clozapine and eticlopride

Non-coding RNA molecules such as miRNAs have emerged as critical regulators of neuronal functions. The present study investigates a role for miRNA-143, a highly conserved miRNA, in locomotorhyperactivity induced bythe psychotomimetic phencyclidine (PCP), a non-selective antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor. Following acute PCP administration to mice, the content of miRNA-143 was reduced in plasma, prefrontal cortex (PFC) and hippocampus, reaching a minimum after 2 h. The antipsychotics haloperidol and clozapine attenuated hyperlocomotion and the decrease in miR-143 expression induced by PCP, as did the selective D2 dopamine receptor antagonist eticlopride but not the selective D1 antagonist SCH23390. To further confirm D2 receptor-mediated miRNA-143 expression, HT-22 neuronal cell line and primary cortical cultured neuronswere studied. Stimulation of D2 receptors with the selective D2 receptor agonist quinpirole decreased expression of miRNA-143 in a time-dependent manner. This inhibition was blocked by pretreatment with eticlopride, indicating that the D2 receptor directly regulates the expression of miRNA-143. We further demonstrated that miRNA-143 directly targeted to the 3' un-translated region of neuregulin-1 (NRG1) mRNA to reduce protein expression of NRG1 in HT-22 cells and that administration of the D2 receptor agonist quinpirole to mice enhanced expression of NRG1 in PFC. The present data provide the first evidence that D2 receptors are involved in the expression ofmiRNA-143 in association with antipsychotic drug action and the developmental regulator NRG1.

Topics: Animals; Benzazepines; Clozapine; Dopamine D2 Receptor Antagonists; Haloperidol; Hippocampus; Male; Mice; Mice, Transgenic; MicroRNAs; Motor Activity; Neuregulin-1; Phencyclidine; Prefrontal Cortex; Primary Cell Culture; Quinpirole; Receptors, Dopamine D2; Salicylamides

It is well known that amphetamine induces disrupted prepulse inhibition (PPI) in humans and rodents. We have previously reported that intracerebroventricular (i.c.v.) administration of p-hydroxyamphetamine (p-OHA) induces multiple behavioral responses, such as increased locomotor activity and head-twitch response in rodents. To reveal the characteristics of p-OHA on sensorimotor function in rodents, herein we tested the effects of p-OHA on PPI in mice. i.c.v. administration of p-OHA dose-dependently induced PPI disruptions for all prepulse intervals tested. This effect of p-OHA on PPI was attenuated by pretreatment with haloperidol or clozapine. p-OHA-induced PPI disruptions were also attenuated by pretreatment with L-741,626 (a selective D(2) receptor antagonist), L-745,870 (a selective D(4) receptor antagonist) or 6-hydroxydopamine (a neurotoxin which targets DA-containing neurons), but not by SCH 23390 (a selective D(1) receptor antagonist), eticlopride (a D(2)/D(3) receptor antagonist) or GBR 12909 (a DA-reuptake inhibitor). These results indicate that selective blockade of either the D(2) or D(4) receptor subtype may prevent disruption of PPI induced by p-OHA via presynaptic DA release.

Topics: Animals; Benzazepines; Clozapine; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Haloperidol; Indoles; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Oxidopamine; p-Hydroxyamphetamine; Piperazines; Piperidines; Pyridines; Pyrroles; Reflex, Startle; Salicylamides; Sensory Gating; Sympathomimetics; Synaptic Transmission

The N-methyl-D-aspartate (NMDA) glutamate receptor possesses an obligatory co-agonist site for D-serine and glycine, named the glycineB site. Several clinical trials indicate that glycineB agonists can improve negative and cognitive symptoms of schizophrenia when co-administered with antipsychotics. In the present study we have investigated the effects of glycineB agonists on the endogenous release of dopamine from preparations of rat striatal tissue prisms in static conditions. The glycineB agonists glycine (1 mM) and D-serine (10 microM), but not D-cycloserine (10 microM), substantially increased the spontaneous release of dopamine, but significantly reduced the release of dopamine evoked by NMDA. The effect of glycine on spontaneous release was abolished by the non-competitive NMDA antagonists 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801, 10 microM) and ifenprodil (5 microM), but was only partially suppressed by the competitive antagonist 4-(3-phosphonopropyl)-piperazine-2-carboxylic acid (CPP, 10 microM). The selective inhibitor of the glial glycine transporter GlyT1 N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine (NFPS, 10 microM) significantly increased the release of dopamine in an MK-801-sensitive manner. Interestingly, haloperidol (1 microM), but not clozapine (10 microM), prevented the effects of glycine. This study shows that glycineB modulators can control dopamine release by interacting with a distinctive NMDA receptor subtype with which some typical antipsychotics can interfere.

