Effects of D2 dopamine receptor antagonists on fos protein expression in the striatal complex and entorhinal cortex of the nonhuman primate

Recent studies have reported that acute administration of dopamine D₂ receptor antagonists increases expression of the immediate early gene c-fos in the rat striatal complex. There have been no corresponding studies of the effects of D₂ antagonists in primate species. Since all clinically effective antipsychotic drugs share D₂ receptor antagonism, it is important to define the extent to which these drugs may alter expression of c-fos or its protein product, Fos, in primates. We therefore examined the effects of administration of two D₂ receptor antagonists, haloperidol and metoclopramide, on Fos expression in the striatum and temporal cortices of the vervet monkey. Metoclopramide does not appear to possess significant antipsychotic efficacy but potently produces extrapyramidal side effects, while haloperidol is an effective antipsychotic drug that produces extrapyramidal side effects. Both drugs increased the number of Fos-like immunoreactive (Fos-li) neurons in the caudate nucleus and putamen; the numbers of Fos-li neurons in these regions were increased in both the patch and matrix compartments. Haloperidol but not metoclopramide increased the number of Fos-li neurons in the nucleus accumbens shell. Similarly, haloperidol but not metoclopramide increased the number of Fos-li neurons in the entorhinal cortex. Neither drug altered Fos expression in the inferior temporal cortex. These data suggest that the dorsolateral caudate nucleus and putamen may be sites at which D₂ receptor antagonists elicit extrapyramidal side effects, and the nucleus accumbens shell and entorhinal cortex may be loci at which the therapeutic actions of antipsychotic drugs are manifested. © 1996 Wiley-Liss, Inc.     

Antidopaminergic-lnduced Hypothalamic LHRH Release and Pituitary Gonadotrophin Secretion in 12 Day-Old Female and Male Rats

In previous studies we have shown that the developing rat provides an interesting physiologic model in which the dopaminergic control of both LH and FSH is well defined in contrast to the controversial results obtained in adult rats. We wished to establish the role of testosterone in antidopaminergic induced gonadotrophins release in 12 day-old male and female rats, and evaluate the effect of antidopaminergic drugs at the hypothalamic level during this developmental stage. Haloperidol, an antidopaminergic drug, increased both LH and FSH in female 12 day-old rats but not in male littermates. The effect was blocked by bromocriptine and not by phentolamine indicating that haloperidol acted on the dopaminergic receptor, and that unspecific stimulation of the noradrenergic system was not involved. Haloperidol was ineffective when female rats were previously ovariectomized and injected with testosterone propionate at 9 days of age. If females were treated on the day of birth with testosterone propionate, haloperidol-induced FSH and LH release was also abolished. In control males haloperidol had no effect on the release of LH or FSH. But if males were orchidectomized at birth or at 9 days of age, haloperidol released both LH and FSH during the infantile period. In an attempt to establish the site of action of antidopaminergic drugs on gonadotrophin release, hypothalami (mediobasal and preoptic-suprachiasmatic area) from 12 day-old infant female rats were perfused with either haloperidol or domperidone (2±10^?6 M). Both drugs increased LHRH release into the perifusate. Besides haloperidol did not modify the release of LH or FSH from adenohypophyseal cells incubated in vitro. We therefore conclude that antidopaminergic-induced gonadotrophins release is modulated by serum testosterone concentrations, and that the site of action is probably the LHRH-secreting neuron of the hypothalamus.     

