microM Haloperidol Research Articles

Effects of lithium and haloperidol on human sperm motility in-vitro.

Two psychotropic drugs, lithium and haloperidol, were evaluated for their in-vitro effects on sperm motility using a transmembrane migration method. Sperm motility was measured either immediately after semen had been mixed with the drug or after a 2 h incubation period at 37 degrees C. Lithium inhibited human sperm motility in a dose-dependent manner with an EC50 of 10 mM when the semen-lithium mixture had been incubated. Sperm motility was increased to 127% of control when semen had been incubated with 0.027 microM haloperidol; this concentration was within the therapeutic range.

Individual and combined effects of beta-amyloid1-42, donepezil and haloperidol on long-term potentiation in rat hippocampus

Event Abstract Back to Event Individual and combined effects of beta-amyloid1-42, donepezil and haloperidol on long-term potentiation in rat hippocampus Elena Solntseva1* and Nadezhda Kapai1 1 Center of Neurology RAMS, Russia Donepezil is a potent acetylcholinesterase inhibitor used for the treatment of Alzheimer’s disease (AD). Additional therapeutically relevant target for donepezil is sigma1 receptors (Kato et al., 1999). It is generally believed that beta-amyloid peptides (Abeta) contribute to the pathogenesis of AD. Low concentrations of Abeta were shown to impair long-term potentiation (LTP) in hippocampus (Chen et al., 2000). It was shown in our previous work that donepezil in concentration of 1 microM antagonizes the suppressive action of Abeta1-42 on LTP in rat hippocampal slices. We suppose that sigma1 receptors might be involved into mechanism(s) of this effect of donepezil. The purpose of present study was to determine whether donepezil-induced reversal of LTP impaired by Abeta can be abolished by haloperidol, a potent antagonist of sigma1 receptors (Hayashi & Su, 2008). In the control group, the amplitude of population spikes (PS) 30 min post-tetanus reached 146±11% (n = 10). Neither 1 microM donepezil (n = 6), nor 0,5 microM haloperidol (n = 5) changed LTP significantly. Abeta1-42 (200 nM) markedly suppressed the LTP induction or even caused the depression of PS: the amplitude of PS 30 min post-tetanus was 82 ± 15% (p < .005, n = 7). This suppression of LTP could be markedly prevented when donepezil was co-administered with Abeta: the amplitude of PS 30 min post-tetanus was 136 ± 11% (p < .05, n = 5). Further, we co-administered three substances: Abeta, donepezil and haloperidol, and have found that haloperidol antagonizes the stimulating action of donepezil on LTP: the amplitude of PS 30 min post-tetanus was 92 ± 6% (p < .05, n = 5). Results suggest the involvement of sigma1 receptors into mechanisms of the rescue of hippocampal LTP impaired by Abeta by donepezil. Funding: Supported by grant from Russian Foundation for Basic Research. Keywords: AD, Neuropsychiatry Conference: XI International Conference on Cognitive Neuroscience (ICON XI), Palma, Mallorca, Spain, 25 Sep - 29 Sep, 2011. Presentation Type: Poster Presentation Topic: Poster Sessions: Neuropsychiatric Applications Citation: Solntseva E and Kapai N (2011). Individual and combined effects of beta-amyloid1-42, donepezil and haloperidol on long-term potentiation in rat hippocampus. Conference Abstract: XI International Conference on Cognitive Neuroscience (ICON XI). doi: 10.3389/conf.fnhum.2011.207.00226 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 21 Nov 2011; Published Online: 28 Nov 2011. * Correspondence: Dr. Elena Solntseva, Center of Neurology RAMS, Moscow, Russia, soln@front.ru Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Elena Solntseva Nadezhda Kapai Google Elena Solntseva Nadezhda Kapai Google Scholar Elena Solntseva Nadezhda Kapai PubMed Elena Solntseva Nadezhda Kapai Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Haloperidol-induced neuronal apoptosis: role of p38 and c-Jun-NH(2)-terminal protein kinase.

We examined patterns and mechanisms of cell death induced by haloperidol. Cortical cell cultures exposed to 10-100 microM: haloperidol for 24 h underwent neuronal death without injuring glia. The degenerating neurons showed hallmarks of apoptosis, featuring cell body shrinkage, nuclear chromatin condensation and aggregation, nuclear membrane disintegration with intact plasma membrane, and prominent internucleosomal DNA fragmentation. Neither glutamate antagonists nor antioxidants prevented the haloperidol-induced neuronal apoptosis. The c-Jun-NH(2)-terminal protein kinase and p38 mitogen-activated protein kinase were activated within 1 h and were sustained over the next 3 h following exposure of cortical neurons to 30 microM haloperidol. Haloperidol-induced neuronal apoptosis was partially attenuated by 10-30 microM PD169316, a selective inhibitor of p38 mitogen-activated protein kinase. Inclusion of 1 microg/ml cycloheximide, a protein synthesis inhibitor, or 100 ng/ml insulin prevented activation of both kinases and subsequent neuronal death. The present study demonstrates that cortical neurons exposed to haloperidol undergo apoptosis depending on activation of p38 mitogen-activated protein kinase and c-Jun-NH(2)-terminal protein kinase sensitive to cycloheximide and insulin.

