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Clozapine potentiation of N-methyl-D-aspartate receptor currents in the nucleus accumbens: role of NR2B and protein kinase A/Src kinases.
Wittmann M, Marino MJ, Henze DA, Seabrook GR, Conn PJ
(2005) J Pharmacol Exp Ther 313: 594-603
MeSH Terms: Animals, Clozapine, Cyclic AMP-Dependent Protein Kinases, Dose-Response Relationship, Drug, Drug Synergism, Excitatory Postsynaptic Potentials, Nucleus Accumbens, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate, src-Family Kinases
Show Abstract · Added February 19, 2015
Clozapine is an atypical antipsychotic that has a unique clinical profile that distinguishes it from other typical and atypical antipsychotics. At present, the underlying mechanisms of action of clozapine are unclear. Recent studies in the field of schizophrenia suggest that compounds that potentiate N-methyl-d-aspartate (NMDA) receptor function in the appropriate brain regions might be an effective antipsychotic agent. One relevant region in which NMDA receptors play a key role in mediating neurotransmission is the nucleus accumbens. Therefore, we investigated the regulation of NMDA receptor currents and excitatory postsynaptic currents (EPSCs) by clozapine in nucleus accumbens neurons. Whole-cell patch-clamp recordings were performed in rat brain slices. We demonstrate that bath application of clozapine but not haloperidol or the selective 5-hydroxytryptamine 2A antagonist MDL100907 [(R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluoro-phenyl)ethyl]-4-piperidine methanol] induces a robust potentiation of NMDA-evoked currents and of glutamatergic EPSCs and that this potentiation is dependent on dopamine release and postsynaptic activation of D1 receptors. Furthermore, the effect of clozapine is selective for NR2B subtype-containing NMDA receptors and is blocked by the selective Src family kinase inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] and the protein kinase A-selective inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide but not by the protein kinase C-selective inhibitor bisindolylmaleimide I. This effect of clozapine in the nucleus accumbens might underlie the unique clinical profile of this atypical antipsychotic and provides a basis for novel treatment approaches.
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11 MeSH Terms
Effects of typical and atypical antipsychotics on human glycine transporters.
Williams JB, Mallorga PJ, Conn PJ, Pettibone DJ, Sur C
(2004) Schizophr Res 71: 103-12
MeSH Terms: Amino Acid Transport Systems, Neutral, Animals, Antipsychotic Agents, Benzodiazepines, Brain, Chloride Channels, Choriocarcinoma, Clozapine, Female, Glycine, Glycine Plasma Membrane Transport Proteins, Haloperidol, Humans, Membrane Glycoproteins, Membrane Transport Modulators, Membrane Transport Proteins, Olanzapine, Rats, Receptors, N-Methyl-D-Aspartate, Risperidone, Schizophrenia, Sodium Channels, Synapses, Uterine Neoplasms
Show Abstract · Added February 19, 2015
Augmentation strategy in the treatment of schizophrenia with the NMDA receptor co-agonist glycine has demonstrated significant improvement in patient symptoms. Interestingly, the therapeutic efficacy of glycine was more consistent among patients that were not co-administered clozapine suggesting that clozapine modulates glycine levels in brain. Since cerebral glycine concentration in the vicinity of NMDA receptors is thought to be controlled by the glia expressed glycine transporter type 1 (GlyT1), the effects of several typical and atypical antipsychotics on glycine uptake were examined in human placenta choriocarcinoma (JAR) cells expressing human GlyT1a. The selectivity of these compounds was investigated by measuring their inhibitory potency at the closely related glycine transporter type 2 (GlyT2). Typical antipsychotics haloperidol, thioridazine and chlorpromazine non-selectively inhibited [(14)C]glycine uptake mediated by GlyT1a and GlyT2 with potency of 9-21 microM. The atypical antipsychotic, clozapine antagonized glycine transport by human GlyT1a with an IC(50) of 100 microM and was weaker at recombinant GlyT2. Its main metabolites, N-desmethylclozapine and clozapine N-oxide were very weak inhibitors at all glycine transporters. Similarly, olanzapine did not potently block GlyT1a- and GlyT2-mediated uptake. Detailed kinetic analysis of hGlyT1a in the presence and absence of haloperidol and clozapine revealed that both drugs were not competitive inhibitors of glycine uptake. Data also indicated that these compounds did not interact with the Na(+) and Cl(-) sites of hGlyT1a. Our results have revealed the existence of an inhibitory interaction between some antipsychotics and hGlyT1a and raise the possibility that these drugs could interact with GlyT1 function at therapeutic doses.
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24 MeSH Terms
N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity.
