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)

The effects of chronic cortisol treatment on neuroendocrine and behavioral responses to serotonin1 (5-HT1) receptor agonists were studied in conscious, freely moving rats. Seven-day cortisol treatment (25 mg/kg/day with osmotic minipumps) markedly suppressed basal plasma corticotropin (ACTH) and corticosterone concentrations, indicating a suppression of the hypothalamo-pituitary-adrenocortical axis. Cortisol also decreased body weight, food intake, plasma norepinephrine (NE), and epinephrine (E) levels. In the drug challenge studies, we used two 5-HT1 agonists, the 5-HT1B and 5-HT1C agonist, m-chlorophenylpiperazine (m-CPP), and the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), to examine the effect of cortisol on their behavioral and neuroendocrine effects. After 7-day cortisol treatment, plasma prolactin responses to both m-CPP and 8-OHDPAT were significantly decreased. While the plasma NE, E, and food intake responses to m-CPP were also significantly reduced by cortisol treatment, these same responses to 8-OHDPAT were unchanged. The effect of m-CPP on locomotor activity was also decreased. Since only the responses to m-CPP and 8-OHDPAT previously shown to be antagonized by pretreatment with the 5-HT1/5-HT2 antagonist, metergoline, were significantly attenuated after cortisol treatment, these changes may be specific to 5-HT receptors. These data indicate that chronic exposure to high glucocorticoid levels alters 5-HT1 receptor-mediated functions and provides additional evidence relevant to the contribution of glucocorticoid elevation to the symptoms of depression.
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PMID:Long-term cortisol treatment impairs behavioral and neuroendocrine responses to 5-HT1 agonists in the rat. 255 39

5.7-Dinitro-quinoxaline-2.3-dione (MNQX) displaced [3H]glycine binding to cortical membranes but had no effect n [3H]3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ([3H]CPP) binding. MNQX potently antagonized N-methyl-D-aspartate (NMDA)-evoked release of [3H]GABA from cultured cortical neurones, NMDA evoked spreading depression and NMDA depolarizations in the rat neo-cortex. All of these responses were reversed by addition of glycine to the perfusion media. These results suggested that MNQX is an antagonist at the strychnine-insensitive glycine receptor associated with the NMDA receptor/ionophore complex. Furthermore the compound was found to antagonise audiogenic seizures in DBA-2 mice indicating the potential of glycine antagonists of this type in anticonvulsant therapy.
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PMID:A potent antagonist of the strychnine insensitive glycine receptor has anticonvulsant properties. 256 Sep 79

Involvement of the brain serotonin (5-HT) neurotransmitter system in obsessive-compulsive disorder (OCD) was originally suggested on the basis of therapeutic effects found with the semiselective serotonin uptake inhibitor, clomipramine. More recent studies directly comparing clomipramine with non-selective or norepinephrine-selective uptake inhibitors, such as desipramine or nortriptyline, as well as studies with new, more selective serotonin uptake inhibitors, including fluvoxamine and fluoxetine, have supported that hypothesis. Clomipramine's antiobsessional effect has been augmented with the serotonin precursor, L-tryptophan, or with lithium, which has prominent serotonergic effects. Patients whose OCD symptoms improved on clomipramine worsened when the drug was discontinued (regardless of duration of therapy) and improved when clomipramine was reinstituted. OCD symptoms also worsened when metergoline, a 5-HT antagonist, was given to patients who had improved with clomipramine. Metergoline given alone had no effect. Administration of m-chlorophenylpiperazine (m-CPP), a 5-HT receptor agonist, to untreated OCD patients increased their anxiety, depression, and dysphoria, and exacerbated their OC symptoms. After 4 months of clomipramine therapy, m-CPP failed to produce the same behavioural effects, suggesting an alteration of a 5-HT subsystem (possibly downregulation of some 5-HT receptors). The data reviewed suggest an important role for an abnormal brain 5-HT subsystem in patients with OCD.
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PMID:Obsessive-compulsive disorder as a 5-HT subsystem-related behavioural disorder. 269 36

A mature sacrococcygeal in vitro spinal preparation from the rat has been used to demonstrate effects of neutral amino acids and their antagonists. gamma-Aminobutanoate (GABA), glycine and taurine (0.5-5 mM) produced dose-dependent depression of spontaneous paroxysmal activity generated in Mg2+ -free medium. The depressant effect of GABA was antagonised selectively by picrotoxin (25-50 microM) and the depressant effects of glycine and taurine were antagonised selectively by strychnine (0.2 microM). Glycine (0.5-5 mM) had a dose-dependent depolarizing action which was present at the central ends of isolated ventral roots. gamma-Aminobutanoate and taurine, had only weak depolarizing actions on ventral root fibres. Depolarizing responses to glycine showed a marked fading. Reduction in the fading appeared to be responsible for a paradoxical potentiation of glycine-induced depolarizations, which occurred in the presence of strychnine (0.2-2 microM). Strychnine (2-10 microM), picrotoxin (10-50 microM) or bicuculline (10 microM) had little or no effect on the amplitude, duration or latency of the monosynaptic component of ventral root reflexes evoked by supramaximal stimulation of dorsal roots (DR-VRP). However all three antagonists introduced slow, NMDA receptor mediated, components to these ventral root potentials. Picrotoxin and bicuculline, but not strychnine, reversibly depressed the dorsal root potential evoked from an adjacent dorsal root (DR-DRP). The depressant actions of 2-amino-5-phosphonopentanoate (AP5), kynurenate and 3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) revealed both NMDA and non-NMDA receptor mediated components in the dorsal root potential.
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PMID:Effects of depressant amino acids and antagonists on an in vitro spinal cord preparation from the adult rat. 276 79