In vitro study on the involvement of CYP1A2, CYP2D6 and CYP3A4 in the metabolism of haloperidol and reduced haloperidol.

To investigate in vitro which CYP isoforms (CYP1A2, CYP2D6 and CYP3A4) are involved in the biotransformation of haloperidol (HAL) and reduced haloperidol (RHAL). The biotransformation of HAL and RHAL is evaluated by measuring HAL and RHAL remaining after incubation with human liver microsomes and with supersomes from human baculovirus-infected cells expressing human P(450) isoforms. The influence of chemical- and immuno-inhibition of specific isoforms on the disappearance of HAL and RHAL was also studied. After 60-min incubation of 2 microM and 20 microM HAL or RHAL with human liver microsomes, for HAL, 58% and 64%, respectively, remained in the incubation mixture, for RHAL, 53% and 66%, respectively. Ketoconazole had the most pronounced inhibitory effect on the biotransformation of both substrates, while for quinidine and furafylline there was only a weak or no influence. Anti-CYP3A4 antibodies inhibited strongly the biotransformation of HAL and RHAL, while the influence of anti-CYP2D6 antibodies was much less pronounced. After incubation with supersomes of recombinant CYP3A4, HAL and RHAL disappeared rapidly; disappearance was slow after incubation with CYP2D6 supersomes, and negligible with CYP1A2 supersomes. The results show that CYP3A4 is the most important CYP isoenzyme involved in the biotransformation of HAL and RHAL, and that the metabolism by CYP2D6 is only a minor pathway; CYP1A2 has no or only a negligible influence.

The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes.

1. The antipsychotic drug haloperidol can induce a marked QT prolongation and polymorphic ventricular arrhythmias. In this study, we expressed several cloned cardiac K+ channels, including the human ether-a-go-go related gene (HERG) channels, in Xenopus oocytes and tested them for their haloperidol sensitivity. 2. Haloperidol had only little effects on the delayed rectifier channels Kv1.1, Kv1.2, Kv1.5 and IsK, the A-type channel Kv1.4 and the inward rectifier channel Kir2.1 (inhibition < 6% at 3 microM haloperidol). 3. In contrast, haloperidol blocked HERG channels potently with an IC50 value of approximately 1 microM. Reduced haloperidol, the primary metabolite of haloperidol, produced a block with an IC50 value of 2.6 microM. 4. Haloperidol block was use- and voltage-dependent, suggesting that it binds preferentially to either open or inactivated HERG channels. As haloperidol increased the degree and rate of HERG inactivation, binding to inactivated HERG channels is suggested. 5. The channel mutant HERG S631A has been shown to exhibit greatly reduced C-type inactivation which occurs only at potentials greater than 0 mV. Haloperidol block of HERG S631A at 0 mV was four fold weaker than for HERG wild-type channels. Haloperidol affinity for HERG S631A was increased four fold at +40 mV compared to 0 mV. 6. In summary, the data suggest that HERG channel blockade is involved in the arrhythmogenic side effects of haloperidol. The mechanism of haloperidol block involves binding to inactivated HERG channels.

Spectral plasticity of H1 horizontal cells in carp retina: independent modulation by dopamine and light-adaptation.

It was shown previously that the spectral sensitivity of luminosity/H1-type horizontal cells (HCs) in carp retinae reflects the absorption spectrum of red-sensitive cones for long wavelengths but can appear highly variable and "truncated' in the short-wavelength region of the spectrum. We have found that light-adaptation sharpened the red-sensitive spectral peak and decreased the blue/red response amplitude ratio (B/R ratio), mainly by decreasing the response to short-wavelength stimuli. The adaptation effect was more pronounced for red background light than for blue. During dark adaptation, the B/R ratio increased steadily. Exogenous dopamine (DA; 5 microM) changed the spectral response profile in a similar way to light-adaptation. However, the effect of light-adaptation in reducing the B/R ratio was still seen in retinae bathed in 5 microM DA. This effect of background adaptation was also recorded in retinae bathed in 37 microM haloperidol, as well as in retinae pretreated with 6-hydroxydopamine (i.e. DA-depleted). The results suggest that (i) short-wavelength-sensitive cones play a dynamic role in determining the spectral response profile of H1 HCs and (ii) spectral response characteristics are modulated independently by exogenous DA and an unknown endogenous neuromodulator which is activated by light-adaptation.