Topics: Animals; Antipsychotic Agents; Clozapine; Corpus Striatum; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Synergism; Glycine; Haloperidol; Magnesium; Male; N-Methylaspartate; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Salicylamides

The two mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinase 1 and 2 (ERK1/2), are involved in the control of gene expression via phosphorylation and activation of the transcription factors cyclic AMP response element binding protein (CREB) and Elk-1. Here, we have examined the effect of haloperidol and clozapine, two anti-psychotic drugs, and eticlopride, a selective dopamine D2 receptor antagonist, on the state of phosphorylation of ERK1/2, CREB and Elk-1, in the mouse dorsal striatum. Administration of the typical anti-psychotic haloperidol stimulated the phosphorylation of ERK1/2, CREB and Elk-1. Virtually identical results were obtained using eticlopride. In contrast, the atypical anti-psychotic clozapine reduced ERK1/2, CREB and Elk-1 phosphorylation. This opposite regulation was specifically exerted by haloperidol and clozapine on ERK, CREB, and Elk-1 phosphorylation, as both anti-psychotic drugs increased the phosphorylation of the dopamine- and cyclic AMP-regulated phosphoprotein of 32 kDa (DARPP-32) at the cyclic AMP-dependent protein kinase (PKA) site. The activation of CREB and Elk-1 induced by haloperidol appeared to be achieved via different signalling pathways, as inhibition of ERK1/2 activation abolished the stimulation of Elk-1 phosphorylation without affecting CREB phosphorylation. This study shows that haloperidol and clozapine induce distinct patterns of phosphorylation in the dorsal striatum. The results provide a novel biochemical paradigm elucidating the molecular mechanisms underlying the distinct therapeutic actions of typical and atypical anti-psychotic agents.

Topics: Animals; Antipsychotic Agents; Clozapine; Corpus Striatum; Cyclic AMP Response Element-Binding Protein; DNA-Binding Proteins; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Antagonists; Drug Interactions; ets-Domain Protein Elk-1; Haloperidol; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Nerve Tissue Proteins; Phosphoproteins; Phosphorylation; Proto-Oncogene Proteins; Salicylamides; Transcription Factors

The purpose of this work was (1) to assess the ability of selected antipsychotic and comparison drugs to induce arrest of movement phenomena during operant responding and (2) to evaluate the capacity of muscarinic anitcholinergics to block such effects. The effects of haloperidol (0.02-0.12 mg/kg, i.p., 45 min), raclopride (0.05-0.80 mg/kg, i.p., 30 min) eticlopride (0.02-0.16 mg/kg, i.p., 45 min), clozapine (1.0-8.0 mg/kg, i.p., 60 min) and SCH 23390 (0.01-0.16 mg/kg, i.p., 30 min) were administered to rats for 4 weeks in a between-groups dosing design. Operant responses in 15 min and the maximum duration of the rat's muzzle entry into the reinforcement dipper well (the measure of arrest of movement that reflected microcatalepsy) were the quantitative measures of behavior. The D2 antagonists dose-relatedly decreased operant responding and increased maximum muzzle duration, effects that were significantly reversed by the anticholinergic scopolamine (0.1 mg/kg) or atropine (6.0 mg/kg). Although the atypical antipsychotic drug clozapine and the selective D1 antagonist SCH 23390 both significantly reduced operant responding, these drugs did not produce microcatalepsy. The results suggested that microcatalepsy expressed in the context of ongoing operant behavior may model low-dose extrapyramidal side effects.