The diagnosis, treatment, and pathophysiology of obsessive-compulsive disorder (OCD) were examined in a series of studies utilizing psychobiological approaches. Putative biological markers previously reported in depression were studied in this disorder and revealed that on some measures [Dexamethasone Suppression Test and rapid eye movement (REM) latency on sleep electroencephalogram (EEG)], OCD patients resemble those with major depressive disorder (MDD), whereas on others [REM density, platelet serotonin uptake, probably platelet 3H-imipramine binding, and 5-hydroxy-indoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF)] they do not. The relationship between OCD and MDD was further explored in a double-blind, randomized crossover study designed to compare the antiobsessional effects of two tricyclic antidepressants, clomipramine (CMI) and desipramine (DMI), in a nondepressed cohort of OCD patients. CMI was found to have significant antiobsessional effects in this group, whereas in the same patients, DMI lacked therapeutic effects. These results suggest that not all antidepressants are antiobsessive and that some property of CMI, such as its potent serotonergic effects, may be of pathophysiological relevance for OCD. The role of serotonin in this disorder was then tested using the pharmacological challenge strategy. A novel serotonin postsynaptic receptor (5HT-1) agonist, m-chlorophenylpiperazine (m-CPP), was administered orally (0.5 mg/kg) under double-blind, placebo-controlled conditions to OCD patients and controls. In addition, a serotonergic receptor antagonist, metergoline (4 mg), was given to a subset of OCD patients. Relative to healthy volunteers, the OCD patients became significantly more anxious, depressed, and dysphoric after m-CPP administration. Moreover, in the OCD patients, obsessive-compulsive symptoms increased markedly after m-CPP and decreased significantly following metergoline administration. These results demonstrate that agents that bind to the 5HT-1 receptor can acutely affect the symptoms of OCD patients. The striking behavioral effects of these direct postsynaptic receptor ligands and the relative specificity of clomipramine as an antiobsessional agent suggest that serotonergic neurons may play a role in the pathophysiology, as well as mediating the pharmacological reduction, of obsessional symptoms.
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PMID:Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment, and pathophysiology. 303 59

Blood flow was recorded with an electromagnetic flow probe on one internal carotid artery (ICA) during cardiopulmonary bypass (CPB) in 5 patients. The ICA flow was monitored continuously along with arterial blood pressure, epidural intracranial pressure, and cerebral electrical activity using a cerebral function monitor (3 patients). The ICA flow increased by 50 to 100% at the inception of extracorporeal circulation. This rapid enhancement of flow occurred within a thirty-second period and was due to rapid arterial hemodilution caused by introduction of the priming solution. A transitory fall in ICA flow was observed during subsequent minutes when the well-recognized drop in blood pressure took place and the cerebral perfusion pressure (CPP = blood pressure - epidural intracranial pressure) was reduced to less than 30 mm Hg. In only one instance, however, when CPP fell to 15 mm Hg, was the fall in flow lower than the prebypass level. Throughout the rest of CPB, with steady-state hemodilution and CPP levels in the range of 30 to 50 mm Hg, ICA flow was markedly enhanced (50 to 100% above the prebypass level). The flow pattern, however, disclosed a pressure-passive system, indicating that cerebral autoregulation was impaired or that the CPP levels were lower than the individual lower limit of cerebral autoregulation during the period of steady-state hemodilution on CPB. A transient depression of cerebral electrical activity was seen in 2 patients shortly after the introduction of CPB. This phenomenon is suggestive of qualitatively insufficient perfusion and was observed even when ICA bulk flow was increased (hematocrit values, 13 to 17%).
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PMID:Some observations on cerebral perfusion during cardiopulmonary bypass. 398 7