Inhibitors of human immunodeficiency virus-1 protease

We have shown that the interaction of pepstatin A with human immunodeficiency virus-1 protease (HIV-1 protease) can be characterized by a high-affinity mode (Ki = 478 +/- 27 nM), resulting in pure competitive inhibition of the hydrolytic activity of HIV-1 protease toward the fluorogenic substrate. Binding of pepstatin in this mode induces a blue shift in the endogenous fluorescence arising from the tryptophan residues in HIV-1 protease. This shift is maximal in the presence of 10 microM pepstatin. Haloperidol, in contrast, interacts with HIV-1 protease with weaker affinity (Ki = 19 +/- 1 microM) in a mode which results in pure noncompetitive inhibition of the hydrolytic activity of HIV-1 protease. Binding of haloperidol in this mode induces a red shift in the endogenous fluorescence arising from the tryptophan residues in HIV-1 protease. This shift is maximal in the presence of 200 microM haloperidol. Addition of both pepstatin and haloperidol at concentrations in the range of their Ki values results in additive inhibition of the hydrolytic activity of HIV-1 protease, as well as an additive effect on the tryptophan fluorescence of protease. However, at saturating concentrations of pepstatin and haloperidol, the effect of haloperidol was predominant, as measured by the changes in the intrinsic fluorescence of HIV-1 protease.

(125I)iodoazidococaine, a photoaffinity label for the haloperidol-sensitive sigma receptor.

A carrier-free radioiodinated cocaine photo-affinity label, (-)-3-(125I)iodo-4-azidococaine [(125I)IACoc], has been synthesized and used as a probe for cocaine-binding proteins. Photoaffinity labeling with 0.5 nM (125I)IACoc resulted in selective derivatization of a 26-kDa polypeptide with the pharmacology of a sigma receptor in membranes derived from whole rat brain, rat liver, and human placenta. Covalent labeling of the 26-kDa polypeptide was inhibited by 1 microM haloperidol, di(2-tolyl)guanidine (DTG), 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP), dextromethorphan, and carbetapentane. Stereoselective protection of (125I)IACoc photolabeling by 3-PPP [(+)-3-PPP more potent than (-)-3-PPP] was observed. (125I)IACoc labeling of the 26-kDa polypeptide was also inhibited by 10 microM imipramine, amitriptyline, fluoxetine, benztropine, and tetrabenazine. The size of the (125I)I-ACoc-labeled proteins is consistent with the size of proteins photolabeled in guinea pig brain and liver membranes by using the sigma photolabel azido-[3H]DTG. Kinetic analysis of (125I)IACoc binding to rat liver microsomes revealed two sites with Kd values of 19 and 126 pM, respectively. The presence or absence of proteolytic inhibitors during membrane preparation did not alter the size of the photolabeled sigma receptor, indicating that the 26-kDa polypeptide was not derived from a larger protein. In summary, (125I)IACoc is a potent and highly specific photoaffinity label for the haloperidol-sensitive sigma receptor and will be useful for its biochemical and molecular characterization.

Penfluridol, chlorprothixene and haloperidol block fast axonal transport in an order of potency consistent with a mechanism related to inhibition of calmodulin

The effects of the inhibitors of calmodulin penfluridol, chlorprothixene and haloperidol on fast axonal transport, the content of adenosine triphosphate and creatine phosphate and the density of axonal microtubules, were measured in spinal nerves of the bullfrog in vitro. These drugs inhibited the fast orthograde transport of [3H]leucine-labelled proteins: 35 microM penfluridol, 70 microM cis-chlorprothixene, and 200 microM haloperidol were needed to produce and approximately 50% inhibition of transport, and the order of potency was, therefore, penfluridol greater than cis-chlorprothixene greater than haloperidol; the trans isomer of chlorprothixene was as effective as the cis isomer-of chlorprothixene in inhibiting fast axonal transport. None of these drugs significantly reduced the density of microtubules in unmyelinated axons of nerves, incubated as for a transport experiment. Exposure to the concentration of these drugs which inhibited transport did not reduce significantly the content of adenosine triphosphate of the nerves, except for a 22% reduction by trans-chlorprothixene, and they had no significant effect on the content of creatine phosphate except for a 27% reduction by penfluridol and a 20% reduction by trans-chlorprothixene. The inhibition of axonal transport by these drugs can therefore not be explained either by an interference with oxidative metabolism or by disruption of microtubules. The order of potency of penfluridol, chlorprothixene and haloperidol as inhibitors of fast axonal transport parallels their known order of potency as antagonists of calmodulin; inhibition of axonal transport may therefore be related to inhibition of the function of calmodulin by these drugs.