Antipsychotic drug binding in the substantia nigra: An examination of high metoclopramide binding in the brains of normal,Alzheimer's disease,Huntington's disease,and Multiple Sclerosis patients,and its relation to tardive dyskinesia

This project was done in order to determine why the annual incidence of metoclopramide‐associated tardive dyskinesia is much higher than that for the commonly used antipsychotics. To test the hypothesis that metoclopramide tardive dyskinesia may be associated with high concentrations of metoclopramide in the substantia nigra under clinical conditions, the nonspecific binding of tritiated antipsychotics to the dissected melaninized regions of postmortem human substantia nigra was measured. The nonspecific binding at 1 nM [³H]ligand was 7.3, 4.2, 2.6, 0.91 and 0.66 fmoles/mg for [³H]haloperidol, [³H]clozapine, [³H]raclopride, [³H]metoclopramide, and [³H]olanzapine, respectively. After adjusting these values for the known free concentrations of these drugs in plasma or spinal fluid, the amounts that would be bound under clinical conditions would be 231, 113, 15, 11, and 3.4 fmoles/mg for metoclopramide, clozapine, raclopride, haloperidol, and olanzapine, respectively. Using rat striatum as baseline to define antipsychotic binding to nonnigral tissue, the excess amount of binding to the Alzheimer nigral tissue under clinical conditions would be 209, 19, 0, 3.4 and 0.8 fmole/mg for metoclopramide, clozapine, raclopride, haloperidol, and olanzapine, respectively, with a similar pattern for nigral tissues from Huntington and Multiple Sclerosis patients. The high accumulation of metoclopramide is sufficiently high to cause nigral nerve cell membrane damage by metoclopramide's detergent‐like action, possibly explaining metoclopramide's toxic ability to elicit early tardive dyskinesia. In addition, the nonspecific binding of metoclopramide was much higher in Alzheimer‐diseased substantia nigra, consistent with the fact that older individuals are relatively more vulnerable to metoclopramide tardive dyskinesia. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Sulpiride blocks postsynaptic dopamine receptors in the nucleus accumbens

Summary Intra-accumbens injection of sulpiride, tiapride, and metoclopramide antagonized locomotor hyperactivity induced by intraperitoneal administration of apomorphine in rats and measured over the first five minutes after introducing the animal to an open-field cage. Sulpiride was slightly more potent than tiapride which was more than 10 times more potent than metoclopramide and haloperidol. The threshold dose of sulpiride was as low as 0.001g, bilaterally. Intra-accumbens injection of sulpiride also blocked exploratory hypermotility induced by bilateral intra-accumbens injections of apomorphine and picrotoxin. The threshold dose of sulpiride for blocking these two effects was about 0.01g, bilaterally. Sulpiride was more than 10 times more potent than haloperidol in blocking this apomorphine-induced hypermotility. Haloperidol did not influence the picrotoxin hypermotility.The results obtained indicate strong postsynaptic dopamine antagonist properties of sulpiride, tiapride and metoclopramide.     

The DRD2 TaqIA polymorphism and demand of dopaminergic medication in Parkinson's disease

Previous studies have demonstrated that the TaqIA polymorphism of the D2 dopamine receptor gene (DRD2) is associated with response to dopaminergic and antidopaminergic treatment in Parkinson's disease (PD) and schizophrenia, respectively. We tested whether the TaqIA genotype in PD is responsible for demand of dopaminergic medication, measured in total dopaminergic load per year of disease, in a large scale association study based on the gene bank of the German Competence Network on Parkinson's disease. Regression analysis yielded no significant differences between the TaqIA genotypes. We conclude that the DRD2 TaqIA polymorphism alone has no pivotal role for interindividual variability of dopaminergic requirement in PD. We propose a practicable system of measuring dopaminergic treatment for future pharmacogenetic studies in PD. © 2007 Movement Disorder Society     

Recurrent acute dystonic reaction and oculogyric crisis despite withdrawal of dopamine receptor blocking drugs

Adverse events of dopamine‐blocking agents include acute dystonic reactions and oculogyric crises (OGCs). OGCs may be recurrent on maintenance of or re‐exposure to the drug. Thus, complete withdrawal is recommended. Recurrent episodes of acute dystonia despite withdrawal and the lack of further exposure to antidopaminergic agents are usually not seen. Here, we report three cases with recurrent OGCs despite complete withdrawal of neuroleptics. Triggering or priming factors were a single dose of haloperidol in two cases and a single dose of metoclopramide in one case. Episodes reoccurred spontaneously, but responded to anticholinergics. The pathomechanisms of acute dystonic reactions and OGCs remain unclear. Parallels to levodopa‐induced dyskinesias in Parkinson's disease, as well as to dopa‐responsive dystonia, paroxysmal dyskinesias, and channelopathies are discussed here. Whether there is a genetic susceptibility or some other reason for only some patients developing this phenomenon remains unclear. © 2009 Movement Disorder Society     

