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)

Aniracetam, 1-p-anisoyl-2-pyrrolidinone, is known to be a nootropic or cognitive activator. Aniracetam protects against memory and learning deficits without causing effects on motor function and the autonomic nervous system. A drug dependence study on aniracetam utilizing the intragastric route of administration was performed in male cynomolgus monkeys. The behavioral observation test after acute administration revealed that aniracetam at the dose of 25-400 mg/kg did not change the gross behavior. In the self-administration initiation test, animals were exposed to two or three unit doses of aniracetam and references for a total available period of 7 weeks. Aniracetam at the dose of 25, 50 and 75 mg/kg/injection did not initiate self-administration in the respective group of 4, 4 and 2 animals. In the study with d-methamphetamine hydrochloride at the dose of 0.1 mg/kg/injection, 1 out of 4 animals started to consistently self-administer the drug. Self-administration of cocaine hydrochloride at the dose of 10 mg/kg/injection was confirmed in 3 out of 5 animals, and these 3 animals died from overdosing later. In the physical dependence direct induction test, animals received aniracetam (50 mg/kg) and sodium pentobarbital (25 mg/kg: the dose inducing intermediate CNS depression) intragastrically twice a day for 31 consecutive days. Abrupt withdrawal of aniracetam did not elicit abstinent signs (including changes in appetite and body weight) in all 6 animals, whereas withdrawal of pentobarbital produced typical abstinent behavioral signs and decreases in appetite and body weight. In conclusion, aniracetam was confirmed to develop neither physical dependence nor psychic dependence in cynomolgus monkeys.
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PMID:[Drug dependence test on a cerebral insufficiency improver, aniracetam]. 357 Jan 3

Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses occurs when these synapses are activated in conjunction with direct activation of voltage-gated calcium (Ca2+) channels of PCs. In the present study, we have used Aniracetam to test whether the expression of LTD at PF-PC synapses is due to a genuine modification of properties of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptors of these neurons. Whole-cell recordings of PF-mediated EPSCs were performed in thin slices taken from 16-22-day-old rats. In all tested cells, bath application of Aniracetam potentiated PF-mediated EPSCs and prolonged their decay without notably changing their rising phase. On the other hand, Aniracetam prevented the induction of LTD by a pairing protocol with Ca2+ spikes and, conversely, the nootropic compound had a larger potentiating effect on PF-mediated EPSCs during expression of LTD than normally, when this change in synaptic efficacy had been induced prior to Aniracetam application. These data strongly suggest that LTD involves a desensitization of postsynaptic AMPA receptors at PF-PC synapses, or, at least, a change in their functional characteristics.
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PMID:Properties of glutamate receptors are modified during long-term depression in rat cerebellar Purkinje cells. 800 49

Transmission at the end-bulb synapse formed by auditory nerve terminals onto the soma of neurons in the avian nucleus magnocellularis is characterized by high transmitter release probability and strong synaptic depression. Activation of presynaptic GABA(B) receptors minimizes depression at this synapse and significantly enhances synaptic strength during high-frequency activity. Here we investigate synaptic mechanisms underlying this phenomenon. EPSC amplitudes evoked by 200 Hz trains increased more than twofold when release probability was reduced with Cd(2+) or baclofen. This effect was not exhibited by a transmitter depletion model of presynaptic depression, which predicts that EPSC amplitudes reach a common steady-state amplitude during high-frequency trains, despite alterations of initial release probability. However, an additional source of postsynaptic depression was sufficient to explain our findings. Aniracetam, a modulator of AMPA receptors that reduces desensitization, decreased the amount of synaptic depression during trains, indicating that desensitization occurred during trains of stimuli. However, this effect of aniracetam was absent when release probability was lowered with baclofen or Cd(2+). No effect of aniracetam on the NMDA component of the EPSC was seen, confirming a postsynaptic site of action of aniracetam. When desensitization was reduced with aniracetam, steady-state EPSC amplitudes during trains were found to converge over a wide range of release probabilities, as predicted by the depletion model. Additional evidence of AMPA receptor desensitization was provided by direct measurement of quantal amplitudes immediately after stimulus trains. Thus, presynaptic modulation by GABA(B) receptors regulates the extent of AMPA receptor desensitization and controls synaptic strength, thereby modulating the flow of information at an auditory synapse.
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PMID:Minimizing synaptic depression by control of release probability. 1124 70

