Chronic antipsychotic treatment exerts limited effects on the mania-like behavior of dopamine transporter knockdown mice.

BACKGROUND: Bipolar disorder is a life-threatening disorder linked to dopamine transporter (DAT) polymorphisms, with reduced DAT levels seen in positron emission tomography and postmortem brains. AIMS: The purpose of this study was to examine the effects of approved antipsychotics on DAT dysfunction-mediated mania behavior in mice. METHODS: DAT knockdown mice received either D2-family receptor antagonist risperidone or asenapine and mania-related behaviors were assessed in the clinically-relevant behavioral pattern monitor to assess spontaneous exploration. RESULTS: Chronic risperidone did not reverse mania-like behavior in DAT knockdown mice. Chronic asenapine reduced mania behavior but this effect was more pronounced in wild-type littermates than in DAT knockdown mice. CONCLUSION: Taken together, these findings suggest that while acute antipsychotic treatment may be beneficial in management of bipolar mania, more targeted therapeutics may be necessary for long-term treatment. Specific investigation into DAT-targeting drugs could improve future treatment of bipolar mania.

Brexpiprazole blocks post-traumatic stress disorder-like memory while promoting normal fear memory.

A cardinal feature of post-traumatic stress disorder (PTSD) is a long-lasting paradoxical alteration of memory with hypermnesia for salient traumatic cues and amnesia for peri-traumatic contextual cues. So far, pharmacological therapeutic approach of this stress-related disorder is poorly developed mainly because of the lack of animal model for this paradoxical memory alteration. Using a model that precisely recapitulates the two memory components of PTSD in mice, we tested if brexpiprazole, a new antipsychotic drug with pro-cognitive effects in rodents, may persistently prevent the expression of PTSD-like memory induced by injection of corticosterone immediately after fear conditioning. Acute administration of brexpiprazole (0.3 mg/kg) 7 days' post-trauma first blocks the expression of the maladaptive fear memory for a salient but irrelevant trauma-related cue. In addition, it enhances (with superior efficacy when compared to diazepam, prazosin, and escitalopram) memory for the traumatic context, correct predictor of the threat. This beneficial effect of brexpiprazole is overall maintained 1 week after treatment. In contrast brexpiprazole fully spares normal/adaptive cued fear memory, showing that the effect of this drug is specific to an abnormal/maladaptive (PTSD-like) fear memory of a salient cue. Finally, this treatment not only promotes the switch from PTSD-like to normal fear memory, but also normalizes most of the alterations in the hippocampal-amygdalar network activation associated with PTSD-like memory, as measured by C-Fos expression. Altogether, these preclinical data indicate that brexpiprazole could represent a new pharmacological treatment of PTSD promoting the normalization of traumatic memory.

Adjunctive treatment with brexpiprazole and escitalopram reduces behavioral stress responses and increase hypothalamic NPY immunoreactivity in a rat model of PTSD-like symptoms.

The study explored effects of brexpiprazole (partial D2/5-HT1A agonist, 5-HT2A and α1B/2C-adrenoceptor antagonist) in rats exposed to predator scent stress (PSS), a proposed model of PTSD-like phenotype. Brexpiprazole (3.0mg/kg, PO), escitalopram (5.0mg/kg, IP) and their combination were administered twice daily for 14 days, starting 14 days after exposure to PSS or sham-PSS, shortly after a situational stress reminder. One day after last treatment behavioral responsivity was assessed. Brexpiprazole+escitalopram-treated rats spent more time in open arms, entered open arms more often and exhibited a lower anxiety index in the elevated plus maze than vehicle-treated, PSS-exposed rats. Adjunct brexpiprazole+escitalopram treatment reduced startle amplitude, compared with vehicle-treated, PSS-exposed rats. Treatment with either drug alone did not attenuate anxiety-like behaviors following PSS exposure. Use of cut-off behavioral criteria confirmed that adjunct treatment shifted prevalence of PSS-exposed rats from extreme towards minimal behavioral responders. One day following behavioral tests, brains were prepared for immunohistochemical analysis of number of BDNF-positive cells and of NPY-positive cells/fibers. PSS exposure decreased BDNF levels in hippocampus, but this was not affected by drug treatments. PSS exposure decreased number of NPY positive cells/fibers in paraventricular and arcuate nuclei of hypothalamus. Adjunct treatment with brexpiprazole+escitalopram increased NPY in PSS- and sham-exposed rats. Treatment with brexpiprazole alone had no effects, while treatment with escitalopram alone increased NPY in the arcuate nucleus of PSS-exposed rats. In conclusion, treatment with brexpiprazole+escitalopram may be an effective intervention for the attenuation of PTSD-like stress responses, which in part may be mediated by activating NPY function.