The antidopaminergic action of S-20098 is mediated by benzodiazepine/GABAA receptors in the striatum

The naphthalenic compound S-20098, which is a melatonergic agonist, inhibits [³H]diazepam binding in striatal membranes. S-20098 also inhibits apomorphine-induced turning in 6-hydroxydopamine lesioned rats. This antidopaminergic effect is blocked by either intraperitoneal injection of the central-type benzodiazepine (BZ) antagonist, flumazenil, or intrastriatal injection of the GABA_A antagonist, bicuculline. These findings indicate that S-20098 can activate central-type BZ receptors, and its antidopaminergic action, like that of melatonin, involves a GABAergic mechanism in the striatum.     

NMDA-coupled periaqueductal gray glycine receptors modulate anxioselective drug effects on plus-maze performance

The present study was carried out to investigate a possible interaction between the effects of anxiety modulating drugs which act at the GABA-A receptor complex and selective N-methyl-

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-aspartic acid (NMDA) coupled glycine receptor (GLY-B receptor) ligands within the dorsal periaqueductal gray (DPAG). The plus-maze performance of rats pretreated with diazepam (0.37 and 0.75 mg/kg, i.p.) or pentylenetetrazole (15 and 30 mg/kg, i.p.), standard anxiolytic and anxiogenic drugs respectively, was assessed following intra-periaqueductal injections of either glycine (0.2 M, 0.4 μl/30 s, i.c.) or its competitive antagonist, 7-chlorokynurenic acid (7ClKYN, 0.02 M, 0.4 μl/30 s, i.c.). Whilst diazepam produced a typical anxiolytic effect in intracranially-injected CSF rats, increasing open arm exploration, pentylenetetrazole displayed an opposite anxiogenic profile. Either anxiogenic or anxiolytic effects were seen in peripherally-injected vehicle rats following intra-periaqueductal injections of glycine or 7ClKYN, respectively. Intra-periaqueductal injection of glycine markedly attenuated the anxiolytic effect of diazepam. Moreover, while the anxiogenic effects of pentylenetetrazole were barely changed by glycine, they were markedly attenuated by intra-periaqueductal injection of 7ClKYN. Interaction of diazepam and 7ClKYN produced non-selective sedative-like effects which masked any possible anxiolytic action. Accordingly, the present results suggest that the NMDA-coupled glycine receptors located in the DPAG interfere with anxioselective effects of GABA-A acting drugs on the elevated plus-maze. In spite of the prevailing notion that the NMDA coupled glycine receptor is saturated at in vivo brain concentrations of glycine, our results also suggest that either unoccupied or low-affinity GLY-B receptors are likely to be activated by glycine injection into DPAG.     

Treatment of tardive dyskinesia with levetiracetam in a transplant patient

Objective –  To describe successful treatment of tardive dyskinesia with levetiracetam.
Background –  Tardive dyskinesia is a late-onset movement disorder caused by exposure to dopamine receptor blocking agents, most commonly neuroleptics. Metoclopramide is frequently used to treat gastrointestinal dysmotility. It has antidopaminergic properties, and is estimated to be responsible for two-thirds of drug-related movement disorders.
Design/methods –  Case report.
Results –  A 68-year-old woman presented with a history of intestinal transplantation (12 years ago; short gut syndrome related to bowel resection for rectal carcinoma) and renal transplantation (1 year ago; diabetes). She developed involuntary movements with stereotypic oro-buccal-lingual dyskinesias and right-sided choreiform movements. Her Abnormal Involuntary Movement Scale score (AIMS) score was 27. She has been treated with metoclopramide for gastrointestinal dysmotility for more than 10 years and was diagnosed with tardive dyskinesia. Treatment with levetiracetam 250 mg orally b.i.d. led to a significant improvement of abnormal movements within a week. Her AIMS score decreased to 8.
Discussion –  Tardive dyskinesia may be quite disabling and options include withdrawal of offending medication, or use of tetrabenazine or reserpine. Several reports also suggested improvement of tardive movement disorders with levetiracetam. In our patient, levetiracetam relieved symptoms of tardive dyskinesia and allowed continuous use of metoclopramide. Larger studies are needed to confirm its efficacy.     