Sur C, Mallorga PJ, Wittmann M, Jacobson MA, Pascarella D, Williams JB, Brandish PE, Pettibone DJ, Scolnick EM, Conn PJ
(2003) Proc Natl Acad Sci U S A 100: 13674-9
MeSH Terms: Allosteric Site, Animals, Brain, Cell Line, Clozapine, Cricetinae, DNA, Complementary, Dose-Response Relationship, Drug, Electrophysiology, Guanosine 5'-O-(3-Thiotriphosphate), Hippocampus, Humans, Inhibitory Concentration 50, Mutagenesis, Site-Directed, Neurons, Protein Binding, Rats, Receptor, Muscarinic M1, Receptors, N-Methyl-D-Aspartate, Time Factors
Show Abstract · Added February 19, 2015
The molecular and neuronal substrates conferring on clozapine its unique and superior efficacy in the treatment of schizophrenia remain elusive. The interaction of clozapine with many G protein-coupled receptors is well documented but less is known about its biologically active metabolite, N-desmethylclozapine. Recent clinical and preclinical evidences of the antipsychotic activity of the muscarinic agonist xanomeline prompted us to investigate the effects of N-desmethylclozapine on cloned human M1-M5 muscarinic receptors. N-desmethylclozapine preferentially bound to M1 muscarinic receptors with an IC50 of 55 nM and was a more potent partial agonist (EC50, 115 nM and 50% of acetylcholine response) at this receptor than clozapine. Furthermore, pharmacological and site-directed mutagenesis studies suggested that N-desmethylclozapine preferentially activated M1 receptors by interacting with a site that does not fully overlap with the acetylcholine orthosteric site. As hypofunction of N-methyl-d-aspartate (NMDA) receptor-driven neuronal ensembles has been implicated in psychotic disorders, the neuronal activity of N-desmethylclozapine was electrophysiologically investigated in hippocampal rat brain slices. N-desmethylclozapine was shown to dose-dependently potentiate NMDA receptor currents in CA1 pyramidal cells by 53% at 100 nM, an effect largely mediated by activation of muscarinic receptors. Altogether, our observations provide direct evidence that the brain penetrant metabolite N-desmethylclozapine is a potent, allosteric agonist at human M1 receptors and is able to potentiate hippocampal NMDA receptor currents through M1 receptor activation. These observations raise the possibility that N-desmethylclozapine contributes to clozapine's clinical activity in schizophrenics through modulation of both muscarinic and glutamatergic neurotransmission.
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20 MeSH Terms
Differential activation of orexin neurons by antipsychotic drugs associated with weight gain.
Fadel J, Bubser M, Deutch AY
(2002) J Neurosci 22: 6742-6
MeSH Terms: Amphetamine, Animals, Antipsychotic Agents, Body Weight, Carrier Proteins, Cell Count, Central Nervous System Stimulants, Clozapine, Dopamine Antagonists, Fornix, Brain, Haloperidol, Hypothalamic Area, Lateral, Immunohistochemistry, Intracellular Signaling Peptides and Proteins, Male, Neurons, Neuropeptides, Orexins, Prefrontal Cortex, Proto-Oncogene Proteins c-fos, Rats, Rats, Sprague-Dawley, Weight Gain
Show Abstract · Added May 27, 2014
Weight gain is one side effect of many antipsychotic drugs (APDs). A small number of lateral hypothalamic/perifornical area (LH/PFA) neurons express the orexins, peptides that are critically involved in body weight regulation and arousal. We examined the ability of APDs to activate orexin neurons, as reflected by induction of Fos. APDs with significant weight gain liability increased Fos expression in orexin neurons, but APDs with low or absent weight gain liability did not. The weight gain liability of APDs was correlated with the degree of Fos induction in orexin neurons of the lateral LH/PFA. In contrast, amphetamine, which causes weight loss, increased Fos expression in orexin neurons of the medial but not lateral LH/PFA. We compared the effects of amphetamine and clozapine, an APD with weight gain liability, on orexin neurons innervating the prefrontal cortex. Clozapine induced Fos in 75% of the orexin neurons that project to the cortex, but amphetamine induced Fos in less than a third of these cells. These data suggest that APD-induced weight gain is associated with activation of distinct orexin neurons and emphasize the presence of anatomically and functionally heterogeneous populations of orexin neurons.
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23 MeSH Terms
Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum.
