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)

Alterations in photically-evoked cortical responses were assessed in immobilized artificially respired cats following intraraphe microinjections of LSD and serotonin (5-HT) and IV administration of LSD and l-tryptophan. Both systemic (10-100 micrograms/kg; N = 5) and intraraphe (0.25 microgram; N = 10) LSD significantly increased the amplitudes of the three primary components of the visual evoked response (VER). In contrast, the same VER components were significantly depressed following intraraphe 5-HT (30 micrograms; N = 4) and IV l-tryptophan (100 mg/kg; N = 6), a serotonin precursor that elevates raphe 5-HT levels. Intraraphe cinanserin (180 micrograms; 30 minute pretreatment) completely reversed LSD-induced enhancements in all three components (p less than 0.01). Depressions of VER following intraraphe 5-HT (30 micrograms) were also antagonized by cinanserin, although to lesser degree (p less than 0.05 for first 2 components only) than with LSD. The depressive effects of l-tryptophan (100 mg/kg) were unaffected by cinanserin. Modification of raphe neuronal activity can significantly alter photically evoked responses, and may explain the perceptual disturbances associated with LSD, i.e., depression of an area (raphe) normally inhibiting forebrain areas of the visual system.
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PMID:Differential effects of LSD serotonin and l-tryptophan on visually evoked responses. 705 13

The effects of picrotoxin (0.75 and 1.5 mg/kg), an antagonist of GABA mediated chloride ion conductance changes, were examined on the acquisition and performance of a bidirectional active avoidance (BAA) response and on locomotor activity. Treatment with this agent disrupted both the acquisition and performance of this task and decreased locomotor activity. This picrotoxin-induced suppression of BAA was reversed by pretreatment with diazepam (2 mg/kg), d-amphetamine (d-AMP, 2.0 mg/kg) and lysergic acid diethylamide (LSD, 10 micrograms/kg) and was reversed partially by cinanserin (5 mg/kg) and methysergide (5 mg/kg). Picrotoxin-induced activity decreases in locomotor activity were antagonized by d-AMP, were partially reversed by LSD but were not reversed by methysergide. It is proposed that picrotoxin disrupts bidirectional active avoidance behavior by increasing the response suppressive effects of aversive stimuli and by inducing a general depression of motility.
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PMID:Picrotoxin-induced disruption of bidirectional active avoidance behavior and locomotor activity. 717 14

Experiments involving the use of LSD and observing its effects on neurons involved in the processing of visual information are reviewed. These studies typically involved either intravenous or iontophoretic application of the compound. Both modes of application appeared to block the optic afferent synapse at the level of the dorsal lateral geniculate nucleus and to alter the evoked activity of visual cortical neurons. Increasing the dose of LSD regardless of the manner in which it was applied tended to produce depression of both spontaneous and visually driven activity. The receptive field properties of the neurons at all levels of the visual system appear to remain intact after LSD despite changes in spontaneous activity. The effect of LSD on non-specific afferents to the dorsal lateral geniculate nucleus is depicted in relationship to two of the different kind of relay cells located in this structure. Data on LSD interaction with the effects of midbrain stimulation on "X" and "Y" neurons is presented.
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PMID:Electrophysiological studies of d-lysergic acid diethylamide in the visual system. 717 10

CNS deficiency of 5-hydroxytryptamine (serotonin) has been implicated as a biochemical basis in some forms of depression. Existing drug modalities for treating depression include some with serotonergic effects. Studies suggest that psychedelic drugs are also serotonergic. This may indicate a role for psychedelics in the treatment of depression. Such treatment has already been attempted using psychedelic drugs in both the indoleamine and phenylalkylamine categories. Encouraging results seem to recommend further research, with special emphasis on drugs in the phenylisopropylamine subgroup of phenylalkylamines that are only peripherally psychedelic. Certain of these, called entactogens or empathogens, cause substantially less distortion of normative consciousness than classic psychedelics, such as LSD or mescaline. They could therefore be more easily assimilated into existing psychotherapy approaches, where their function would be to enhance the normal psychotherapeutic process rather than serving a maintenance role as chemotherapeutic agents. Their usefulness in such an application would be mainly at the start of psychotherapy in order to (1) reduce the client's "fear response" that often inhibits ability to deal with repressed traumatic material; (2) facilitate the client's interpersonal communications with the therapist, spouse or significant others; and (3) accelerate formation of a therapeutic alliance between client and therapist.
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PMID:Psychedelic and entactogenic drugs in the treatment of depression. 791 28