Effects of drugs on γ-aminobutyric acid receptors, uptake, release and synthesis in vitro

The effects of various convulsant and anticonvulsant drugs have been studied using in vitro assays for the postsynaptic action of the neurotransmitter γ-aminobutyric acid (GABA). GABA caused a receptor-ionophore mediated increase in chloride permeability in crayfish muscle. At 100 μM concentrations, benzyl penicillin, bicuculline, diethyl barbiturate, diazepam, imipramine, and haloperidol partially inhibited this response while picrotoxinin inhibited it 100% (I₅₀ = 3 μM). Muscimol (potently) andβ-(p-chlorphenyl) GABA (weakly) mimic GABA action in this assay. Muscimol and bicuculline (potent), and benzyl penicillin andβ-(p-chlorphenyl) GABA (weak), but not the other drugs, probably exerted their effects at the GABA receptor level, because only these four drugs among those tested were inhibitors of GABA receptor binding sites in mouse brain homogenates (sodium-independent sites having the specificity expected of receptor sites). Pentylenetetrazol weakly inhibited GABA receptor binding and GABA-induced chloride flux. Several other convulsants suspected of GABA antagonist activity, such as trimethyl caprolactam, isopropyl bicyclophosphate, tetramethylene disulfotetramine, andD-tubocurarine, showed no direct inhibition of either GABA receptor sites in mouse brain or of GABA-stimulated chloride flux in crayfish muscle.The drugs were also examined for effects on in vitro assays of GABA uptake, glutamate decar☐ylase activity (GAD), and Ca²⁺-stimulated GABA release with mouse brain homogenates. GABA uptake by mouse brain particulate fractions was inhibited 50% by approximately 100μM haloperidol, imipramine, chlorpromazine, diazepam, benzyl penicillin, bicuculline, andβ-(p-chlorophenyl) GABA, but by muscimol only at concentrations near1m M. Diazepam and benzyl penicillin also stimulatedCa²⁺-independent efflux of GABA from mouse brain fractions enriched in synaptosomes. Diazepam, chlorpromazine, imipramine, and haloperidol inhibitedCa²⁺-dependent release of GABA from brain particles enriched in synaptosomes. No drugs tested were found to inhibitL-glutamate decar☐ylase (GAD) activity at concentrations under100 μM.The drugs diphenylhydantoin and diethyl barbiturate showed no effects on these GABA neurochemical assays which could be related to anticonvulsant action. Convulsant activity of benzyl penicillin appears to be related to competitive antogonism of GABA receptors, although the drugs is not very potent or specific. Diazepam at concentrations of50–100 μM affected GABA transport in a manner consistent with anti-convulsant activity, although at similar concentrations it also could inhibit GABA release and postsynaptic action. Lioresal seems to be a definite GABA agonist, although weak and non-specific, while muscimol is a very potent and specific GABA agonist. Analogues of both these compounds are promising candidates for treatment of neurological disorders involving GABA dysfunction.     

