Biomedical subjects

I Nalepa

Publications and source records attributed to I Nalepa.

At least 19 recordsLinked to original sources

PubMed2005

Formalin hindpaw injection induces changes in the [3H]prazosin binding to alpha1-adrenoceptors in specific regions of the mouse brain and spinal cord.

Involvement of the alpha1-adrenoceptor subtypes in early and late phases of formalin pain was investigated by quantitative in vitro autoradiography in the spinal cord and brain structures of CD-1 mice. Total alpha1-adrenoceptors binding (including all alpha1-adrenoceptor subtypes) was assessed with [3H]prazosin; alpha(1B)-adrenoceptor was assessed with [3H]prazosin in the presence of 10 nM WB4101 to mask remaining alpha1-adrenoceptor subtypes. Early after formalin injection the alpha1-adrenoceptors (mainly alpha1B receptor) binding was reduced in the contralateral hind limb area of the somatosensory cortex and in the secondary motor cortex. A reduction occurred also in the ipsilateral laminae I-III of the spinal cord (both alpha1B- and non-alpha1B-adrenoceptors). Lately an increase of alpha1-adrenoceptors binding (mostly subtypes other than alpha1B) appeared in discrete amygdaloid and thalamic nuclei. These results provide the first description of changes at the level of central alpha1-adrenoceptors' binding during the formalin-induced pain in mice. Their distribution suggests that they may have a functional meaning.

Amygdala↗

PubMed2003

The interaction of tetrahydroisoquinoline derivatives with antinociceptive action of morphine and oxotremorine in mice.

To extend our earlier data on synergistic action of tetrahydroisoquinolines and morphine, we have investigated the analgesic effects of 1,2,3,4-tetrahydroisoquinoline (TIQ) and its 1-methyl-(1-MeTIQ) and N-methyl (N-MeTIQ) analogs on analgesia induced by morphine and oxotremorine. 1-MeTIQ and N-MeTIQ induced a moderate, delayed and prolonged analgesic action measured in the tail-flick test in CD-1 mice; 1-MeTIQ and TIQ prolonged the opiate (morphine, 2.5 mg/kg i.p.) analgesia while TIQ and N-TIQ potentiated cholinergic (oxotremorine, 0.02 mg/kg i.p.) analgesia. The involvement of the opioid and noradrenergic systems in this effect is discussed.

Acetylcholine↗

PubMed2001

Opposite effect of simple tetrahydroisoquinolines on amphetamine- and morphine-stimulated locomotor activity in mice.

Endogenous tetrahydroisoquinolines, such as 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), were tested for their interaction with motor effects of amphetamine and morphine in C57BL/6 mice. TIQ binding to cortical adrenergic alpha1, alpha2 and beta receptors, striatal dopamine D1 and D2 receptors and cortical L-type calcium channels in the Wistar rat was also studied. Both compounds in high doses reduced the mouse locomotor activity, and in doses not affecting activity inhibited the motor stimulation induced by amphetamine, 2 or 3 mg/kg i.p., but facilitated the hyperactivity induced by 10 mg/kg of morphine. TIQ did not displace ligands that are antagonists for several receptor sites (including D1 and D2 receptors), but displaced an agonist of alpha2-adrenoceptor, clonidine. It is proposed that TIQ and salsolinol specifically antagonize the agonistic conformation of dopamine receptor and that endogenous 1,2,3,4-tetrahydroisoquinolines may play a role of natural feedback regulators of the activity of dopaminergic system.

Adrenergic alpha-Agonists↗

PubMed2000

Antidepressants: past, present and future.

Since the discovery of first antidepressants in mid-1950's, the field has been intensively studied. Several new classes of compounds emerged and several hypotheses on the mechanism of their action were proposed. The novel antidepressants are either selective and reversible monoamine oxidase inhibitors, (e.g., moclobemide), or selective serotonin reuptake inhibitors (e.g., citalopram or paroxetine), or serotonin and noradrenaline reuptake inhibitors (e.g. , venlafaxine). Recently neuropeptides (e.g., thyrotropin-releasing hormone,TRH) or antagonists of neuropeptide receptors (e.g., tachykinin NK(1) receptor) undergo clinical tests. Several hypotheses proposed the predominant involvement of one or few neurotransmitter receptors in the mechanism of antidepressant action, but it is now assumed that several distinct receptor mechanisms' trigger different but converging intracellular signal cascades that activate transcription factors, which, in turn, promote the expression of genes encoding for proteins, that play a crucial role in restoring of neuronal functions involved in mood regulation.