The antipsychotic drug brexpiprazole reverses phencyclidine-induced disruptions of thalamocortical networks.

Brexpiprazole (BREX), a recently approved antipsychotic drug in the US and Canada, improves cognitive dysfunction in animal models, by still largely unknown mechanisms. BREX is a partial agonist at 5-HT1A and D2 receptors and antagonist at α1B- and α2C-adrenergic and 5-HT2A receptors all with a similar potency. The NMDA receptor antagonist phencyclidine (PCP), used as pharmacological model of schizophrenia, activates thalamocortical networks and decreases low frequency oscillations (LFO; <4 Hz). These effects are reversed by antipsychotics. Here we assessed the ability of BREX to reverse PCP-induced hyperactivity of thalamocortical circuits, and the involvement of 5-HT1A receptors in its therapeutic action. BREX reversed PCP-induced neuronal activation at a lower dose in centromedial/mediodorsal thalamic nuclei (CM/MD; 0.5mg/kg) than in pyramidal medial prefrontal cortex neurons (mPFC, 2mg/kg), perhaps due to antagonism at α1B-adrenoceptors, abundantly expressed in the thalamus. Conversely, a cumulative 0.5 mg/kg dose reversed a PCP-induced LFO decrease in mPFC but not in CM/MD. BREX reduced LFO in both areas, yet with a different dose-response, and moderately excited mPFC neurons. The latter effect was reversed by the 5-HT1A receptor antagonist WAY-100635. Thus, BREX partly antagonizes PCP-induced thalamocortical hyperactivity, differentially in mPFC versus CM/MD. This regional selectivity may be related to the differential expression of α1B-, α2C-adrenergic and 5-HT2A receptors in both regions and/or different neuronal types. Furthermore, the pro-cognitive properties of BREX may be related to the 5-HT1A receptor-mediated increase in mPFC pyramidal neuron activity. Overall, the present data provide new insight on the brain elements involved in BREX's therapeutic actions.

Asenapine modulates mood-related behaviors and 5-HT1A/7 receptors-mediated neurotransmission.

AIM: Asenapine is a new atypical antipsychotic prescribed for the treatment of psychosis/bipolar disorders that presents higher affinity for serotonergic than dopaminergic receptors. The objective of this study was to investigate its antidepressant-like and antimanic-like properties on relevant animal models of depression and mania and to assess the acute and chronic effect of Asenapine on dorsal raphe nucleus (DRN) 5-HT cell firing activity. METHODS: We assessed the effects of Asenapine using in vivo electrophysiological and behavioral assays in rats. RESULTS: Behavioral experiments showed that Asenapine had no significant effect on immobility time in the forced swim test (FST) in control rats. In the ACTH-treated rats, a model of antidepressant-resistance, Asenapine failed to alter immobility time in the FST. In contrast in the sleep deprivation (SD) model of mania, acute administration of Asenapine significantly decreased the hyperlocomotion of SD rats. In the DRN, acute administration of Asenapine reduced the suppressant effect of the selective 5-HT7 receptor agonist LP-44 and of the prototypical 5-HT1A receptor agonist 8-OH-DPAT on 5-HT neuronal firing activity. In addition, chronic treatment with Asenapine enhanced DRN 5-HT neuronal firing and this effect was associated with an alteration of the 5-HT7 receptor responsiveness. CONCLUSION: These results confirm that Asenapine displays robust antimanic property and effective in vivo antagonistic activity at 5-HT1A/7 receptors.