Conditioned immunomodulation: investigations of the role of endogenous activity at μ, κ, and δ opioid receptor subtypes

The present investigations were designed to determine the role of activity at μ, κ, and δ opioid receptor subtypes in conditioned immunomodulation by evaluating the effects of selective opioid receptor antagonists on conditioned stimulus-induced alterations in immune status. Lewis rats were exposed to an aversive conditioned stimulus that was developed through pairings with electric footshock. This aversive conditioned stimulus induces a reduction in splenic natural killer cell activity, splenocyte proliferation in response to mitogens, and diminished levels of interferon-γ (IFN-γ) production by splenocytes. Intracerebroventricular (ICV) administration of the opioid antagonist naltrexone or the μ₁-selective antagonist naloxonazine blocked conditioned alterations of immune status, indicating that activity at μ-opioid receptors is involved in conditioned immunomodulation. Further support for the involvement of μ-opioid receptors within the central nervous system is provided by data showing that peripheral administration of naloxonazine, at doses shown to be effective when administered ICV, had no effect on conditioned alterations of immune status. Ventricular administration of the κ receptor antagonist nor-binaltorphimine (nor-BNI) did not antagonize the immunomodulatory effects of the conditioned stimulus. Administration of the δ receptor antagonist naltrindole also did not antagonize the conditioned alterations of immune status. Collectively, the results of this study indicate that the alterations of immune status produced by an aversive conditioned stimulus require activity at μ-opioid receptors, possibly μ₁, within the central nervous system.     

Non-additivity of D2 receptor proliferation induced by dopamine denervation and chronic selective antagonist administration: evidence from quantitative autoradiography indicates a single mechanism of action

Experiments were conducted to investigate whether chronic dopamine (DA) D2 receptor blockade and DA denervation exert additive effects on striatal D2 receptor density. We employed for the first time chronic treatment with a pure D2 antagonist, metoclopramide, and measured regional striatal DA receptor binding with quantitative receptor autoradiography. Rats with extensive unilateral DA denervation induced by intracerebral 6-hydroxydopamine (6-OHDA) were injected daily for 21 days with either metoclopramide (30 mg/kg i.p.) or saline. Following a 72-h drug wash-out period, rats were sacrificed and brain sections through the caudate-putamen and nucleus accumbens were incubated with [3H]spiroperidol or [3H]SCH 23390 to assay D2 and D1 receptors, respectively. Autoradiographic analysis revealed that chronic metoclopramide treatment increased the density of D2 sites in the intact hemisphere for all regions examined without further augmenting the already increased density of D2 receptors seen in the 6-OHDA-treated hemisphere. In addition, chronic metoclopramide and 6-OHDA treatment by themselves exhibited remarkably parallel anterior-posterior gradients in their effects on D2 receptor density. D1 receptor density was not affected by metoclopramide treatment but was slightly reduced in the DA-denervated hemisphere. [3H]Mazindol labelling of high-affinity DA uptake sites indicated that the extent of DA denervation was greater than 98% in both saline- and metoclopramide-treated rats. These findings are consistent with the view that chronic D2 receptor blockade and DA denervation act via a single, common mechanism to increase D2 receptor density. Work from other laboratories, in which additive effects of denervation and chronic neuroleptic treatment have been purported, may have resulted from incomplete denervation. Experimental discrepancies may also be due to differing means by which the mesotelencephalic dopaminergic neurons are injured.     

Antagonist activity of the antipsychotic drug lithium chloride and the antileukemic drug imatinib mesylate during glioblastoma treatment in vitro

Objectives: Glioblastoma (GBM), the most common primary tumour of the central nervous system, is characterised by a high malignancy and poor prognosis. The aims of this study were to investigate whether the combination of imatinib mesylate (IM) and lithium chloride (LiCl) exhibited a synergistic effect in treatment and to determine whether midkine (MK) affected the fate of this treatment in vitro.

Methods: Monolayer and spheroid cultures of the T98G human GBM cell line were treated with an IM and LiCl combination for 72 h. The cell proliferation index, apoptotic index, cell cycle distribution, apoptotic and anti-apoptotic protein levels, and cAMP level as well as the cellular morphology and ultrastructure were evaluated.

