Spontaneous Potentiation Research Articles

Effect of early embryonic exposure to morphine on defects in the GABAergic system of day-old chicks

Embryonic morphine exposure (EME) leads to abnormal brain development and behavior in the offspring, and the functional alteration of γ-aminobutyric acid (GABA) system is considered to be one of the important mechanisms. To mimic the problem of susceptibility of human gestational drug abuse on addictive drugs in offspring, we administered morphine exposure on days 5–8 and 13–16 of chicken embryo development and examined the functions of GABA neurons and their receptors in postnatal chicks by neuroelectrophysiology, immunohistochemistry and behavioral methods. We found that morphine exposure during embryonic stages 5–8 (MorphineE5–8) significantly reduced the incidence of spontaneous inhibitory postsynaptic potentiation (IPSP) and the induction of evoked IPSP and the mean amplitude of GABAA agonist muscimol-induced response in the intermediate medial interstitial (IMM) region, compared to naïve controls or saline-exposed chicks. The results of immunocytochemistry further suggest that MorphineE5–8 decreased the synaptic density of GAD-expressing sites in the IMM, while increased the expression of the GABAA receptor subtype γ2 isoform. Behavioral results found that Morphine5–8 treatment de-inhibited morphine-induced psychomotor responses in postnatal chicks. Morphine exposure at embryonic stages 13–16 (MorphineE13–16) showed no significant changes in the above indicators compared to the saline group. Evidence suggests that early embryonic morphine exposure leads to defects in GABAergic function in the IMM, which in turn alters the responsiveness of postnatal chicks to addictive drugs. These results will help to understand the GABA mechanisms by which embryonic addictive drug exposure contributes to offspring susceptibility to addiction.

Spontaneous Acetylcholine Release Potentiation Induced by 2-Arachidonoylglycerol and Anandamide in Mouse Motor Synapses

Spontaneous Acetylcholine Release Potentiation Induced by 2-Arachidonoylglycerol and Anandamide in Mouse Motor Synapses

Potential of Pandanus odoratissimus as a CNS depressant in Swiss albino mice

In this study, several neuropharmacological effects of methanolic leaf extract of Pandanus odoratissimus (PO) (family; Pandanaceae) were studied in albino mice using various experimental models. The effect of PO on the CNS was studied by using different neuropharmacological paradigms including spontaneous motor activity, rota-rod performance and potentiation of Pentobarbital sodium sleeping time in albino mice. Preliminary phytochemical evaluation and acute toxicity studies were also carried out where LD50 >2000 mg/kg was considered non-toxic through acute exposure in rats by the oral route. The methanolic leaf extract (50,100 and 200 mg/kg i. p.) produced a reduction in spontaneous motor activity, motor coordination and prolonged Pentobarbital sodium sleeping time. Preliminary qualitative chemical studies indicated the presence of steroids, saponins, terpinoids, glycosides, tannins, flavonoids and phenolics in the extract. These observations suggest that the leaf of Pandanus odoratissimus contains some active principles which possess potential CNS-depressant action

Distinct Profiles of Anxiety and Dysphoria during Spontaneous Withdrawal from Acute Morphine Exposure

The negative motivational aspects of withdrawal include symptoms of both anxiety and depression, and emerge following termination of chronic drug use as well as after acute drug exposure. States of acute withdrawal are an inherent part of intermittent drug use in humans, but the contribution of acute withdrawal to the development of addiction has received limited systematic investigation, due to a lack of preclinical models for withdrawal states that emerge spontaneously after acute drug exposure. Here, we have characterized a spontaneous increase in the magnitude of the acoustic startle reflex (i.e., spontaneous withdrawal-potentiated startle) that emerges following acute morphine administration in rats, and compared the time course of startle potentiation and place conditioning. We find that startle potentiation appears related to a decrease in opiate receptor occupancy and reflects an anxiety-like state with a pharmacological profile similar to other signs of opiate withdrawal. Spontaneous startle potentiation emerges before the rewarding effects of morphine have subsided, even though naloxone administration after a single morphine exposure causes both startle potentiation and conditioned place aversion (CPA). These results demonstrate that negative emotional signs of withdrawal develop following just one exposure to morphine, and are likely a recurrent aspect of intermittent drug use that may contribute to the earliest adaptations underlying the development of addiction. Furthermore, the dissociation between spontaneous startle potentiation and CPA suggests anxiogenic and dysphoric manifestations of opiate withdrawal may be mediated by distinct neural mechanisms that are progressively engaged as withdrawal unfolds.