Brexpiprazole reduces hyperactivity, impulsivity, and risk-preference behavior in mice with dopamine transporter knockdown-a model of mania.

RATIONALE: Bipolar disorder (BD) is a unique mood disorder defined by periods of depression and mania. The defining diagnosis of BD is the presence of mania/hypomania, with symptoms including hyperactivity and risk-taking. Since current treatments do not ameliorate cognitive deficits such as risky decision-making, and impulsivity that can negatively affect a patient's quality of life, better treatments are needed. OBJECTIVES: Here, we tested whether acute treatment with brexpiprazole, a serotonin-dopamine activity modulator with partial agonist activity at D2/3 and 5-HT1A receptors, would attenuate the BD mania-relevant behaviors of the dopamine transporter (DAT) knockdown mouse model of mania. METHODS: The effects of brexpiprazole on DAT knockdown and wild-type littermate mice were examined in the behavioral pattern monitor (BPM) and Iowa gambling task (IGT) to quantify activity/exploration and impulsivity/risk-taking behavior respectively. RESULTS: DAT knockdown mice exhibited hyper-exploratory behavior in the BPM and made fewer safe choices in the IGT. Brexpiprazole attenuated the mania-like hyper-exploratory phenotype and increased safe choices in risk-preferring DAT knockdown mice. Brexpiprazole also reduced safe choices in safe-preferring mice irrespective of genotype. Finally, brexpiprazole reduced premature (impulsive-like) responses in both groups of mice. CONCLUSIONS: Consistent with earlier reports, DAT knockdown mice exhibited hyper-exploratory, risk-preferring, and impulsive-like profiles consistent with patients with BD mania in these tasks. These behaviors were attenuated after brexpiprazole treatment. These data therefore indicate that brexpiprazole could be a novel treatment for BD mania and/or risk-taking/impulsivity disorders, since it remediates some relevant behavioral abnormalities in this mouse model.

Involvement of presynaptic 5-HT1A receptors in the low propensity of brexpiprazole to induce extrapyramidal side effects in rats.

Previous studies have shown that partial and full 5-HT1A receptor agonists reduce antipsychotic-induced catalepsy. Consequently, some antipsychotics combining balanced efficacy between dopamine (DA) D2 antagonism or partial agonism and 5-HT1A receptor agonism have a low propensity to induce extrapyramidal side effects (EPS), as reflected by low cataleptogenic activity in rodents. In the present experiments, we attempted to explore the importance of pre- and postsynaptic 5-HT1A agonistic properties of brexpiprazole and aripiprazole in the context of neurological side-effect liabilities. Additional measures of prefrontal cortical serotonin (5-HT) and DA levels using microdialysis were used to support that brexpiprazole has a preferential agonist effect on presynaptic 5-HT1A receptors. Brexpiprazole (3.0 and 10mg/kg, p.o.) as well as aripiprazole (8.0 and 30mg/kg, p.o.) failed to induce catalepsy in rats. Brexpiprazole (10mg/kg, p.o.) significantly reduced the cataleptic response induced by haloperidol (0.63mg/kg, s.c.), while aripiprazole (1.0-100mg/kg, p.o.) failed to reverse the effect of haloperidol and only showed a numeric decrease at 10mg/kg, (p.o.). When 5-HT1A receptors were blocked by the selective antagonist, WAY100635 (1.0mg/kg, s.c.), cataleptogenic properties of brexpiprazole (10mg/kg; p.o), but not aripiprazole (8.0 and 30mg/kg, p.o.) were unmasked. The ("biased") 5-HT1A receptor agonists F15599 (postsynaptic preference) and F13714 (presynaptic preference) had differential effects on haloperidol-induced catalepsy: F13714 (0.16mg/kg, s.c.) counteracted catalepsy, whereas F15599 (0.040mg/kg, s.c.) had no significant effect at regionally-selective doses. These data support a role of presynaptic 5-HT1A receptors in the anticataleptic effect of brexpiprazole. The selective 5-HT2A antagonist M100907 (0.10mg/kg, s.c.) had no effect on haloperidol-induced catalepsy, arguing against a major role of 5-HT2A receptors in the cataleptogenic profile of brexpiprazole. The findings with brexpiprazole were supported using microdialysis studies: Brexpiprazole (3.0 and 10mg/kg, p.o.) decreased extracellular 5-HT levels in the medial prefrontal cortex (mPFC), while it failed to affect extracellular DA in the same samples, suggesting that the 5-HT1A agonist properties of brexpiprazole may be preferentially presynaptic. In conclusion, these results confirm that brexpiprazole and aripiprazole have low propensities to induce EPS. However, the low EPS risk of brexpiprazole is more likely dependent on its agonist properties on presynaptic 5-HT1A receptors, while that of aripiprazole is less sensitive to 5-HT1A receptor antagonism.