Results: All applications inhibited cell proliferation and induced apoptosis. The most substantial decreases in cell proliferation and the caspase-3, epidermal growth factor receptor (EGFR), platelet derived growth factor receptor-alpha (PDGFR-α), multidrug resistance protein-1 (MRP-1), aquaporin-4 (AQP-4) and cAMP levels were induced by the LiCl treatment, which exhibited more pronounced effects compared with the combination treatment. LiCl was less effective in decreasing the MK and B cell lymphoma-2 (Bcl-2) levels compared with the combination treatment. The most substantial decrease in the p170 levels was identified following the combination treatment, whereas IM induced the second greatest decrease. LiCl alone had no effect on the p170 levels. IM induced the most substantial decrease in the phospho-glycogen synthase kinase 3-beta (p-GSK-3β)/glycogen synthase kinase 3-beta (GSK-3β) ratio, and LiCl induced the second most substantial decrease. Both LiCl and the combination treatment induced G2 + M arrest, whereas IM induced G0 + G1 arrest after 72 h of exposure. An apoptotic appearance and autophagic vacuoles were commonly identified in the LiCl, combination and IM groups, respectively.

Conclusions: The combination of IM and LiCl exhibited an antagonist effect, and MK had a role at this antagonism.     

Involvement of adenosine and glutamate receptors in the induction of c-fos in the striatum by haloperidol

The psychostimulant drugs amphetamine and cocaine induce the expression of immediate early genes, such as c-fos, in the striatum via D₁ dopamine receptor activation. This occurs primarily in the striato-nigral neurons. Conversely, neuroleptic drugs, such as haloperidol, which block D₂-type dopamine receptors, induce c-fos expression in striatal neurons projecting to the globus pallidus. In order to gain insight into the neurochemical substrates of neuroleptic-induced c-fos expression, we examined the effects of adenosine A₂ and N-methyl-D-aspartate (NMDA) receptor antagonists as well as inhibition of nitric oxide synthase, on haloperidol-induced Fos immunoreactivity in the striatum. While blockade of D₁ receptors had no effect on haloperidol-induced Fos expression, adenosine A₂ receptor antagonists decreased the number of neurons in the striatum expressing haloperidol-induced Fos by half. NMDA receptor antagonists also potently blocked the induction of Fos immunoreactivity by haloperidol, while inhibition of nitric oxide synthase activity had no effect. These results indicate that in the presence of a dopamine D₂ antagonist, Fos expression in striato-pallidal neurons is mediated in part through activation of A₂ receptors by adenosine, and via NMDA receptor activation by glutamate. © 1996 Wiley-Liss, Inc.     

GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility

Abstract There is an urgent clinical need for a safe, efficacious stimulant of gastric emptying; current therapies include erythromycin (an antibiotic with additional properties which preclude chronic use) and metoclopramide (a 5‐hydroxytryptamine type 4 receptor agonist and an antagonist at brain D₂ receptors, associated with movement disorders). To move away from the complex motilide structure of erythromycin, a small molecule motilin receptor agonist, GSK962040, was identified and characterized. The compound was evaluated using recombinant human receptors, rabbit and human isolated stomach preparations known to respond to motilin and in vivo, by measuring its ability to increase defecation in conscious rabbits. At the human motilin receptor, the pEC₅₀ (the negative logarithm to base 10 of the EC₅₀ value, the concentration of agonist that produces 50% of the maximal response) values for GSK962040 and erythromycin as agonists were, respectively, 7.9 and 7.3; GSK962040 had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, GSK962040 300 nmol L^?1–10 μmol L^?1 caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 ± 47% at 3 μmol L^?1. In human‐isolated stomach, GSK962040 10 μmol L^?1, erythromycin 10 μmol L^?1 and [Nle¹³]‐motilin 100 nmol L^?1, each caused muscle contraction of similar amplitude. In conscious rabbits, intravenous doses of 5 mg kg^?1 GSK962040 or 10 mg kg^?1 erythromycin significantly increased faecal output over a 2‐h period. Together, these data show that GSK962040, a non‐motilide structure, selectively activates the motilin receptor. Simplification of the structural requirements to activate this receptor greatly facilitates the design of potentially new medicines for gastroparesis.     