Aniracetam is a pyrrolidinone-type cognition enhancer that has been clinically used in the treatment of behavioral and psychological symptoms of dementia following stroke and in Alzheimer's disease. New discoveries in the behavioral pharmacology, biochemistry and pharmacokinetics of aniracetam provided new indications for this drug in the treatment of various CNS disorders or disease states. This article reviews these new findings and describes the effects of aniracetam in various rodent models of mental function impairment or cerebral dysfunction. Also, several metabolites of aniracetam have been reported to affect learning and memory in animals. It is, therefore, conceivable that major metabolites of aniracetam contribute to its pharmacological effects. The animal models, used in pharmacological evaluation of aniracetam included models of hypoattention, hypovigilance-arousal, impulsiveness, hyperactivity, fear and anxiety, depression, impaired rapid-eye movement sleep, disturbed temporal regulation, behavioral performance, and bladder hyperactivity. These are models of clinical disorders or symptoms that may include personality disorders, anxiety, depression, posttraumatic stress disorder, attention-deficit/hyperactivity disorder, autism, negative symptoms of schizophrenia, and sleep disorders. At present, there is no convincing evidence that promising effects of aniracetam in the animal models will guarantee its clinical efficacy. It is conceivable, however, that clinical trials will demonstrate beneficial effects of aniracetam in the above listed disease states. New findings regarding the mechanism of action of aniracetam, its central target sites, and its effects on signal transduction are also discussed in this review article.
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PMID:Aniracetam: its novel therapeutic potential in cerebral dysfunctional disorders based on recent pharmacological discoveries. 1207 May 27

The mechanism of action of aniracetam on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors was examined in outside-out patches and at glutamatergic synapses in neurons of the chick cochlear nucleus. A combination of rapid-flow analysis, using glutamate as an agonist, and kinetic modeling indicated that aniracetam slows both the rate of channel closing, and the microscopic rates of desensitization, even for partially liganded receptors. Little effect was observed on the rate of recovery from desensitization or on the response to the weakly desensitizing agonist kainate. Aniracetam's effects on receptor deactivation saturated at lower concentrations than its effects on desensitization, suggesting that cooperativity between homologous binding sites was required to regulate desensitization. Analysis of responses to paired pulses of agonist also indicated that AMPA receptors must desensitize partially even after agonist exposures too brief to permit rebinding. In the presence of aniracetam, evoked excitatory synaptic currents (EPSCs) and miniature EPSCs in low quantal-content conditions had decay times similar to the time course of receptor deactivation. Under these conditions, the time course of both transmitter release and clearance must be <1 to 2 ms. However, in high quantal-content conditions, the evoked EPSC in aniracetam decayed with a time course intermediate between deactivation and desensitization, suggesting that the time course of transmitter clearance is prolonged because of pooling of transmitter in the synaptic cleft. Moreover, by comparing the amounts of paired-pulse synaptic depression and patch desensitization prevented by aniracetam, we conclude that significant desensitization occurs in response to rebinding of transmitter to the AMPA receptors.
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PMID:The mechanism of action of aniracetam at synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors: indirect and direct effects on desensitization. 1286 31

The master circadian pacemaker located in the suprachiasmatic nucleus (SCN) is entrained by light intensity-dependent signals transmitted via the retinohypothalamic tract (RHT). Short-term plasticity at glutamatergic RHT-SCN synapses was studied using stimulus frequencies that simulated the firing of light sensitive retinal ganglion cells. The evoked excitatory postsynaptic current (eEPSC) was recorded from SCN neurons located in hypothalamic brain slices. The eEPSC amplitude was stable during 0.08 Hz stimulation and exhibited frequency-dependent short-term synaptic depression (SD) during 0.5 to 100 Hz stimulus trains in 95 of 99 (96%) recorded neurons. During SD the steady-state eEPSC amplitude decreased, whereas the cumulative charge transfer increased in a frequency-dependent manner and saturated at 20 Hz. SD was similar during subjective day and night and decreased with increasing temperature. Paired-pulse stimulation (PPS) and voltage-dependent Ca(2+) channel (VDCC) blockers were used to characterize a presynaptic release mechanism. Facilitation was present in 30% and depression in 70% of studied neurons during PPS. Synaptic transmission was reduced by blocking both N- and P/Q-type presynaptic VDCCs, but only the N-type channel blocker significantly relieved SD. Aniracetam inhibited AMPA receptor desensitization but did not alter SD. Thus we concluded that SD is the principal form of short-term plasticity at RHT synapses, which presynaptically and frequency-dependently attenuates light-induced glutamatergic RHT synaptic transmission protecting SCN neurons against excessive excitation.
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PMID:Retinohypothalamic tract synapses in the rat suprachiasmatic nucleus demonstrate short-term synaptic plasticity. 2022 78