Discriminative stimulus properties of 1.25mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors.

The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/α1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1H-indol-5-yl)piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 receptor antagonist Lu 38-012 and the α1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the discriminative stimulus properties of 1.25mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus.

Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator.

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT1A) and D2/3 receptors, combined with potent antagonist effects on 5-HT2A, α1B-, and α2C-adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED50 = 6.0 mg/kg), apomorphine- or d-amphetamine-induced hyperactivity (ED50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED50 = 2.9) in rats at clinically relevant D2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED50 = 20) well above clinically relevant D2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D2 occupancies. In the NOR test, the 5-HT1A agonist buspirone and the 5-HT2A antagonist M100907 [(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)piperidin-4-yl]methanol] partially but significantly reversed PCP-induced impairment. Furthermore, the effect of brexpiprazole was reversed by cotreatment with the 5-HT1A antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate). The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. The effects of brexpiprazole in the cognitive tests are superior to those of aripiprazole. We propose that the pharmacologic profile of brexpiprazole be based on its balanced effects on 5-HT1A, D2, and 5-HT2A receptors, with possible modulating activity through additional monoamine receptors.

Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator.

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.

Bifeprunox: a partial agonist at dopamine D2 and serotonin 1A receptors, influences nicotine-seeking behaviour in response to drug-associated stimuli in rats.

Environmental stimuli repeatedly associated with the self-administered drugs may acquire motivational importance. Because dopamine (DA) D(2) /D(3) partial agonists and D(3) antagonists interfere with the ability of drug-associated cues to induce drug-seeking behaviour, the present study investigated whether bifeprunox, 7-[4-([1,1'biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone mesylate), a high-affinity partial agonist of the D(2) subfamily of DA receptors and of serotonin(1A) receptors, influences reinstatement of drug-associated cue-induced nicotine-seeking behaviour. The study also explored whether bifeprunox reduced motivated behaviour by evaluating its effects on reinstatement induced by stimuli conditioned to sucrose. To verify whether bifeprunox interferes with the primary reinforcing properties of either drug or sucrose, we compared its effects on nicotine self-administration and on sucrose-reinforced behaviour. Different groups of experimentally naïve, food-restricted Wistar rats were trained to associate a discriminative stimulus with response-contingent availability of nicotine or sucrose and tested for reinstatement after extinction of nicotine or sucrose-reinforced behaviour. Bifeprunox (4-16 µg/kg, s.c.) dose-dependently attenuated the response-reinstating effects of nicotine-associated cues. Higher doses (64-250 µg/kg, s.c.) reduced spontaneous locomotor activity and suppressed operant responding induced by sucrose-associated cues and by the primary reinforcing properties of nicotine or sucrose. Provided they can be extrapolated to abstinent human addicts, these results suggest the potential therapeutic use of partial DA D(2) receptor agonist to prevent cue-controlled nicotine-seeking and relapse. The profile of action of high doses of bifeprunox remains to be examined for potential sedation or anhedonia effects.