ROBO1 polymorphisms,callosal connectivity,and reading skills

The genetic effects on specific behavioral phenotypes are putatively mediated by specific neural functions. It remains unexplored how the axon‐guidance‐receptor gene ROBO1 influences reading performance through the neural system despite the identification of ROBO1 as a susceptibility gene for dyslexia. To address this issue, the present study recruited a group of children with a wide range of reading abilities. Two previously identified reading‐related ROBO1 polymorphisms were genotyped, and diffusion and structural MRI were acquired to measure the fiber microstructure of the corpus callosum (CC), the major white‐matter tract that connects inter‐hemispheric cortical regions. The results confirmed the significant influence of the ROBO1 polymorphisms on reading scores. The fiber microstructures of the midline‐CC segments around the genu and splenium were also affected by the ROBO1 polymorphisms. Moreover, a mediation analysis further revealed that the genu could significantly mediate the effects of the ROBO1 polymorphisms on word‐list reading performance, which suggests a ROBO1‐to‐genu‐to‐reading pathway. The genu‐linked cortical morphology, however, was not associated with either the ROBO1 polymorphisms or reading performance. These findings offer direct evidence supporting ROBO1‐callosum association in humans and also provide valuable insight into the functions of ROBO1 and the gene‐to‐brain mechanisms that underlie human reading. Hum Brain Mapp 38:2616–2626, 2017. © 2017 Wiley Periodicals, Inc.     

Gastric emptying of hexose sugars: role of osmolality,molecular structure and the CCK1 receptor

Background It is widely reported that hexose sugars slow gastric emptying (GE) via osmoreceptor stimulation but this remains uncertain. We evaluated the effects of a panel of hexoses of differing molecular structure, assessing the effects of osmolality, intra‐individual reproducibility and the role of the CCK₁ receptor, in the regulation of GE by hexoses. Methods Thirty one healthy non‐obese male and female subjects were studied in a series of protocols, using a ¹³C‐acetate breath test to evaluate GE of varying concentrations of glucose, galactose, fructose and tagatose, with water, NaCl and lactulose as controls. GE was further evaluated following the administration of a CCK₁ receptor antagonist. Three subjects underwent repeated studies to evaluate intra‐individual reproducibility. Key Results At 250 mOsmol, a hexose‐specific effect was apparent: tagatose slowed GE more potently than water, glucose and fructose (P < 0.05). Fructose (P < 0.05) also slowed GE, but with substantial inter‐, but not intra‐, individual differences. As osmolality increased further the hexose‐specific differences were lost. At 500 mOsmol, all hexoses slowed GE compared with water (P < 0.05), whereas lactulose and saline did not. The slowing of GE by hexose sugars appeared to be CCK₁ receptor‐dependent. Conclusions & Inferences The effects of hexose sugars on GE appear related to their molecular structure rather than osmolality per se, and are, at least in part, CCK₁ receptor‐dependent.     

Not only dopamine D2 receptors involved in Peony-Glycyrrhiza Decoction,an herbal preparation against antipsychotic-associated hyperprolactinemia