Topics: Animals; Antipsychotic Agents; Benzazepines; Catalepsy; Clozapine; Conditioning, Operant; Haloperidol; Male; Raclopride; Rats; Rats, Sprague-Dawley; Salicylamides

The human D4 dopamine receptor has been expressed in Sf9 insect cells where it appears to couple to endogenous G proteins. Increased guanine nucleotide exchange to G proteins is a reflection of receptor activation and can be followed using a [35S]GTP gamma S binding assay. By measuring D4 receptor stimulation of [35S]-GTP gamma S binding we have been able to characterize several dopaminergic compounds for their functional activity at this receptor. In Sf9 cells expressing the D4 receptor, dopamine, quinpirole, and dp-2-aminodihydroxy-1,2,3,4-tetrahydronaphthalene were all full agonists, whereas (-)-apomorphine appeared to be a partial agonist. No increase in [35S]GTP gamma S binding was observed for noninfected cells or cells infected with an unrelated sequence. The quinpirole-stimulated [35S]GTP gamma S binding could be inhibited by the antagonists clozapine, eticlopride, and haloperidol, and a Schild analysis of these data showed that all three compounds were acting as competitive antagonists of D4 receptors. The rank order of affinities derived from the Schild analysis correlated with that obtained from [3H]spiperone competition binding assays. In conclusion, we have shown that, using this assay system, it is possible to investigate functionally the pharmacology of a recombinant G protein-coupled receptor in the absence of any information regarding the eventual second messenger pathways involved.

Topics: Animals; Cell Line; Clozapine; DNA; Dopamine; Dopamine Agents; Ergolines; Guanosine 5'-O-(3-Thiotriphosphate); Haloperidol; Humans; Ligands; Moths; Quinpirole; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Recombinant Proteins; Salicylamides; Spiperone; Sulfur Radioisotopes; Tritium

The present studies were conducted to evaluate the modification of the behavioral effects of the selective D2 agonist (+)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO] by dopamine receptor blockade. In squirrel monkeys responding under a fixed-ratio schedule of stimulus-shock termination, the effects of (+)-PHNO were determined alone and in combination with the selective D2 antagonist eticlopride, the selective D1 antagonist (-)-trans-6,7,7a,8,9,13b- hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo(d)naphtho-(2,1)azepine (SCH 39166), the nonselective D1/D2 antagonist cis-flupentixol or the atypical neuroleptic clozapine. When administered alone, (+)-PHNO produced dose-dependent decreases in rates of responding. Pretreatment with eticlopride and cis-flupentixol resulted in dose-dependent right-ward shifts of the (+)-PHNO dose-effect curve, indicative of surmountable antagonism. Pretreatment with SCH 39166 and clozapine failed to antagonize the effects of (+)-PHNO and resulted in a downward shift of the (+)-PHNO dose-effect curve. Other experiments were conducted to determine the duration of either catalepsy-associated behavior or repetitive scratching produced by (+)-PHNO alone and in combination with selected dopamine receptor blockers. Low doses of (+)-PHNO (0.001-0.003 mg/kg) increased the duration of catalepsy-associated behavior, whereas higher doses (0.003-0.01 mg/kg) restored the duration of catalepsy-associated behavior to control values and produced increases in the duration of repetitive scratching.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Benzazepines; Clozapine; Dopamine Agents; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Interactions; Flupenthixol; Male; Oxazines; Receptors, Dopamine D1; Receptors, Dopamine D2; Saimiri; Salicylamides

The effects of typical and atypical neuroleptics on MK-801-induced locomotor activity and stereotyped sniffing were tested. Pretreatment with the typical neuroleptic haloperidol (0.01, 0.05, 0.1, 0.5 mg/kg SC) and the dopamine D2 receptor selective antagonist eticlopride (0.005, 0.01, 0.05 mg/kg SC) each resulted in significant and dose-dependent reductions of locomotor activity and sniffing. The atypical neuroleptic clozapine (1.0, 5.0, 10.0 mg/kg SC) was somewhat unique in that all doses reduced locomotor activity, but only the highest dose (10.0 mg/kg) significantly reduced sniffing. The data support a functional interaction between glutamate and dopamine systems, and suggest that the behavioral activation associated with MK-801 may represent a valid model for detecting potential therapeutic agents in the treatment of schizophrenia. The data should be viewed as preliminary, however, until neuroleptics are characterized in other glutamate-based models that minimized or exclude the possible influence of nonspecific motor effects.

Topics: Animals; Antipsychotic Agents; Clozapine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Haloperidol; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Salicylamides; Stereotyped Behavior