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 D-family receptor antagonist risperidone or asenapine and mania-related behaviors were assessed in the clinically-relevant behavioral pattern monitor to assess spontaneous exploration.

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 D/5-HT agonist, 5-HT and α-adrenoceptor antagonist) in rats exposed to predator scent stress (PSS), a proposed model of PTSD-like phenotype. Brexpiprazole (3.0mg/kg, PO), escitalopram (5.

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-HT and D receptors and antagonist at α- and α-adrenergic and 5-HT 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).

Asenapine modulates mood-related behaviors and 5-HT 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.

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

Previous studies have shown that partial and full 5-HT receptor agonists reduce antipsychotic-induced catalepsy. Consequently, some antipsychotics combining balanced efficacy between dopamine (DA) D antagonism or partial agonism and 5-HT 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-HT agonistic properties of brexpiprazole and aripiprazole in the context of neurological side-effect liabilities.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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).

Bifeprunox and aripiprazole suppress in vivo VTA dopaminergic neuronal activity via D2 and not D3 dopamine autoreceptor activation.

Bifeprunox and aripiprazole are two novel antipsychotics presenting partial agonistic activity for the D(2) and D(3) dopamine (DA) receptors. Using in vivo electrophysiological paradigms in anaesthetized rats, we have previously shown that both drugs independently inhibit the spontaneous firing and bursting activity of ventral tegmental area (VTA) dopaminergic neurons and partially reverse the suppressing effect of the full DA receptor agonist apomorphine. Moreover, we have also shown that the D(2/3) receptor antagonist haloperidol prevents the inhibitory effects of these antipsychotics, confirming their partial D(2)-like agonistic activities [L.

Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour.

The atypical antipsychotic bifeprunox is a partial dopamine D(2) and 5-HT(1A) receptor agonist. Using in-vivo electrophysiological and behavioural paradigms in the rat, the effects of bifeprunox and aripiprazole were assessed on ventral tegmental area (VTA) dopamine and dorsal raphe serotonin (5-HT) cell activity and on foot shock-induced ultrasonic vocalisation (USV). In VTA, bifeprunox and aripiprazole decreased (by 20-50%) firing of dopamine neurons.

Reversal of subchronic PCP-induced deficits in attentional set shifting in rats by sertindole and a 5-HT6 receptor antagonist: comparison among antipsychotics.

Currently accepted treatments for schizophrenia can effectively control positive symptoms but have limited impact on cognitive deficits in schizophrenia. The purpose of these experiments was to address this unmet need by characterizing the effects of classical and second-generation antipsychotics on cognitive impairments associated with schizophrenia. An additional aim was to characterize the part(s) of the pharmacological profile of drugs that were important to reverse deficits.

Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole), a dopamine D4 receptor antagonist and serotonin reuptake inhibitor: characterisation of its in vitro profile and pre-clinical antipsychotic potential.

The present study describes the pharmacological profile of the putative antipsychotic drug Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole). The in vitro receptor profile of Lu 35-138 revealed high affinity (K(i)=5 nM) and competitive antagonism (K(b)=8 nM) at dopamine D(4) receptors combined with potent 5-HT uptake inhibition (IC(50)=3.2 nM) and moderate alpha(1)-adrenoceptor affinity (K(i)=45 nM).

Reversal of PCP-induced learning and memory deficits in the Morris' water maze by sertindole and other antipsychotics.

Rationale: In humans, the N-methyl-D-aspartate antagonist phencyclidine (PCP) induces behavioral changes that mimic schizophrenia symptoms, including positive and negative symptoms as well as cognitive deficits. In clinic, the cognitive deficits are closely associated with functional outcome. Thus, improvement of cognition may have high impact on patients' daily life.