Clinical studies have demonstrated the effectiveness of an herbal preparation called Peony-Glycyrrhiza Decoction (PGD) in alleviating antipsychotic-induced hyperprolactinemia (hyperPRL). In the present study, we further examined the pharmacological action of PGD on prolactin (PRL) secretion using in vitro and in vivo models, with specific attention to the role of dopaminergic mediators and other sex hormones. Treatment with PGD at 1–5 mg/ml significantly suppressed PRL secretion and synthesis in MMQ cells, a model of hyperPRL derived from pituitary adenoma cells. The suppressive effects were completely abolished by pretreatment with 10 μM haloperidol, a dopamine D₂ receptor antagonist. Consistent with a D₂-action, PGD did not affect PRL in rat pituitary lactotropic tumor-derived GH3 cells that lack the D₂ receptor expression but significantly increased the expression of D₂ receptors and dopamine transporters (DAT) in PC12 cells. In a rat model of hyperPRL, produced by repeated injection of the dopamine blocker metoclopramide (MCP), chronic PGD (2.5–10 g/kg daily) significantly reduced elevated serum PRL. The reduction in magnitude was similar to that elicited by bromocriptine (BMT), a dopamine D₂ receptor agonist currently used for treatment of hyperPRL. Neither PGD nor BMT altered serum estradiol, but PGD reversed decreased serum progesterone to control level, whereas BMT did not. These results indicate that the anti-hyperPRL effects of PGD are associated not only with D₂ receptor and DAT modulation, but also with a normalization of other sex hormone dysfunction. This experimental evidence supports clinical use of PGD as an effective treatment of antipsychotic-induced hyperPRL.     

Effects of pharmacological entopeduncular manipulations on idiopathic dystonia in the dt sz mutant hamster

The pathophysiology of idiopathic dystonias is still unknown, but it is regarded as a basal ganglia disorder. Previous experiments in the dt ^sz hamster, a model of primary paroxysmal dystonia, demonstrated reduced discharge rates and an abnormal pattern within the entopeduncular nucleus (EPN), a basal ganglia output structure. To clarify if this is based on abnormal γ-aminobutyric acid(GABA)ergic or glutamatergic input, microinjections into the EPN were done in mutant hamsters in the present study. The GABA_A receptor antagonists pentylenetetrazole and bicuculline exerted moderate antidystonic effects, while previous systemic administrations worsened dystonia in the dt ^sz mutant. GABA-potentiating drugs, i.e., the GABA_A receptor agonist muscimol and the GABA transporter inhibitor 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxy-lic acid (NNC-711), which are known to improve dystonia after systemic treatment in mutant hamsters, did not exert significant effects after EPN injections, but NNC-711 tended to increase the severity at the highest dose (2.5 ng bilateral). The NMDA receptor antagonist d(−)-2-amino-5-phosphopentanoic acid (AP-5) retarded the onset of a dystonic attack. However, this effect was not dose dependent and the AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol(f)quinoxaline (NBQX) alone or in combination with AP-5 and NNC-711, also failed to show any effects on dystonia. The present data do not provide clear evidence for an enhanced striatal GABAergic input or a reduced glutamatergic activation of the EPN via the subthalamic nucleus, i.e., more pronounced antidystonic effects of GABA_A receptor antagonists and stronger prodystonic effects of GABAmimetics and glutamate receptor antagonists were expected. Nevertheless, previously found changes in entopeduncular activity probably play a critical pathophysiological role in dystonic hamsters.     

The muscarinic receptor agonist BuTAC, a novel potential antipsychotic, does not impair learning and memory in mouse passive avoidance

(5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane) (BuTAC) is a novel, selective muscarinic receptor ligand with partial agonist mode of action at muscarinic M2 and M4 and antagonist mode of action at M1, M3 and M5 receptor subtypes in cloned cell lines. BuTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for dopamine receptors, and parasympathomimetic effects in mice are produced only at doses well beyond the doses exhibiting the antipsychotic-like effects. In the present study we investigated the effects of BuTAC and the antipsychotic compounds clozapine, sertindole and olanzapine using one trial passive avoidance with mice as a model of learning and memory. Pharmacologically relevant doses of BuTAC and reference antipsychotics were identified, based on inhibition of apomorphine-induced climbing in mice as an assay measuring antidopaminergic potency. When ratios between the minimum effective dose (MED) for impairment of retention in passive avoidance and the MED for inhibition of apomorphine-induced climbing were calculated, BuTAC displayed a high ratio of >10, compared with clozapine (0.3), sertindole (3) and olanzapine (3). These data suggest that BuTAC is a potential novel antipsychotic which may have favourable effects on aspects of learning and memory.