Some Neuropharmacological Effects of the Crude Venom Extract of <i>Conus musicus</i> in Mice

This study reports some neuropharmacological effects of the crude venom extract of Conus musicus (family Conidae) in mice using various experimental models. The crude venom was found to significantly increase tail flick reaction time in mice. The effects of the venom on the central nervous system were studied by observing spontaneous motor activity, gross behaviour, rota-rod performance and potentiation of pentobarbitone sleeping time in mice. Preliminary acute toxicity evaluation was also carried out and the LD50 was found to be 460.23 μg/kg following intraperitoneal administration. At a dose of 200 μg/kg i.p., the extract produced a reduction in spontaneous motor activity, altered gross behavior and motor coordination and prolonged pentobarbitone-sleeping time. A liquid chromatography mass spectroscopic study has indicated the presence of ω-conotoxin in the crude venom extract. Keywords: Conus musicus, sedation, spontaneous motor activity, gross behavior, motor coordination East and Central African Journal of Pharmaceutical Sciences Vol. 10 (2) 2007: pp. 27-33

Anxiolytic and Antiseizure Effects of Sida tiagii Bhandri

The central nervous system (CNS) pharmacological effects of ethylacetate extract (EAS) of Sida tiagii Bhandri collected from northern province (Rajasthan) of India wer ea ssessed by elevated plus-maze, pentobarbitone induced sleeping time, spontaneous motor activity, pentylenetetrazole-induced seizure, forced swim test and rotarod tests. The results of the present study demonstrated the CNS depressant potential, i.e. ,a nxiolytic, antiseizure, reduction in spontaneous locomotion and potentiation of pentobarbital-induced hypnosis of the plant under investigation.

Some Neuropharamacological Effects of the Crude Extract of Conus parvatus in Mice

The present study was aimed to characterize the type of conotoxin present in Conus parvatus. (CP) belongs to family conidae, through neuro-pharmacological activities of the crude venom extract on some of the CNS animal experiment using mice as animal model. The effects of CP on CNS were studied, by using spontaneous motor activity, gross behavior, rota-rod performance, analgesic activity and potentiation of pentobarbitone sleeping time in mice. Preliminary evaluation of acute toxicity was also carried out; The LD50 value was found to be 425.20 mcg kg(-1) by i.p. route. The extract (200 mcg kg(-1) i.p.) was found to produce, reduction in spontaneous motor activity, potent analgesic activity, reduction in motor coordination and prolonged pentobarbitone-sleeping time. From the above all pharmacological activities, it may concluded that, the conotoxin present in CP is most likely to be a alpha-conotoxin and also it will be more suitable to continue the studies in the areas of analgesic and other CNS depressant therapeutic areas after isolation of the pure cono-peptide from CP.

NMDA Receptor Subunit Composition Controls Synaptic Plasticity by Regulating Binding to CaMKII

Calcium entry through postsynaptic NMDA-Rs and subsequent activation of CaMKII trigger synaptic plasticity in many brain regions. Active CaMKII can bind to NMDA-Rs, but the physiological role of this interaction is not well understood. Here, we test if association between active CaMKII and synaptic NMDA-Rs is required for synaptic plasticity. Switching synaptic NR2B-containing NMDA-Rs that bind CaMKII with high affinity with those containing NR2A, a subunit with low affinity for CaMKII, dramatically reduces LTP. Expression of NR2A with mutations that increase association to active CaMKII recovers LTP. Finally, driving into synapses NR2B with mutations that reduce association to active CaMKII prevents LTP. Spontaneous activity-driven potentiation shows similar results. We conclude that association between active CaMKII and NR2B is required for different forms of synaptic enhancement. The switch from NR2B to NR2A content in synaptic NMDA-Rs normally observed in many brain regions may contribute to reduced plasticity by controlling the binding of active CaMKII.