Serotonin 5-hydroxytryptamine (5-HT)2 receptors are implicated in the etiology of mental disease and depression. Drugs that interact with the 5-HT2 receptor are used therapeutically to treat such illnesses, and their mechanisms of action are of great interest. In this study 5-HT2 receptor-ligand interactions were examined by site-directed mutagenesis in which three aspartic acid to asparagine mutants (Asn-120, Asn-155, and Asn-172) were created and expressed in NIH3T3 cells. The Asp-120 to asparagine mutant exhibited the same affinity for 125I-lysergic acid diethylamide (125I-LSD) as did the wild-type receptor and showed a decreased and GTP-insensitive binding affinity for the agonists 5-HT and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (approximately 10-fold) and the antagonists ketanserin and mianserin (approximately 10-fold) but not spiperone. The mutation also abolished agonist-stimulated formation of [3H]polyphosphoinositides (PI). The Asn-155 mutant showed reduced binding affinity for 125I-LSD (Kd, 2.8 nM versus 0.6 nM for the wild-type receptor) and had reduced affinity for agonists (approximately 30-fold) and for antagonists (14-75-fold). However, the Asn-155 receptor retained GTP sensitivity and the ability to stimulate PI formation. The Asn-172 mutant retained the wild-type Kd value for 125I-LSD, exhibited only approximately 5-fold reduced affinity for 5-HT and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane while retaining GTP-sensitive agonist binding showed no change in affinity for ketanserin, and had a small decrease in mianserin and spiperone binding (approximately 6-fold). The Asn-172 receptor also retained the ability to form PI. These results indicate that Asp-120 is necessary for allosteric activation of the guanine nucleotide-binding protein. Asp-155 is necessary for high affinity binding, probably by acting as a counterion for the amine group of the ligand. The different effects of the three mutations on ketanserin, mianserin, and spiperone binding affinity suggest that these antagonists may share overlapping but different binding domains. The information provided by this study may facilitate the design of therapeutic site-selective compound based on the structure of the 5-HT2 receptor.
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PMID:Site-directed mutagenesis of the serotonin 5-hydroxytrypamine2 receptor: identification of amino acids necessary for ligand binding and receptor activation. 831 24

The human platelet 5-HT2 receptor may resemble a peripheral model of central 5-HT2 binding sites and has been linked to changes in 5-HT2 receptor function in depression. Therefore, evaluation of the human platelet 5-HT2 binding characteristics is important. Comparing [3H]ketanserin and [3H]LSD as ligands clearly indicated [3H]LSD as ligand of choice for binding studies dealing with the human platelet 5-HT2 receptor. [3H]LSD binding was specific, saturable, and depended upon incubation time, protein concentration and previous handling of tissue, i.e., use of fresh or frozen tissue. In contrast, studies with [3H]ketanserin were unsatisfactory. Although mean receptor densities and affinities have been relatively constant between individuals and over time in healthy subjects with [3H]LSD, examination of the individual data showed considerable variations within single subjects. Thus, KD ranged between 0.50 and 0.68 nM, and Bmax was in the range of 64.9 to 97.1 fmol/mg protein in healthy individual subjects. Therefore, we recommend [3H]LSD as ligand of choice to study platelet 5-HT2 receptor binding in humans. Furthermore, repeated measurement of individual data over time should be interpreted cautiously, especially when data from depressed patients are under examination.
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PMID:Human platelet 5-HT2 receptor binding sites re-evaluated: a criticism of current techniques [corrected]. 832 69

