ABSTRACT
BACKGROUND: Substantial clinical data support the addition of low doses of atypical antipsychotic drugs to selective serotonin reuptake inhibitors (SSRIs) to rapidly enhance the antidepressant effect in treatment-resistant depression. Preclinical studies suggest that this effect is at least partly explained by an increased catecholamine outflow in the medial prefrontal cortex (mPFC). METHODS: In the present study we used in vivo microdialysis in freely moving rats and in vitro intracellular recordings of pyramidal cells of the rat mPFC to investigate the effects of adding the novel atypical antipsychotic drug asenapine to the SSRI escitalopram with regards to monoamine outflow in the mPFC and dopamine outflow in nucleus accumbens as well as glutamatergic transmission in the mPFC. RESULTS: The present study shows that addition of low doses (0.05 and 0.1 mg/kg) of asenapine to escitalopram (5 mg/kg) markedly enhances dopamine, noradrenaline, and serotonin release in the rat mPFC as well as dopamine release in the nucleus accumbens. Moreover, this drug combination facilitated both N-methyl-d-Aspartate (NMDA)- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced currents as well as electrically evoked excitatory postsynaptic potentials in pyramidal cells of the rat mPFC. CONCLUSIONS: Our results support the notion that the augmentation of SSRIs by atypical antipsychotic drugs in treatment-resistant depression may, at least in part, be related to enhanced catecholamine output in the prefrontal cortex and that asenapine may be clinically used to achieve this end. In particular, the subsequent activation of the D1 receptor may be of importance for the augmented antidepressant effect, as this mechanism facilitated both NMDA and AMPA receptor-mediated transmission in the mPFC. Our novel observation that the drug combination, like ketamine, facilitates glutamatergic transmission in the mPFC may contribute to explain the rapid and potent antidepressant effect obtained when atypical antipsychotic drugs are added to SSRIs.
Subject(s)
Antipsychotic Agents/pharmacology , Biogenic Monoamines/metabolism , Citalopram/pharmacology , Glutamic Acid/metabolism , Heterocyclic Compounds, 4 or More Rings/pharmacology , Prefrontal Cortex/drug effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Synaptic Transmission/drug effects , Animals , Benzazepines/pharmacology , Bicuculline/pharmacology , Dibenzocycloheptenes , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Excitatory Amino Acid Agents/pharmacology , Excitatory Postsynaptic Potentials/drug effects , GABA-A Receptor Antagonists/pharmacology , Male , Neurons/drug effects , Prefrontal Cortex/cytology , Rats , Rats, Wistar , Time FactorsABSTRACT
The psychotropic drug asenapine is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. Asenapine exhibits higher affinity for several 5-HT receptors and α(2)-adrenoceptors than for D(2) receptors. Noteworthy, blockage of both the 5-HT(2A) and α(2)-adrenergic receptors has been shown to enhance prefrontal dopamine release induced by D(2) receptor antagonists. Previous results show that asenapine, both systemically and locally, increases dopamine, noradrenaline, and serotonin release in the medial prefrontal cortex (mPFC), and that the increased dopamine release largely depends on an intracortical action. Using reverse microdialysis in freely moving rats, we here assessed the potency of low concentrations of asenapine to cause a pharmacologically significant blockage in vivo of 5-HT(2A) receptors and α(2)-adrenoceptors within the mPFC, and thus its ability to affect cortical monoamine release by these receptors. Intracortical administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT(2A/2C) receptor agonist, increased cortical monoamine release, effects that were antagonized both by asenapine and the selective 5-HT(2A) antagonist M100907. Application of clonidine, an α(2)-adrenoceptor agonist, significantly reduced monoamine release in the mPFC. The selective α(2)-adrenoceptor antagonist idazoxan blocked, whereas asenapine partially blocked clonidine-induced cortical dopamine and noradrenaline decrease. The effects of asenapine and idazoxan on clonidine-induced serotonin decrease were less pronounced. Our results propose that low concentrations of asenapine in the mPFC exhibit a pharmacologically significant 5-HT(2A) and α(2) receptor antagonistic activity, which may contribute to enhance prefrontal monoamine release in vivo and, secondarily, its clinical effects in schizophrenia and bipolar disorder.