Postsynaptic modulation of AMPA- and NMDA-receptor currents by Group III metabotropic glutamate receptors in rat nucleus accumbens

Whole cell patch clamp recordings from rat nucleus accumbens neurons were made in order to study the effect of metabotropic glutamate receptors and dopamine on postsynaptic glutamate receptor mediated currents. AMPA- and NMDA-R currents were evoked by flash photolysis of caged glutamate, while spike-dependent release of neurotransmitters was prevented by adding tetrodotoxin and bicuculline to the bath solution. Spontaneous potentiation of NMDA- but not AMPA-R current was observed in the early phase of stimulation, followed by depotentiation and subsequent stabilization. The Group III metabotropic glutamate receptor antagonist MAP4 induced a transient potentiation of both AMPA- and NMDA-R current amplitudes, without affecting rise times and decay time constants. In contrast, the Group I–II metabotropic glutamate receptor antagonist MCPG and the neurotransmitter dopamine did not exert significant effects on either AMPA- or NMDA-R currents. These data suggest that at least one of the Group III subtypes is located postsynaptically in the nucleus accumbens and is able to dampen the activity of ionotropic glutamatergic receptors. In contrast, our results do not support a modulation of postsynaptic AMPA- and NMDA-R currents by Group I/II metabotropic glutamate receptors or dopamine. Modulation of both AMPA- and NMDA-R currents in the nucleus accumbens is likely to play a major role in setting the cellular excitability in response to behaviourally relevant limbic inputs, and in regulating the plasticity of these responses.

Protein kinase C potentiation of currents from mouse ζ1/ε2 NMDA receptors expressed in Xenopus oocytes depends on f-actin/g-actin cycling

NMDA currents from Xenopus oocytes expressing recombinant ζ1/ε2 NMDA receptors can be potentiated by activation of protein kinase-C (PKC) and also demonstrate time-dependent rundown. In order to determine whether cytoskeletal proteins are involved in either of these phenomena, experiments were performed using the f-actin stabilizer phalloidin, the f-actin de-stabilizer cytochalasin-D, and the microtubule stabilizer taxol. Phalloidin treatment both prevented rundown and inhibited PKC-potentiation of whole-cell currents but did not affect baseline current amplitudes. Treatment with cytochalasin-D also prevented rundown and inhibited PKC-potentiation of whole-cell currents, but baseline currents from cytochalasin treated cells were only 50% as large as those from control cells. Taxol had no effect on either rundown or PKC potentiation of NMDA currents. The results indicate that both spontaneous rundown and PKC potentiation of currents from heterologously expressed ζ1/ε2 NMDA receptors depend on dynamic actin polymerization/depolymerization but do not involve changes in microtubules.

The flavonoid constituents of two Polypodium species (Calaguala) and their effect on the elastase release in human neutrophils.

Five flavonoid compounds were isolated from two Polypodium species (P.decumanum and P.triseriale) with the common name Calaguala. Structure elucidation was carried out using different NMR techniques and revealed the presence of one new glycoside (kaempferol 3-O-beta-D-xylopyranosyl-(1-2)-beta-D-arabinopyranoside) (1), two known flavonoid glycosides, rutin and kaempferol 3-O-alpha-D-arabinopyranoside (2,3), the trimeric proanthocyanidin, selligueain (4), and the coumarinic acid derivative, melilotoside (5). The compounds were tested for their activity in PAF induced exocytosis in human neutrophils but none of the compounds showed PAF specific activity. Instead, they showed more general effects on the neutrophil including inhibition of the spontaneous elastase release (5) and potentiation of the release induced by PAF (1). Selligueain was found to inhibit the proteolytic enzyme, elastase in vitro.

Spontaneous potentiation of focal potentials of the CA1 field in long-surviving hippocampal slices of the rat in the absence of electrical stimulation.

The changes in the efficiency of the synaptic transmission in the Schaffer collaterals-field CA1 neurons pathways following prolonged deprivation of afferentation, the cessation (up to four hours) of stimulation of the tested input with brief series of tests every hour (the control afferent inputs, were stimulated throughout the entire experiment at a frequency of 0.05/sec), were investigated in surviving slices of the hippocampus of rats. The evoked focal potentials, population spikes (PS) and population excitatory postsynaptic potentials (pEPSP) were recorded. The prolonged cessation of stimulation led to a significant (p < 0.001) increase in the amplitude of the PS (up to 208% in relation to the baseline level). This phenomenon of potentiation was specific in relation to input and exhibited the properties of "E-S potentiation". A hypothesis is advanced regarding the association of mechanisms responsible for the development of "deprivational" potentiation and of the late phase of long-term posttetanic potentiation.