M-Chlorophenylpiperazine (m-CPP) produces effects on the central serotonergic system in animals compatible with direct agonist activity on postsynaptic serotonin receptors. Although it is a metabolite of the antidepressant trazodone, m-CPP has not previously been given to humans. To evaluate the neuroendocrine, behavioral, and physiological effects of m-CPP, 15 normal subjects were given 0.5 mg/kg m-CPP, orally. Administered acutely under double blind, placebo-controlled conditions, m-CPP was well tolerated by 14 of the 15 subjects; it produced significant increases in plasma PRL and cortisol and in body temperature, without changing pulse or blood pressure. The mean (SD) maximal increases over baseline for PRL, cortisol and temperature were 13.4 (9.9) ng/ml, 10.1 (6.7) micrograms/100 ml, and 0.4 (0.2) C, respectively. A small but significant increase in self-rated activation-euphoria and anxiety was noted by some subjects, whereas there were no significant effects on ratings of depression, dysphoria, altered self-reality, or functional impairment. These results are similar to those for other serotonin agonists and, thus, suggest that m-CPP merits further study as a pharmacological probe of serotonergic responsivity in humans. The results also support the hypothesis that serotonin plays a role in the regulation of PRL, cortisol, body temperature, and mood.
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PMID:Neuroendocrine effects of M-chlorophenylpiperazine, a serotonin agonist, in humans. 405 85

We have recently demonstrated that hyperthermia induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and m-chlorophenylpiperazine (m-CPP) are separately mediated by selective stimulation of 5-HT2A and 5-HT2C receptors, respectively in Wistar rats. Furthermore, hyperthermia induced by either DOI or m-CPP was found to be significantly less in Fawn-Hooded rats (a rat strain suggested to represent a genetic model of depression) relative to Wistar rats. In the present study, we studied the effects of long-term antidepressant treatments on DOI (2.5 mg/kg)-induced and m-CPP (2.5 mg/kg)-induced hyperthermia in male Fawn-Hooded rats. Long-term (21 days) treatment with the tricyclic antidepressants, imipramine or clomipramine (each 5 mg/kg/day), attenuated DOI-induced hyperthermia, while m-CPP-induced hyperthermia was accentuated. On the other hand, long-term (21 days) treatment with the monoamine oxidase type-A inhibiting antidepressant, clorgyline (1 mg/kg/day), did not modify m-CPP-induced hyperthermia, but significantly attenuated DOI-induced hyperthermia. These findings demonstrate that long-term antidepressant treatments alter 5-HT2A and 5-HT2C receptor-mediated hyperthermia in a genetic animal model of depression.
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PMID:Long-term antidepressant treatments alter 5-HT2A and 5-HT2C receptor-mediated hyperthermia in Fawn-Hooded rats. 749 90

Administration of various doses of DOI (a 5-HT2A/5-HT2C agonist) produced hyperthermia that was significantly less in the FH rat strain relative to the Wistar rat strain. Similarly, administration of various doses of ipsapirone (a 5-HT1A agonist) produced hypothermia that was significantly less in the FH rat strain relative to the Wistar rat strain. Furthermore, m-CPP (a 5-HT agonist)-induced increases in growth hormone levels were also significantly less in the FH rat strain relative to the Wistar rat strain. There was no significant difference in the levels of either 5-HT or 5-HIAA between the two rat strains in the frontal cortex, hippocampus, hypothalamus, and striatum. In the brain stem, however, both 5-HT and 5-HIAA levels were significantly lower in the FH rat strain relative to the Wistar rat strain. On the other hand, 5-HT turnover rate was significantly higher in the hypothalamus and striatum and significantly lower in the hippocampus in the FH rat strain relative to the Wistar rat strain. These findings provide further evidence for altered serotonergic function in the FH rat strain and, in addition, suggest that the FH rat strain may prove to be a useful genetic model for some neuropsychiatric disorders with possible abnormalities in serotonergic function such as depression, obsessive-compulsive disorder, and the eating disorders.
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PMID:Functional and biochemical evidence for altered serotonergic function in the fawn-hooded rat strain. 753 10

The consequence of long-term potentiation (LTP) of hippocampal commissural inputs was investigated in an auditory gating paradigm. Auditory evoked potentials (AEPs) were recorded in the CA3b region of the hippocampus of rats anesthesitized with chloral hydrate. Two tones were delivered 0.5 sec apart; in this paradigm, the second AEP is diminished compared to the first. Electrical stimulation was applied to hippocampal commissural fibers to generate field potentials and population spikes which were recorded at the same site as the AEPs. LTP of the commissural input (initiated by three trains of 250 Hz/1 sec stimulation) was associated with changes in the AEPs: on average, the response to the first tone decreased and the response to the second tone increased, resulting in the disruption of auditory gating. When high-frequency stimulation of the commissural input failed to result in LTP, no effect on the AEPs was seen. If 3-(2-carboxypiperazin-4-yl)-propyl-L-phosphonic acid (CPP; 6 mg/kg, i.p.), an antagonist to the NMDA subclass of glutamate receptors, was administered prior to high-frequency stimulation, LTP induction was blocked and AEPs were not affected. Finally, reversal of LTP, achieved by high-frequency stimulation of CA3 input that was heterosynaptic to the particular commissural fibers at which the LTP was originally generated, caused disrupted auditory gating to return to normal. A model of reciprocal LTP and heterosynaptic depression of commissural and auditory input pathways is proposed to explain these findings.
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PMID:Long-term potentiation disrupts auditory gating in the rat hippocampus. 764 22


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