Animals↗

PubMed2000

Different regulation of phospholipase D activity in glioma C6 cells by sphingosine, propranolol, imipramine and phorbol ester.

In has been found that sphingosine, propranolol, imipramine and phorbol ester (12-O-tetradecanoylphorbol-13-acetate, TPA) have a stimulatory effect on phospholipase D activity in glioma C6 cells. The cells were prelabelled with [1-(14)C]palmitic acid and phospholipase D-mediated synthesis of [(14)C]phosphatidylethanol was measured. The enhancing effect of TPA was almost completely blocked by a specific protein kinase C inhibitor, GF 109203X. In contrast, GF 109203X failed to inhibit the sphingosine, imipramine and propranolol stimulatory effects, indicating that their stimulation was independent of protein kinase C. The effect of TPA on phospholipase D was also blocked by imipramine and propranolol, whereas sphingosine additively potentiated TPA-mediated phospholipase D activity, both at shorter and longer (2-60 min) times of incubation. These results suggest that in glioma C6 cells, sphingosine is not only involved in a different phospholipase D activation than the TPA regulatory system, but also that it operates in a different compartment of the cell.

Animals↗

PubMed2000

Splenectomy and adoptive cell transfer reveal a prominent role for splenic memory lymphocytes in the development of chronic relapsing experimental autoimmune encephalomyelitis.

We previously reported that acute experimental autoimmune encephalomyelitis (EAE), induced by active immunization of SJL mice, could be converted into chronic relapsing EAE (CR-EAE) by a pretreatment with neuroantigen and killed mycobacteria 2 months earlier. This finding indicates that immune memory, established by the pretreatment, influences the subsequent EAE induction. The present study shows that splenectomy and lymphadenectomy, applied 1 week before the subsequent active immunization of the pretreated mice, efficiently abort the chronic nature of CR-EAE. Furthermore, we have found that adoptive transfer of lymphocytes from the spleen (but not of those from the local draining lymph nodes) of the pretreated mice to naive syngeneic recipients 1 week before the acute EAE-induction immunization results in the development of CR-EAE. On the other hand, the transfer of lymphocytes from the local draining lymph nodes aggravates the acute disease. These data support a critical role for immune memory of the previous suboptimal challenge in the development of chronic relapsing demyelinating disease.

Adoptive Transfer↗

PubMed1998

Lack of beta adrenoceptor desensitization in brain following the dual noradrenaline and serotonin reuptake inhibitor venlafaxine.

Venlafaxine, a dual amine reuptake inhibitor, was utilized to delineate the role of the individual aminergic components of the 'serotonin/noradrenaline link' in modifying receptor-linked second messenger cascades. Venlafaxine (20 mg/kg i.p. bid for 10 days) failed to alter in normal animals either the density of beta adrenoceptors or the response of the beta adrenoceptor-coupled adenylate cyclase system to noradrenaline but significantly decreased the cyclic AMP response to noradrenaline in the brain of rats with selective depletion of brain serotonin by p-chlorophenylalanine. The studies provide evidence for a cross-talk between noradrenergic and serotonergic receptor cascades at the level of mechanisms involved in the desensitization of the beta adrenoceptor-coupled adenylate cyclase system.

Adenylyl Cyclases↗

PubMed1997

Does Ca2+ channel blockade modulate the antidepressant-induced changes in mechanisms of adrenergic transduction?