Catecholaminergic projections to tuberoinfundibular neurones of the paraventricular nucleus: III. Effects of adrenoceptor agonists and antagonists

Stimulation of the ventral noradrenergic ascending bundle (VNAB) at low frequencies ( 0.5 5 Hz) excited the majority ( 37 46 , 80%) of single paraventricular nucleus (PVN) tuberoinfundibular neurones, with high frequency (50 Hz) trains of stimuli reversing the direction of the response to inhibition for 7 16 (44%) of these excited cells. Iontophoretic application of noradrenaline, or the α1-adrenoceptor agonist 1-phenylephrine, increased the spontaneous electrical activity of most of the cells tested (94% and 72%), whilst application of the α1-antagonist, ergotamine reduced the spontaneous activity of 44% of the cells tested and prevented the excitation following VNAB stimulation for 84% of the cells examined. Application of the β-adrenoceptor antagonist, propranolol, increased the spontaneous activity of 77% of cells and prevented the inhibitory PVN neuronal responses following high frequency VNAB stimulation of 94% of the cells, often reversing the response to excitation similar to that observed following low frequency VNAB stimulation. The α2-adrenoceptor antagonist, tolazoline, was found to evoke mixed responses from the cells examined but a trend towards a suppression of spontaneous activity and potentiation of VNAB stimulation-evoked responses was observed. The α2-adrenoceptor agonist, clonidine, elicited an initial excitation from the majority of cells tested, with most of the cells then exhibiting an inhibition, either with or without continued application. Excitatory responses following stimulation of the sciatic nerve were recorded from the majority of cells (82.5%) and ergotamine was able to suppress this response for all four cells so tested. The results of this study extend the previous data demonstrating that the VNAB provides an excitatory input to the PVN, indicating that this input is primarily regulated by α1-adrenoceptors and that there is a tonic stimulation of such receptors. In addition, the increased spontaneous activity and blockade of inhibitory responses (following high frequency VNAB stimulation) during iontophoretic application of propranolol indicate the involvement of an inhibitory β-adrenoceptor mechanism mediating a tonic down-regulation of PVN neuronal activity and the inhibitory responses recorded following high frequency VNAB stimulation. The data are discussed in the context of the neural regulation of hypothalamo-pituitary-adrenocortical regulation.

肺循環とプロスタノイド 特に低酸素性肺血管収縮におけるプロスタノイドの関与

Hypoxic pulmonary vasoconstriction (HPV) is known to be an important physiological response to preserve an appropriate ventilation-perfusion ratio in the lung. The precise mechanism of HPV remains to be controversial, but recently the role of prostaglandins for mediating and/or modulating HPV has been emphasized. From this viewpoint, we studied the effect of PAF on HPV in anesthetized, open chest mongrel dogs. HPV was assessed by the change of total pulmonary resistance (TPR, PPA-PLA/QAO) . After the stable condition was established, 15-min exposure to 10% O2 followed by 15-min exposure to 100% O2 was repeated 6 times.In control group (N=5), spontaneous potentiation of HPV was observed during the 1st to the 5th hypoxic exposures, but an attenuation was occurred in the 6th hypoxic exposure.In PAF treatment group (N=5), the 6th hypoxic exposure was performed during continuous infusion of PAF at the dose of 33 ng/kg/min for 30 min (totally 1μg/kg) . This group showed no attenuation but potentiation of HPV in the 6th hypoxic exposure.Pretreatment with CV-3988 (10mg/kg), a specific antagonist of PAF, blocked the potentiating effect on HPV induced by PAF but pretreatment with OKY-046 (10mg/kg), a specific thromboxane synthetase inhibitor, did not block the effect of PAF.It is suggested that PAF, at the dose of 1μg/kg, acts as vasoconstrictor even in the condition of elevated pulmonary vascular tone induced by HPV in mongrel dogs.