Characterization of [³H]Lu AE60157 ([³H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) binding to 5-hydroxytryptamine6 (5-HT6) receptors in vivo.

The serotonin6 (5-HT(6)) receptor has received attention for its proposed role in cognitive impairments associated with schizophrenia and Alzheimer's disease. This has lead to a search for selective 5-HT(6) receptor ligands useful for in vivo imaging in animals and humans. The novel 5-HT(6) receptor antagonist Lu AE60157 (8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) displays high affinity for the human (h) 5-HT(6) receptor (K(d) 0.2nM), and broad profiling in 60 additional binding and enzyme assays showed that Lu AE60157 displays 16-fold selectivity to the h5-HT(2A) receptor (K(i) 3.2nM) and >100-fold selectivity to all other evaluated targets. Lu AE60157 was labeled with tritium in the N-methyl group and evaluated as a radioligand in vitro as well as in vivo in rats and mice. Autoradiography experiments showed that [(3)H]Lu AE60157 bound preferentially to rat brain regions with expected high 5-HT(6) receptor density. Furthermore, [(3)H]Lu AE60157 showed good brain penetration after systemic administration and high (about 75%) specific in vivo binding to the striatal 5-HT(6) receptor in rats. The striatal binding of [(3)H]Lu AE60157 was fully displaced by selective 5-HT(6) receptor antagonists (SB-742457; Lu AE58054) and antipsychotics known to inhibit the binding of 5-HT(6) receptors in vitro (clozapine; olanzapine; sertindole), but was not displaced by antipsychotics lacking high 5-HT(6) receptor affinities (risperidone; haloperidol; quetiapine). No specific binding to mouse brain tissue in vivo could be obtained. In conclusion, [(3)H]Lu AE60157 is suitable for measuring in vivo occupancies of 5-HT(6) receptor ligands in rat brain regions in which 5-HT(2A) receptors do not interfere.

Serotonin 2A receptor antagonists for treatment of schizophrenia.

INTRODUCTION: All approved antipsychotic drugs share an affinity for the dopamine 2 (D(2)) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. AREAS COVERED: Preclinical, clinical and post-mortem studies of the serotonin 5-HT(2A) system in schizophrenia are reviewed. The implications of a combined D(2) and 5-HT(2A) receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT(2A) receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT(2A) receptor antagonists for the treatment of schizophrenia. EXPERT OPINION: 5-HT(2A) receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT(2A) receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT(2A) receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia.

Clozapine and N-methyl-D-aspartate have positive modulatory actions on their respective discriminative stimulus properties in C57BL/6 mice.

The impairment of N-Methyl-D-Aspartate receptors is thought to contribute to negative symptoms and cognitive deficits. In vitro studies suggest that atypical antipsychotic drugs like clozapine may help to alleviate these deficits by enhancing glutamatergic function. The present study examined the in vivo interaction of clozapine with N-Methyl D-aspartate by training one group of C57BL/6 mice to discrimination 2.5 mg/kg clozapine from vehicle and another group to discriminate 30 mg/kg N-Methyl D-aspartate from vehicle in a two-lever drug discrimination task. Cross-generalization testing revealed that N-Methyl D-aspartate (3-56 mg/kg) failed to substitute for clozapine in the clozapine-trained mice, while clozapine (0.625 mg/kg) produced partial substitution in the N-Methyl D-aspartate-trained mice. Interestingly, administration of a low, non-generalizing dose of each training drug in combination with the full range of doses of the alternate training drug produced full and dose-dependent substitution in both clozapine- and N-Methyl D-aspartate-trained mice. The α(1) antagonist prazosin fully and dose-dependently substituted for both clozapine and N-Methyl D-aspartate. These results suggest that the shared discriminative stimulus properties between clozapine and N-Methyl D-aspartate may be mediated through indirect mechanisms, possibly in part through α(1) adrenergic antagonism.

Sertindole restores attentional performance and suppresses glutamate release induced by the NMDA receptor antagonist CPP.