Bubser M, Deutch AY
(2002) Eur J Neurosci 15: 713-20
MeSH Terms: Animals, Antipsychotic Agents, Clozapine, Dyskinesia, Drug-Induced, Excitatory Amino Acid Antagonists, Haloperidol, Male, Muscarinic Antagonists, Neostriatum, Neurons, Neuropil, Proto-Oncogene Proteins c-fos, Raclopride, Rats, Rats, Sprague-Dawley, Receptors, Neurotransmitter, Serotonin Antagonists
Show Abstract · Added May 27, 2014
Administration of typical antipsychotic drugs (APDs) is often accompanied by extrapyramidal side-effects (EPS). Treatment with atypical APDs has a lower incidence of motor side-effects and atypical APDs are superior to typical APDs in treating the negative symptoms of schizophrenia. Although typical APDs strongly induce the immediate-early gene c-fos in the striatum while atypical APDs do so only weakly, it is possible that the effects of atypical APDs are more pronounced within certain regions of the striatum. The striatum contains two histochemically defined compartments, the striosome (patch) and the matrix. These compartments have been well characterized anatomically but their functional attributes are unclear. We therefore examined the effects of typical and atypical APDs on Fos expression in the striosome and matrix of the rat. Typical and atypical APDs were distinguished by the pattern of striatal compartmental activation they induced: the striosome : matrix ratio of Fos-li neurons was greater in rats treated with atypical APDs. Pretreating animals with selective antagonists of receptors that atypical APDs target with high affinity did not increase the striosome : matrix Fos ratio of typical APD-treated rats and thus did not mimic the ratio seen in response to atypical APDs. However, pretreatment with the atypical APD clozapine did recapitulate the characteristic compartmental Fos pattern seen in response to typical APDs. These data suggest that some characteristics of atypical APDs, such as the lower EPS liability and greater reduction of negative symptoms, may be linked to the coordinate regulation of the striatal striosome and matrix.
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17 MeSH Terms
Procedural learning improvements after six weeks of clozapine treatment.
Purdon SE, Woodward ND, Mintz A, LaBelle A
(2002) Schizophr Res 53: 165-6
MeSH Terms: Adult, Clozapine, Humans, Male, Neuropsychological Tests, Pilot Projects, Practice, Psychological, Problem Solving, Prospective Studies, Psychomotor Performance, Schizophrenia, Schizophrenic Psychology
Added February 15, 2016
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12 MeSH Terms
Stoichiometry of tyrosine hydroxylase phosphorylation in the nigrostriatal and mesolimbic systems in vivo: effects of acute haloperidol and related compounds.
Salvatore MF, Garcia-Espana A, Goldstein M, Deutch AY, Haycock JW
(2000) J Neurochem 75: 225-32
MeSH Terms: Animals, Benzazepines, Brain, Clozapine, Corpus Striatum, Dopamine Antagonists, Haloperidol, Hypothalamus, Male, Nucleus Accumbens, Phosphorylation, Raclopride, Rats, Rats, Sprague-Dawley, Substantia Nigra, Tyrosine 3-Monooxygenase, Ventral Tegmental Area
Show Abstract · Added April 6, 2017
Electrical stimulation of the medial forebrain bundle increases (32)P incorporation into striatal tyrosine hydroxylase (TH) at Ser (19), Ser(31), and Ser(40). In the present studies, the effects of acute haloperidol and related drugs on sitespecific TH phosphorylation stoichiometry (PS) in the nigrostriatal and mesolimbic systems were determined by quantitative blot immunolabeling using phosphorylation statespecific antibodies. The striatum (Str), substantia nigra (SN), nucleus accumbens (NAc), and ventral tegmental area (VTA) from Sprague-Dawley rats were harvested 30-40 min after a single injection of either vehicle, haloperidol (2 mg/kg), raclopride (2 mg/kg), clozapine (30 mg/kg), or SCH23390 (0.5 mg/kg). In vehicle-injected control rats, Ser(19) PS was 1.5- to 2. 5-fold lower in Str and NAc than in SN and VTA, Ser(31) PS was two-to fourfold higher in Str and NAc than in SN and VTA, and Ser(40) PS was similar between the terminal field and cell body regions. After haloperidol, Ser(40) PS increased twofold in Str and NAc, whereas a smaller increase in SN and VTA was observed. The effects of haloperidol on Ser(19) PS were similar to those on Ser(40) in each region; however, haloperidol treatment increased Ser(31) PS at least 1.6-fold in all regions. The effects of raclopride on TH PS were comparable to those of haloperidol, whereas clozapine treatment increased TH PS at all sites in all regions. By contrast, the effects of SCH23390 on TH PS were relatively small and restricted to the NAc. The stoichiometries of site-specific TH phosphorylation in vivo are presented for the first time. The nigrostriatal and mesolimbic systems have common features of TH PS, distinguished by differences in TH PS between the terminal field and cell body regions and by dissimilar increases in TH PS in the terminal field and cell body regions after acute haloperidol.
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17 MeSH Terms
Intracellular modulation of NMDA receptor function by antipsychotic drugs.
