indications of striatal dopaminergic biochemical and receptor changes in depression seem, according to the present study, not to be reflected by alterations in density or affinity of dopamine uptake sites in depressed suicide victims.
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PMID:Unchanged density of caudate nucleus dopamine uptake sites in depressed suicide victims. 950 81

1. The arachidonic acid derivative arachidonylethanolamide (anandamide) is an endogeneous ligand of cannabinoid receptors that induces pharmacological actions similar to those of cannabinoids such as delta9-tetrahydrocannabinol (THC). We examined whether anandamide can influence excessive neuronal activity by investigating stimulation-induced population spikes and epileptiform activity in rat hippocampal slices. For this purpose, the effects of anandamide were compared with those of the synthetic cannabinoid agonist WIN 55,212-2 and its inactive S(-)-enantiomer WIN 55,212-3. 2. Both anandamide (1 and 10 microM) and WIN 55,212-2 (0.1 and 1 microM) decreased the amplitude of the postsynaptic population spike and the slope of the field excitatory postsynaptic potential (field e.p.s.p.) without affecting the presynaptic fibre spike of the afferents. At a concentration of 1 microM, WIN 55,212-2 completely suppressed the postsynaptic spike, whereas the S(-)-enantiomer WIN 55,212-3 produced only a slight depression. The CB1 receptor antagonist SR 141716 blocked the inhibition evoked by the cannabinoids. SR 141716 had a slight facilitatory effect on neuronal excitability by itself. 3. Anandamide shifted the input-output curve of the postsynaptic spike and the field e.p.s.p. to the right and increased the magnitude of paired-pulse facilitation indicating a presynaptic mechanism of action. 4. Anandamide and WIN 55,212-2, but not WIN 55,212-3, attenuated both stimulus-triggered epileptiform activity in CA1 elicited by omission of Mg2+ and spontaneously occurring epileptiform activity in CA3 elicited by omission of Mg2+ and elevation of K+ to 8 mM. The antiepileptiform effect of these cannabinoids was blocked by SR 141716. 5. In conclusion, cannabinoid receptors of the CB1 type as well as their endogeneous ligand, anandamide, are involved in the control of neuronal excitability, thus reducing excitatory neurotransmission at a presynaptic site, a mechanism which might be involved in the prevention of excessive excitability leading to epileptiform activity.
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PMID:Effects of the endogeneous cannabinoid, anandamide, on neuronal activity in rat hippocampal slices. 1037 27

Cannabinoids receptors have been reported to modulate synaptic transmission in many structures of the CNS, but yet little is known about their role in the prefrontal cortex where type I cannabinoid receptor (CB-1) are expressed. In this study, we tested first the acute effects of selective agonists and antagonist of CB-1 on glutamatergic excitatory postsynaptic currents (EPSCs) in slices of rat prefrontal cortex (PFC). EPSCs were evoked in patch-clamped layer V pyramidal cells by stimulation of layer V afferents. Monosynaptic EPSCs were strongly depressed by bath application (1 microM) of the cannabinoid receptors agonists WIN55212-2 (-50.4 +/- 8.8%) and CP55940 (-42.4 +/- 10.9%). The CB-1 antagonist SR141716A reversed these effects. Unexpectedly, SR141716A alone produced a significant increase of glutamatergic synaptic transmission (+46.9 +/- 11.2%), which could be partly reversed by WIN55212-2. In the presence of strontium in the bath, the frequency but not the amplitude of asynchronous synaptic events evoked in layer V pyramidal cells by stimulating layer V afferents, was markedly decreased (-54.2 +/- 8%), indicating a presynaptic site of action of cannabinoids at these synapses. Tetanic stimulation (100 pulses at 100 Hz, 4 trains) induced in control condition, no changes (n = 7/18), long-term depression (LTD; n = 6/18), or long-term potentiation (LTP; n = 5/18) of monosynaptic EPSCs evoked by stimulation of layer V afferents. When tetanus was applied in the presence of WIN 55,212-2 or SR141716-A (1 microM) in the bath, the proportion of "nonplastic" cells were not significantly changed (n = 7/15 in both cases). For the plastic ones (n = 8 in both cases), WIN 55,212-2 strongly favored LTD (n = 7/8) at the apparent expense of LTP (n = 1/8), whereas the opposite effect was observed with SR141716-A (7/8 LTP; 1/8 LTD). These results demonstrate that cannabinoids influence glutamatergic synaptic transmission and plasticity in the PFC of rodent.
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PMID:Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons. 1084 48

Interactions between neurotransmitter receptors involved in the pathophysiology of depression, anxiety and ethanol consumption and two extracts (hydromethanolic and lipophilic extracts obtained with hypercritical CO2) from Hypericum Perforatum L or St. John's wort (SJW) and three constituents (hyperforin, hypericin and biapigenin) were evaluated by in vitro binding assays. The two extracts, tested at 10 microg/ml, did not inhibit ligand binding at the following receptors: serotonin 5-HT6 and 5-HT7, benzodiazepine, sigma and neuropeptide Y (NPY) Y1 and Y2 receptors. The hydromethanolic extract, but not the lipophilic extract, interacted with GABA(A) receptors (IC50 5.5 microg/ml), while both interacted with the dopamine (DA) transporters, albeit with high IC50 values (24.5 and 12.9 microg/ml, respectively). Biapigenin (1 microg/ml, 2 microM) inhibited ligand binding at benzodiazepine receptors only (IC50: 2 microM). Hyperforin (1 microg/ml, 2 microM) only inhibited [3H]WIN-35,428 binding to DA transporters, although the IC50 (5 microM) was higher than the IC50 found for inhibition of the synaptosomal DA reuptake (0.8 microM). This finding extended the same observation previously described for the 5-HTergic system to the DAergic system, confirming that the inhibition of monoamine reuptake is due to a different mechanism than that of synthetic antidepressants. Hypericin showed micromolar affinities for both NPY-Y1 and Y2 receptors and for sigma receptors (IC50 3-4 microM). These hypericin activities might be of interest because NPY and sigma receptors have been associated with anxiety disorders, depressive illnesses and ethanol consumption. However, they were present at relatively high hypericin concentrations, and were also light-dependent (i.e. the IC50 values increased when binding assays were carried out in the dark). Thus, our in vitro binding results may suggest that either the pharmacological effects of SJW are due to other molecules than hypericin or hyperforin (other constituents or active metabolites), or that the mechanism of action is different from those that have been considered up to now.
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PMID:In vitro binding studies with two hypericum perforatum extracts--hyperforin, hypericin and biapigenin--on 5-HT6, 5-HT7, GABA(A)/benzodiazepine, sigma, NPY-Y1/Y2 receptors and dopamine transporters. 1151 75


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