We investigated how the L-type calcium channel blockade (CCB) with nifedipine affects the cyclic AMP responses to noradrenaline or isoproterenol in cerebral cortical slices from rats receiving antidepressant treatments that induce (electroconvulsive shock, imipramine) or do not induce (amitriptyline) beta-downregulation. To assess the role of protein kinase C (PKC) in receptor crosstalk under CCB conditions, the cyclic AMP responses were tested also in the presence of a PKC activator, TPA. CCB alone induced no changes, but modulated the action of those antidepressants that down regulate the beta-adrenergic system. Chronic ECS and imipramine treatments were differently affected. ECS, under conditions of CCB, down regulated the response to isoproterenol in the presence of TPA, while imipramine ceased to block the TPA-potentiation of cyclic AMP responses. Thus, CCB affects the processes related to the antidepressant-induced changes on the crosstalk between alpha1- and beta-adrenergic receptors, depending on the specific properties of the antidepressant.

Adrenergic Agents↗

PubMed1996

The effect of chronic administration of amitriptyline on the effects of subsequent electroconvulsive treatment on responsiveness of alpha 1-and beta-adrenoceptors in the rat cortical slices.

Both antidepressant drugs and repeated electroconvulsive shock (ECS) produce adaptive changes in cerebral neurotransmitter systems. As in the clinical practice ECS is used almost always after therapeutical failure of pharmacotherapy, we investigated presently how chronic administration of an antidepressant amitriptyline affects the action of subsequent multiple ECS in rats. Amitriptyline differed from ECS and from other classical antidepressant in producing no beta-downregulation and potentiating the inhibitory effect of protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA), on responses of alpha 1-adrenoceptor system to noradrenaline. The action of ECS on alpha 1-adrenoceptor system remained essentially unaffected by previous amitriptyline administration. Its downregulatory effect on responses of beta-adrenoceptor system to noradrenaline, and particularly to isoproterenol, were attenuated by previous drug treatment. The present results suggest that previous chronic administration of antidepressant drugs may alter the effect of subsequent ECS.

Adrenergic alpha-1 Receptor Agonists↗

PubMed1995

Norepinephrine-independent regulation of GRII mRNA in vivo by a tricyclic antidepressant.

Desipramine (DMI), a tricyclic antidepressant drug used in the treatment of depression, has been shown to increase steady-state levels of glucocorticoid receptor type II (GRII) mRNA in vitro and in vivo. To determine whether this effect is secondary to norepinephrine (NE) reuptake inhibition i.e., increases in synaptic NE induced by DMI, GRII mRNA levels were assayed in rat hippocampus following neurotoxic lesioning of NE neurons with DSP4. Chronic DMI treatment significantly increased GRII mRNA levels to the same degree in lesioned and non-lesioned animals. In contrast to DMI, the non-tricyclic antidepressant fluoxetine had no effect on GRII mRNA. These results provide evidence which demonstrates that a tricyclic antidepressant can regulate steady-state mRNA levels in vivo by a mechanism which is independent of its effects on synaptic monoamine levels.

Animals↗

PubMed1994

Reversal by imipramine of beta-adrenoceptor up-regulation induced in a chronic mild stress model of depression.

Male Wistar rats were subjected to a chronic mild stress procedure involving different stress stimuli applied for 8 weeks. During this time the consumption of 1% sucrose solution was monitored at weekly intervals. After the first 3 weeks, when stressed animals displayed a reduction of sucrose consumption, the control and stressed groups were divided into subgroups receiving daily placebo or imipramine (10 mg/kg/day) treatment. After 5 weeks of treatment, 24 h after the last injection, the rats were killed and beta-adrenoceptor density and affinity in cortical membrane preparations and the accumulation of cyclic AMP in cortical slices stimulated with noradrenaline were assessed. While in stressed placebo-treated rats the sucrose consumption remained reduced, in the imipramine-treated group the level of consumption gradually returned to control values. The stressed placebo-treated rats also displayed an increase in cortical beta-adrenoceptor density (by 34%) with no changes in affinity, and an increase (22%) in the cyclic AMP response to noradrenaline in cortical slices. Imipramine, which in non-stressed rats did not affect sucrose intake but depressed the beta-adrenoceptor density and the cyclic AMP response, reversed the stress-induced decrease in sucrose consumption and the increase in the beta-adrenoceptor density; at physiological noradrenaline concentrations it also reduced the enhanced cyclic AMP response. The results suggest that the chronic mild stress procedure produces behavioral and biochemical changes consistent with a realistic model of depression in animals.