Leveque JC, MacĂ­as W, Rajadhyaksha A, Carlson RR, Barczak A, Kang S, Li XM, Coyle JT, Huganir RL, Heckers S, Konradi C
(2000) J Neurosci 20: 4011-20
MeSH Terms: Animals, Antipsychotic Agents, Blotting, Northern, Cells, Cultured, Clozapine, Cycloserine, Dizocilpine Maleate, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Gene Expression Regulation, Genes, fos, Haloperidol, Male, Neostriatum, Neurons, Phosphorylation, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate, Signal Transduction
Show Abstract · Added May 27, 2014
The present study deals with the functional interaction of antipsychotic drugs and NMDA receptors. We show that both the conventional antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine mediate gene expression via intracellular regulation of NMDA receptors, albeit to different extents. Data obtained in primary striatal culture demonstrate that the intraneuronal signal transduction pathway activated by haloperidol, the cAMP pathway, leads to phosphorylation of the NR1 subtype of the NMDA receptor at (897)Ser. Haloperidol treatment is likewise shown to increase (897)Ser-NR1 phosphorylation in rats in vivo. Mutation of (896)Ser and (897)Ser to alanine, which prevents phosphorylation at both sites, inhibits cAMP-mediated gene expression. We conclude that antipsychotic drugs have the ability to modulate NMDA receptor function by an intraneuronal signal transduction mechanism. This facilitation of NMDA activity is necessary for antipsychotic drug-mediated gene expression and may contribute to the therapeutic benefits as well as side effects of antipsychotic drug treatment.
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20 MeSH Terms
Clozapine pretreatment modifies haloperidol-elicited forebrain Fos induction: a regionally-specific double dissociation.
Young CD, Bubser M, Meltzer HY, Deutch AY
(1999) Psychopharmacology (Berl) 144: 255-63
MeSH Terms: Animals, Catalepsy, Clozapine, Drug Interactions, Haloperidol, Immunoblotting, Immunohistochemistry, Oncogene Proteins v-fos, Prosencephalon, Rats, Rats, Sprague-Dawley, Serotonin Antagonists
Show Abstract · Added April 6, 2017
RATIONALE - Acute administration of typical antipsychotic drugs, such as haloperidol, results in the induction of the immediate-early gene c-fos in the dorsolateral striatum. In contrast, the atypical antipsychotic drug clozapine, which lacks significant extrapyramidal side effect liability, does not induce Fos protein in the dorsal striatum. Several studies have attempted to define the mechanisms through which typical antipsychotic drugs induce striatal Fos, often by pretreating animals with specific receptor antagonists. Despite the broad receptor profile of clozapine, there has been no study of the effect of clozapine pretreatment on haloperidol-elicited striatal Fos expression.
METHODS - We examined the effects of clozapine pretreatment of rats on haloperidol-elicited forebrain Fos expression, using both immunoblot and immunohistochemical methods. The effects of clozapine pretreatment were assessed in the dorsal striatum and in the different nucleus accumbens compartments, the septum, and the prefrontal cortex.
RESULTS - Clozapine pretreatment markedly decreased haloperidol-elicited striatal Fos induction and blocked haloperidol-induced catalepsy. Clozapine also attenuated haloperidol-elicited Fos expression in the nucleus accumbens, but in the prefrontal cortex and ventrolateral septum the effects of haloperidol and clozapine were additive.
CONCLUSIONS - An emerging body of literature suggests a high incidence of rapid relapse in schizophrenic patients when clozapine treatment is discontinued. This psychosis is relatively resistant to haloperidol and other neuroleptics, even in patients who had previously responded well to neuroleptics. The present data may shed light on the central sites associated with and perhaps model certain aspects of the relapse associated with clozapine discontinuation.
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12 MeSH Terms
Effects of desmethylclozapine on Fos protein expression in the forebrain: in vivo biological activity of the clozapine metabolite.
Young CD, Meltzer HY, Deutch AY
(1998) Neuropsychopharmacology 19: 99-103
MeSH Terms: Animals, Blotting, Western, Clozapine, Male, Prosencephalon, Proto-Oncogene Proteins c-fos, Rats, Rats, Sprague-Dawley
Show Abstract · Added May 27, 2014
Several products of the hepatic metabolism of clozapine are found in high concentrations in the plasma of schizophrenic patients treated with this atypical antipsychotic drug. One of these metabolites, N-desmethylclozapine, has substantially different affinities for dopamine and serotonin metabolites than does the parent compound. However, it is not known if this metabolite is active in vivo. We examined the effect of acute administration of desmethylclozapine to rats on forebrain Fos protein expression. Clozapine induces expression of this immediate-early gene in a distinct regional pattern in the brain. Desmethylclozapine significantly increased Fos protein expression in the medial prefrontal cortex and nucleus accumbens, but not in the dorsolateral striatum, thus mirroring the effects of the parent compound. These data indicate that the desmethyl metabolite of clozapine has in vivo biological activity.
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8 MeSH Terms