Changes in the central and peripheral serotonergic receptor activity have been reported to be involved in depression and suicidality. To elucidate the interdependence between central and peripheral receptor sites and their regulation by serotonin, we estimated intra-individual serotonin2 receptor binding characteristics in porcine cortex synaptosomes and in platelet membranes using 3H-LSD as ligand and ketanserin as competitor and quantified the relevant serotonin concentrations. A positive correlation between the apparent half maximal saturation concentration, KD, of the receptor in cortex synaptosomes and platelet membranes (r = 0.65, p = 0.0046, n = 18), and between the apparent maximal binding capacity, Bmax, of the receptor in cortex synaptosomes and platelets (r = 0.52, p = 0.027, n = 18) was observed. The blood serotonin concentrations correlated negatively with the maximal binding capacity, Bmax, in platelets (r = -0.77, p = 0.0002, n = 18). These results suggest that the binding characteristics of the central and peripheral serotonin2 receptor are similar, and that the platelet receptor activity may be regulated by blood levels of serotonin.
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PMID:Concurrence of cortex and platelet serotonin2 receptor binding characteristics in the individual and the putative regulation by serotonin. 837 54

Frontal-subcortical circuits provide a comprehensive framework for understanding the anatomy, biochemistry, and pharmacology of behavior. The three principal behaviorally relevant circuits originate in the dorsolateral prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex, respectively. Circuit-specific marker behaviors associated with each circuit are executive dysfunction (dorsolateral prefrontal-subcortical circuit), disinhibition and OCD (orbitofrontal-subcortical circuit), and apathy (medial frontal-subcortical circuit). Environmental dependency is common to all prefrontal-subcortical syndromes and may reflect disruption of working memory. Depression, mania, and psychosis are mediated by structures involved in prefrontal-subcortical circuits and are circuit-related but not circuit-specific behaviors. The actions of PCP, LSD, serotonergic antidepressants, anxiolytics, sedative-hypnotics, antipsychotic agents, and ethanol may all be partially or primarily mediated through transmitter systems and receptor effects expressed through frontal-subcortical circuits.
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PMID:Anatomic and behavioral aspects of frontal-subcortical circuits. 859 19

A group of patients with major depressive disorder, with and without comorbid obsessive-compulsive disorder, completed the Tridimensional Personality Questionnaire (TPQ). Harm Avoidance scores were found to be high compared to published age-matched norms and to display a significant positive correlation with Hamilton Depression Rating Scale scores. Platelet 125I-lysergic acid diethylamide (125I-LSD) and 3H-paroxetine binding Bmax values were measured to test Cloninger's hypothesis that Harm Avoidance scores would correlate significantly with measures of serotonergic function. A significant inverse correlation was found between Harm Avoidance scores and 125I-LSD Bmax values. Correlations between 3H-paroxetine Bmax values and TPQ scale scores were not significant. These results suggest an alternative view of the literature relating platelet 5-hydroxytryptamine-2a receptors and mood disorders in that the temperament dimension, Harm Avoidance, may explain prior inconsistencies involving links with depression and suicidality.
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PMID:Platelet serotonergic markers and Tridimensional Personality Questionnaire measures in a clinical sample. 887 73

The effects of treatment with serotonin (5-HT) reuptake inhibitors on platelet 5-HT2 receptors, 5-HT reuptake sites an 5-HT uptake were studied in a double-blind trial comparing two selective serotonin reuptake inhibitors (SSRI), paroxetine, and fluoxetine, for the treatment of major depression. Hamilton Depression Rating Scale (HAM-D) scores and platelet 5-HT parameters were determined in 21 depressed patients at baseline, after 4 and 8 weeks of treatment, and were compared to 21 healthy controls. Antidepressant treatment did not significantly alter the density of 5-HT reuptake sites, labelled with [3H]paroxetine, or 5-HT2 receptors, labelled with [3H]LSD. However, a strong correlation was observed between the HAM-D suicidality item and 5-HT2 receptor density at baseline. A marked increase in platelet 5-HT2 receptors at baseline was observed in suicidal depressed patients compared to those with no suicidal ideation and healthy controls. Changes in [3H]paroxetine Bmax and in [3H]5-HT uptake significantly correlated with change in HAM-D score at 4 and 8 weeks respectively. These results confirm previous reports of an association between suicidality and platelet 5-HT2 receptor upregulation. Our data also lends support to the use of platelet 5-HT parameters as indicators of antidepressant efficacy, particularly in suicidal depressed patients.
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PMID:Effects of selective serotonin reuptake inhibitors on platelet serotonin parameters in major depressive disorder. 901 88


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