Adenylyl Cyclases↗

PubMed1994

Retrieval associated cholinergic activity and its inhibition by memory updating.

Both hippocampal cholinergic and glutamatergic systems are believed to be engaged in learning and memory. By measuring behavior and ex vivo second messenger inositol phosphate (IP) accumulation, we investigated biochemical responses of cholinergic receptors to retrieval and acquisition processes in rats trained in a spatial task. We report that in rats retrieving spatial information, carbachol--induced IP accumulation strongly and transiently increased above values observed in handled controls and rats acquiring new information, and that this increase was profoundly inhibited by N-methyl-D-aspartate (NMDA). These results suggest that memory retrieval, rather than formation of a memory trace, is related to increased responsiveness of the hippocampal cholinergic system, and that formation of a new memory trace, which updates long-term memory, inhibits this cholinergic activation, possibly by a learning-associated increase in NMDA receptor activation. Moreover, the present study shows that the distinction between acquisition and retrieval processes can be demonstrated on both a behavioral and biochemical level.

Analysis of Variance↗

PubMed1994

The effect of (-)-4-(2-hydroxy-3(N-isopropylamino)-propoxyimino)-cis-carane on basal and forskolin-stimulated accumulation of cyclic AMP in the cerebral cortical slices of the rat.

(-)-4-(2-Hydroxy-3(N-isopropylamino)-propoxyimino)-cis-carane++ +, a local anaesthetic and platelet aggregation inhibitor which is much more potent than lignocaine, facilitated forskolin-induced cyclic (c) AMP accumulation in cerebral cortical slices of the rat. Lignocaine was ineffective in this respect. It is hypothesized that a cAMP-related mechanism may be involved in increased efficacy of the compound.

Analysis of Variance↗

PubMed1994

Altered modulation by excitatory amino acids of cortical phosphatidylinositol system stimulated by carbachol in rats poisoned by an anti-cholinesterase compound, diisopropyl fluorophosphate.

The effects of glutamate and N-methyl aspartate (NMDA) on carbachol-induced inositol phosphate (IP) accumulation were evaluated in slices of the cerebral cortex of rats treated with diisopropyl fluorophosphate (DFP) for 2 weeks. This induced an about 75% inhibition of cholinesterases. The IP accumulation induced by carbachol (expressed as ratio stimulated/basal IP content) was lower in DFP rats than in controls when incorporation of [3H]-myoinositol into membrane phospholipids and their hydrolysis were measured (no washing step between labeling and hydrolytic incubation). There were no differences in carbachol induced IP accumulation between control and DFP rats when only phosphoinositide hydrolysis was determined (hydrolytic incubation of prelabeled washed slices). When both incorporation of [3H]-myoinositol and the hydrolysis were measured, 0.5 mM glutamate and 0.1 mM NMDA caused a significant, about 40%, decrease of carbachol-induced IP accumulation in control rats; the inhibitory effects of glutamate and NMDA were not significant in DFP rats. When only hydrolytic IP accumulation by carbachol was studied, the inhibitory effects of glutamate and NMDA were very similar in control and DFP rats. Additional experiments on inositol phospholipid synthesis showed a significantly lesser [3H]-myoinositol incorporation (by about 30%) in DFP rats. This may explain the differences between the results obtained by the two methods. The overall data suggest that the attenuation of glutamate and NMDA effects in DFP-rats depends on a decrease of carbachol-induced IP accumulation or phosphoinositide synthesis rather than on the EAA specific action.

Animals↗

PubMed1994

The responsiveness of cerebral cortical adrenergic receptors after chronic administration of atypical antidepressant mianserin.