General pharmacological action of 4-(o-benzylphenoxy)-N-methylamine hydrochloride (bifemelane hydrochloride, MCI-2016)--influence on the central nervous system

General pharmacological action of 4-(o-Benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane hydrochloride, MCI-2016) was examined with regard to the effects mainly on the central nervous system. MCI-2016, at 30-100 mg/kg, p.o., only showed a weak sleep prolongation effect (mice), anti-convulsant action (mice) and a moderate facilitation of exploratory behavior, but produced no remarkable behavioral changes. Above the doses of 200 to 300 mg/kg, p.o., MCI-2016 produced a decrease in muscle or body tone, mydriasis and a slight decrease of locomotor activity. The drug, however, showed little influence on exploratory behavior, conditioned avoidance response and normal body temperature (rats). Normal body temperature in rabbits was also little affected by MCI-2016. Effects on EEG was characterized by moderate activation of spontaneous EEG and potentiation of arousal response by stimulation of the midbrain reticular formation (1.5-5 mg/kg, i.v.). The drug, however, did not significantly change the sleep-wakefulness cycle and REM-sleep in rats. MCI-2016 also showed little influence on spinal reflex potentials and neuromuscular junction at high doses (10 mg/kg, i.v.). These results may indicate that MCI-2016 has slight influence on overall behavioral and motor changes. Effects of MCI-2016 on acetic acid-induced writhing, carrageenin edema and corneal reflex were also examined. MCI-2016 showed moderate analgesic and anti-inflammatory actions at 50-100 mg/kg, p.o., and also showed local anesthetic action. The duration of local anesthetic action was relatively long but the drug produced no local damage.

Pharmacological investigations on fruits of Withania coagulans, Dunal.

Pharmacological investigations with alcoholic extract, total alkaloids and aqueous extract of the fruits of Withania coagulans showed the presence of central nervous system depressant effect characterised by decreased spontaneous activity and potentiation of pentobarbitone hypnosis. However, the extracts showed no analgesic and anticonvulsant activity. In addition, alcoholic extract and total alkaloids showed a significant antiinflammatory effect in acute inflammation induced with egg albumin, subacute inflammation induced with formalin and granulation tissue formation by cotton pellet method.

Pharmacology of cis (Z) ‐ Clopenthixol Decanoate, a Depot Neuroleptic

Abstract: The duration and intensity of the neuroleptic effect of cis(Z)‐clopenthixol decanoate in Viscoleo$rG have been compared with those of cis(Z)‐clopenthixol, 2 HCl in aqueous solution in a number of animal experimental models. Cis(Z)‐clopenthixol, 2 HCl had a strong, but short‐lasting neuroleptic effect (apomorphine antagonistic effect in dogs, inhibition of conditioned avoidance response in rats) which was accompanied by marked sedation. In contrast, cis(Z)‐clopenthixol decanoate in oil had an effect which was slower in onset, but of much longer duration and only the highest doses caused a slight sedation. In rats catalepsy could be induced in some animals by high doses of cis(Z)‐clopenthixol decanoate whereas cis(Z)‐clopenthixol, 2 HCl at all the doses tested caused catalepsy in all animals. In mice only high doses of cis(Z)‐clopenthixol decanoate in oil caused reduction of spontaneous motor activity and potentiation of barbiturate anaesthesia. The results are discussed with special reference to the clinical use of the depot preparation.

Pharmacology of cis (Z) ‐ Clopenthixol Decanoate, a Depot Neuroleptic

The duration and intensity of the neuroleptic effect of cis(Z)-clopenthixol decanoate in Viscoleo have been compared with those of cis(Z)-clopenthixol, 2 HCl in aqueous solution in a number of animal experimental models. Cis(Z)-clopenthixol, 2 HCl had a strong, but short-lasting neuroleptic effect (apomorphine antagonistic effect in dogs, inhibition of conditioned avoidance response in rats) which was accompanied by marked sedation. In contrast, cis(Z)-clopenthixol decanoate in oil had an effect which was slower in onset, but of much longer duration and only the highest doses caused a slight sedation. In rats catalepsy could be induced in some animals by high doses of cis(Z)-clopenthixol decanoate whereas cis(Z)-clopenthixol, 2 HCl at all the doses tested caused catalepsy in all animals. In mice only high doses of cis(Z)-clopenthixol decanoate in oil caused reduction of spontaneous motor activity and potentiation of barbiturate anaesthesia. The results are discussed with special reference to the clinical use of the depot preparation.