Neurosecretion of human hypothalamic immunoreactive beta-endorphin: in vitro regulation by dopamine.

An in vitro perifusion system was used to investigate immunoreactive beta-endorphin (beta-END-I) release from adult human hypothalami in response to dopamine (DA) and the DA receptor antagonist haloperidol (HAL). Administration of a 1 microM pulse of DA consistently elicited a mean (+/- SE) 88 +/- 9% increase (p less than 0.05, n = 5) in beta-END-I release, whereas 1 microM HAL had no effect. Administration of 1 microM DA during three perifusions in which 1 microM HAL was added to the medium failed to alter basal beta-END-I release. In contrast, DA did evoke an acute 230 +/- 31% increase (p less than 0.05) in beta-END-I release during three matching perifusions with medium containing the alpha-adrenergic antagonist phentolamine. These studies demonstrate that DA can stimulate in vitro release of beta-END-I from the adult human hypothalamus by a DA receptor mediated mechanism.

Gonadotropin-releasing hormone neurosecretion in the human hypothalamus: in vitro regulation by dopamine.

An in vitro perifusion system was used to investigate GnRH release from adult human hypothalami in response to dopamine (DA) and the DA receptor antagonist haloperidol (HAL). Administration of a 1-microM pulse of DA consistently elicited a mean +/- SE 218 +/- 59% increase (P less than 0.05; n = 5) in GnRH release, whereas 1 microM HAL had no effect. Administration of 1 microM DA during three perifusions in which 1 microM HAL was added to the medium failed to alter basal GnRH release. In contrast, DA did evoke an acute 98 +/- 39% increase (P less than 0.06) in GnRH release during three matching perifusions with medium containing the alpha-adrenergic antagonist phentolamine. These studies demonstrate that DA can stimulate in vitro release of GnRH from the adult human hypothalamus by a DA receptor-mediated mechanism.

Agonist-induced subsensitivity of adenylate cyclase coupled with a dopamine receptor in slices from rat corpus striatum.

Incubation, for 30 min, of striatal slices with 10 microM dopamine, 10 microM apomorphine, or 10 microM SKF 38393 decreased dopamine-stimulated adenylate cyclase activity by 50-60%. This loss in dopamine-stimulated enzyme activity appears to be mediated by a persistent occupancy of recognition sites of the D-1 receptor because: (i) at 10 microM, SKF 38393, a selective D-1 receptor agonist, facilitates desensitization and Ly 141865, a selective D-2 receptor agonist, fails to elicit desensitization of dopamine-dependent adenylate cyclase; and (ii) preincubation with dopamine in the presence of 1 microM haloperidol but not 1 microM sulpiride curtails the desensitization of dopamine-dependent adenylate cyclase. In dopamine-desensitized striatal slices of the Kd for N-propylnorapomorphine binding is increased but the content of membrane-bound calmodulin and the activation of adenylate cyclase by NaF and cholera toxin are decreased significantly. In striatal slices incubated with dopamine for prolonged time periods the coupling of the GTP-binding protein with adenylate cyclase and dopamine recognition sites may be impaired and the content of membrane-bound calmodulin is decreased.

Corticotropin-releasing factors (CRF) secreted by the rat median eminence in vitro in the presence or absence of ascorbic acid: quantitative role of vasopressin and catecholamines.

Microdissected rat median eminences (wet weight, 110 micrograms) were electrically stimulated in vitro in the presence of bacitracin and bovine serum albumin. Incubation media collected at 20-min intervals, were assayed for corticotropin-releasing factor (CRF) with dispersed pituitary cells and for arginine vasopressin (AVP) by a specific RIA. CRF activity of the media or of synthetic AVP was plotted as function of AVP content. Dose (AVP)-response (CRF) curves for media were not significantly different from those of synthetic AVP. Extracts of incubated median eminences had 3 times more CRF activity then the AVP contained within these extracts, showing that CRF distinct from AVP ws contained within the median eminences but had not been released into or had been degraded within the media. In the presence of 1 mM ascorbic acid, AVP release was not significantly different from AVP release in the absence of ascorbic acid, but accounted for only 49-67% of released CRF activity, suggesting that a CRF distinct from AVP had been released into or protected within the medium. At an AVP level similar to that found in hypophysial portal plasma, the total CRF activity of median eminence media were not significantly different in the presence or absence of 0.13 microM haloperidol or 1.3 microM propranolol in ascorbic acid-rich media, but were 12-17% (P less than 0.05) lower in the presence of 0.35 microM phentolamine. The results indicate that CRFs, distinct from AVP, released from the median eminence in vitro can be detected only when ascorbic acid is present in the medium, and furthermore, that AVP and some alpha-adrenergic agonist account for at least 61-84% of released CRF activity.