The aim of this study was to evaluate the effect of mianserin, a second generation tetracyclic antidepressant agent, on the receptors' and second messenger systems related to noradrenergic transmission in the cerebral cortex of the rat. In in vitro experiments we confirmed that mianserin binds with equal potency to alpha 1- and alpha 2-adrenoceptors and does not affect beta 1-adrenoceptors. It inhibited the noradrenaline-stimulated inositol phosphate accumulation and did not change the cyclic AMP responses to noradrenaline and isoproterenol. The drug attenuated the inhibitory action of PKC activator, TPA, on the noradrenergic response from alpha 1-adrenoceptor and the potentiating action of TPA on the cyclic AMP stimulated with noradrenaline and isoproterenol. In chronic experiments we have found that, in contrast to most antidepressants, chronic treatment with mianserin does not produce strong beta-downregulation, but increases the maximal inositol phosphate response from alpha 1-adrenoceptor. The results indicate that alpha 1-upregulation might be a characteristic of those efficient antidepressant drugs which do not produce a strong beta-downregulatory effect.

Animals↗

PubMed1993

Effects of excitatory amino acids on inositol phosphate accumulation in slices of the cerebral cortex of young and aged rats.

The effects of glutamate, NMDA and quisqualate on carbachol- and norepinephrine-elicited formation of inositol phosphate (IP) were evaluated in slices prepared from the cerebral cortex of 3- and 24-month Sprague-Dawley rats. Glutamate, NMDA, and quisqualate antagonized the IP response to carbachol in a concentration-dependent fashion. This antagonism was more pronounced in aged than in young rats, both for glutamate (IC5O 0.114 and 0.210 mM) and NMDA (IC5O 0.0029 and 0.127 mM), but not for quisqualate. Glutamate (but not NMDA) also antagonized in a concentration-dependent fashion the IP response to norepinephrine, IC50s were 0.061 and 0.126 mM for aged and young rats, respectively; quisqualate had an inhibitory effect only at 1 mM concentration in the two age-groups, while in aged rats some stimulatory effect was present at 0.1 mM concentration. Glutamate, NMDA and quisqualate (1 mM) did not affect basal IP accumulation in either young or aged rats; quisqualate, however, at 0.1 mM concentration had some stimulatory effect, more pronounced in aged rats. This effect was probably responsible for the biphasic effect of quisqualate in this age-group. The most important finding consists of the demonstration of an age-related increase in the inhibitory effects of NMDA on carbachol-induced IP accumulation. This implies an altered modulation of cholinergic post-receptor mechanisms by glutamatergic mechanisms.

Aging↗

PubMed1993

Enhancement of the responsiveness of cortical adrenergic receptors by chronic administration of the 5-hydroxytryptamine uptake inhibitor citalopram.

The aim of this study was to evaluate the effect of citalopram, a second generation antidepressant agent producing no beta-down-regulation, on the receptors and second messenger systems related to noradrenergic transmission in the cerebral cortex of the rat. We confirmed that citalopram does not bind to alpha 1-, alpha 2-, and beta 1-adrenoceptors, but we found that it attenuates the inhibitory action of the protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate, on the noradrenergic response from alpha 1-adrenoceptor. In contrast to most antidepressants, chronic treatment with citalopram does not produce beta-down-regulation, but increases the responses to noradrenaline from beta-adrenoceptors without increasing the beta 1-adrenoceptor density. Chronic treatment with citalopram also increases the maximal response from alpha 1-adrenoceptor. The results indicate that beta-down-regulation is not a necessary characteristic of an efficient antidepressant drug.

Adenylyl Cyclases↗

PubMed1993

Centpropazine affinity to cortical noradrenergic receptors and effect on their responsiveness in the rat.

We have studied the in-vitro effect of centpropazine on cerebral cortical noradrenergic receptors measured as the accumulation of second messengers, cyclic AMP and inositol phosphate, stimulated by noradrenaline, and the binding to alpha 1- and beta-adrenoceptors. Centpropazine inhibited inositol phosphate, but not the cyclic AMP accumulation in the cerebral cortical slices of the rat. It moderately antagonized the specific binding of [3H]prazosin, but did not affect the specific binding of the beta-adrenoceptor ligand, [3H]CGP 12177, to cerebral cortical membranes.

Adrenergic beta-Antagonists↗