RATIONALE: Blockade of N-methyl-d-aspartic acid (NMDA) receptors in the rat medial prefrontal cortex (mPFC) impairs performance in the five-choice serial reaction time task (5-CSRTT) and increases glutamate (GLU) release. Recent research suggests that excessive GLU release may be critical for attention deficits. OBJECTIVES: We tested this hypothesis by investigating the effects of the atypical antipsychotics sertindole and clozapine on 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP)-induced performance deficits in the 5-CSRTT and on the CPP-induced GLU release in the mPFC. METHODS: The 5-CSRTT, a test of divided and sustained visual attention providing indices of attentional functioning (accuracy of visual discrimination), response control (anticipatory and perseverative responses) and intracortical microdialysis in conscious rats were used to investigate the effects of sertindole and clozapine. RESULTS: Low doses of sertindole (0.02-0.32 mg/kg) prevented CPP-induced accuracy deficits, anticipatory over-responding and the rise in GLU release. In contrast, doses ranging from 0.6 to 2.5 mg/kg had no effect or even enhanced the effect of CPP on anticipatory responding. Similarly, 2.5 mg/kg sertindole was unable to reverse CPP-induced rise in GLU release. Clozapine (2.5 mg/kg) prevented accuracy deficits and the increase in anticipatory responding and abolished the rise in GLU release induced by CPP. CONCLUSIONS: These findings show that the ameliorating effects of sertindole and clozapine on NMDA receptor dependent attention deficit is associated with suppression in GLU release in the mPFC. This supports the proposal that suppression in GLU release might be a target for the development of novel drugs aimed at counteracting some aspects of cognitive deficits of schizophrenia.

Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole.

RATIONALE: A pivotal role for glutamate in the pathophysiology and treatment of schizophrenia has been suggested. Few reports have investigated the impact of antipsychotics on postsynaptic density (PSD) molecules involved in glutamatergic transmission and synaptic remodeling. Homer is a key PSD molecule putatively implicated in schizophrenia. OBJECTIVES: We studied the effect, in acute and chronic paradigms, of a first and a second generation antipsychotic (haloperidol and sertindole, respectively) on the expression of Homer1a and Homer-interacting PSD molecules. RESULTS: In the acute paradigm, Homer1a expression was induced by haloperidol but not sertindole in the striatum, consistent with the less propensity of sertindole to affect nigrostriatal neurotransmission. The profile of expression of two other inducible genes, Ania3 and Arc, was highly similar to Homer1a. In the cortex, haloperidol reduced Homer1a and induced Ania3. In the chronic paradigm, striatal expression of Homer1a and Ania3 resembled that observed in the acute paradigm. In the cortex, haloperidol induced Homer1a, while sertindole did not. Homer1b expression was increased by haloperidol in the striatum and cortex whereas sertindole selectively induced Homer1b in the cortex. The expression of mGluR5 was increased by both antipsychotics. A modulation by haloperidol was also seen for PSD-95 and αCaMKII. CONCLUSIONS: These results suggest that haloperidol and sertindole may significantly modulate glutamatergic transcripts of the postsynaptic density. Sertindole induces constitutive genes in the cortex predominantly, which may correlate with its propensity to improve cognitive functions. Haloperidol preferentially modulates gene expression in the striatum, consistent with its action at nigrostriatal projections and its propensity to give motor side effects.

Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats.

The in-vitro potency and selectivity, in-vivo binding affinity and effect of the 5-HT(6)R antagonist Lu AE58054 ([2-(6-fluoro-1H-indol-3-yl)-ethyl]-[3-(2,2,3,3-tetrafluoropropoxy)-benzyl]-amine) on impaired cognition were evaluated. Lu AE58054 displayed high affinity to the human 5-HT(6) receptor (5-HT(6)R) with a Ki of 0.83 nm. In a 5-HT(6) GTPgammaS efficacy assay Lu AE58054 showed no agonist activity, but demonstrated potent inhibition of 5-HT-mediated activation. Besides medium affinity to adrenergic alpha(1A)- and alpha(1B)-adrenoreceptors, Lu AE58054 demonstrated >50-fold selectivity for more than 70 targets examined. Orally administered Lu AE58054 potently inhibited striatal in-vivo binding of the 5-HT(6) antagonist radioligand [(3)H]Lu AE60157 ([(3)H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline), with an ED(50) of 2.7 mg/kg. Steady-state modelling of an acute pharmacokinetic/5-HT(6)R occupancy time-course experiment indicated a plasma EC(50) value of 20 ng/ml. Administration of Lu AE58054 in a dose range (5-20 mg/kg p.o.) leading to above 65% striatal 5-HT(6)R binding occupancy in vivo, reversed cognitive impairment in a rat novel object recognition task induced after subchronic treatment for 7 d with phencyclidine (PCP 2 mg/kg b.i.d., i.p. for 7 d, followed by 7 d drug free). The results indicate that Lu AE58054 is a selective antagonist of 5-HT(6)Rs with good oral bioavailability and robust efficacy in a rat model of cognitive impairment in schizophrenia. Lu AE58054 may be useful for the pharmacotherapy of cognitive dysfunction in disease states such as schizophrenia and Alzheimer's disease.

Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT(6) and 5-HT (2A) receptor mechanisms.

AIM: This study examined the efficacy of sertindole in comparison with a selective 5-HT(6) and a 5-HT(2A) receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats. METHODS: In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with sertindole, the selective 5-HT(2A) receptor antagonist M100.907 or the selective 5-HT(6) receptor antagonist SB-742457. RESULTS: The PCP-induced selective reversal learning deficit was significantly improved by sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose-response relationship for sertindole in this study most closely correlates with affinity for 5-HT(6) receptor in vivo binding in striatum, although contribution from binding to 5-HT(2A) receptors in vivo in cortex may also provide an important mechanism. CONCLUSION: The efficacies of selective 5-HT(2A) and 5-HT(6) receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.

Effect of sertindole on extracellular dopamine, acetylcholine, and glutamate in the medial prefrontal cortex of conscious rats: a comparison with risperidone and exploration of mechanisms involved.

RATIONALE: Second-generation antipsychotics have some beneficial effect on cognition. Recent studies, furthermore, indicate differential effects of second-generation antipsychotics on impairment in executive cognitive function. OBJECTIVE: We evaluated the effect of the second-generation antipsychotic drug, sertindole, on extracellular levels of dopamine (DA), acetylcholine (ACh), and glutamate (Glu) in the rat medial prefrontal cortex (mPFC). Risperidone was studied for comparison. Moreover, selective serotonin 5-HT(2A), 5-HT(2C), and 5-HT(6) receptor antagonists were used, given alone and in combination with the preferential DA D(2) receptor antagonist, haloperidol, to further clarify the action of the two drugs. MATERIALS AND METHODS: Rats were treated acutely with vehicle or drugs, and extracellular levels of neurotransmitters were assessed by microdialysis in freely moving animals. RESULTS: Sertindole and risperidone significantly increased extracellular levels of DA. Haloperidol; the 5-HT(2A) receptor antagonist, M100907; the 5-HT(2C) receptor antagonist, SB242084; and the 5-HT(6) receptor antagonist, GSK-742457, induced minor increases in levels of DA, but the three latter compounds raised the DA levels notably in combination with haloperidol. Sertindole and risperidone significantly increased the extracellular levels of ACh but only sertindole raised the extracellular levels of Glu. The selective 5-HT(6) receptor antagonist, SB-271046, significantly increased the extracellular levels of Glu. CONCLUSION: Sertindole and risperidone markedly increased extracellular levels of DA in mPFC. The built-in 5-HT(2A)/5-HT(2C)/D(2) receptor antagonism of the two drugs might be involved in this action. Both drugs increased the extracellular levels of ACh but only sertindole enhanced Glu levels. The high affinity of sertindole for the 5-HT(6) receptor compared to risperidone may differentiate sertindole from risperidone.