Subject(s)
Antipsychotic Agents/pharmacology , Biogenic Monoamines/metabolism , Heterocyclic Compounds, 4 or More Rings/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Receptors, Adrenergic, alpha-2/metabolism , Adrenergic alpha-2 Receptor Antagonists/pharmacology , Amphetamines/pharmacology , Animals , Dibenzocycloheptenes , Fluorobenzenes/pharmacology , Male , Microdialysis , Norepinephrine/metabolism , Piperidines/pharmacology , Rats , Rats, Wistar , Serotonin/metabolism , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Up-RegulationABSTRACT
Compared to both first- and second-generation antipsychotic drugs (APDs), clozapine shows superior efficacy in treatment-resistant schizophrenia. In contrast to most APDs clozapine possesses high affinity for alpha2-adrenoceptors, and clinical and preclinical studies provide evidence that the alpha2-adrenoceptor antagonist idazoxan enhances the antipsychotic efficacy of typical D2 receptor antagonists as well as olanzapine. Risperidone has lower affinity for alpha2-adrenoceptors than clozapine but higher than most other APDs. Here we examined, in rats, the effects of adding idazoxan to risperidone on antipsychotic effect using the conditioned avoidance response (CAR) test, extrapyramidal side-effect (EPS) liability using the catalepsy test, brain dopamine efflux using in-vivo microdialysis in freely moving animals, cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission using intracellular electrophysiological recording in vitro, and ex-vivo autoradiography to assess the in-vivo alpha2A- and alpha2C-adrenoceptor occupancies by risperidone. The dose of risperidone needed for antipsychotic effect in the CAR test was approximately 0.4 mg/kg, which produced 11% and 17% in-vivo receptor occupancy at alpha2A- and alpha2C-adrenoceptors, respectively. Addition of idazoxan (1.5 mg/kg) to a low dose of risperidone (0.25 mg/kg) enhanced the suppression of CAR, but did not enhance catalepsy. Both cortical dopamine release and NMDA receptor-mediated responses were enhanced. These data propose that the therapeutic effect of risperidone in schizophrenia can be enhanced and its EPS liability reduced by adjunctive treatment with an alpha2-adrenoceptor antagonist, and generally support the notion that the potent alpha2-adrenoceptor antagonistic action of clozapine may be highly important for its unique efficacy in schizophrenia.
Subject(s)
Adrenergic alpha-2 Receptor Antagonists/pharmacology , Antipsychotic Agents/pharmacology , Cerebral Cortex/drug effects , Idazoxan/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Risperidone/pharmacology , Synaptic Transmission/drug effects , Adrenergic alpha-2 Receptor Antagonists/administration & dosage , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/metabolism , Avoidance Learning/drug effects , Catalepsy/drug therapy , Catalepsy/metabolism , Cerebral Cortex/metabolism , Dopamine Agonists/administration & dosage , Dopamine Agonists/metabolism , Dopamine Agonists/pharmacology , Electrophysiological Phenomena/drug effects , Excitatory Amino Acid Agents/administration & dosage , Excitatory Amino Acid Agents/metabolism , Excitatory Amino Acid Agents/pharmacology , Idazoxan/administration & dosage , Idazoxan/metabolism , Male , Microdialysis , Rats , Rats, Sprague-Dawley , Rats, Wistar , Risperidone/administration & dosage , Risperidone/metabolismABSTRACT
RATIONALE: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder. MATERIALS AND METHODS: The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-D: -aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed. RESULTS: Asenapine (0.05-0.2 mg/kg, subcutaneous [s.c.]) induced a dose-dependent suppression of CAR (no escape failures recorded) and did not induce catalepsy. Asenapine (0.05-0.2 mg/kg, s.c.) increased dopamine efflux in both the mPFC and the NAc. Low-dose asenapine (0.01 mg/kg, intravenous [i.v.]) increased dopamine efflux preferentially in the shell compared to the core of NAc, whereas at a higher dose (0.05 mg/kg, i.v.), the difference disappeared. Finally, like clozapine (100 nM), but at a considerably lower concentration (5 nM), asenapine significantly potentiated the NMDA-induced responses in pyramidal cells of the mPFC. CONCLUSIONS: These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.
Subject(s)
Antipsychotic Agents/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Schizophrenia/drug therapy , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/adverse effects , Avoidance Learning , Catalepsy/chemically induced , Conditioning, Classical , Dibenzocycloheptenes , Disease Models, Animal , Dopamine/metabolism , Dose-Response Relationship, Drug , Electrophysiology , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Heterocyclic Compounds, 4 or More Rings/adverse effects , Injections, Subcutaneous , Male , Microdialysis , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Rats , Rats, WistarABSTRACT
RATIONALE: Asenapine, a psychopharmacologic agent developed for schizophrenia and bipolar disorder, has higher affinity for 5-HT(2A/C,6,7) and alpha(2) adrenergic receptors than for D(2) receptors. Asenapine exhibits potent antipsychotic-like effects without inducing catalepsy, increases cortical and subcortical dopamine release, and facilitates cortical glutamatergic transmission in rats. In this study, we further analyzed the effects of asenapine on dopaminergic, noradrenergic, and serotonergic systems in the rat brain. MATERIALS AND METHODS: We studied the effects of asenapine on (1) dopaminergic neurons in the ventral tegmental area (VTA) and noradrenergic neurons in the locus coeruleus using in vivo single cell recording, (2) release of dopamine and noradrenaline (medial prefrontal cortex), serotonin (frontal cortex), and dopamine (nucleus accumbens), using in vivo microdialysis. RESULTS: Systemic asenapine increased dopaminergic (0.001-0.2 mg/kg, i.v.) and noradrenergic (0.025-0.05 mg/kg i.v.) neuronal firing, and asenapine (0.1-0.2 mg/kg, s.c) increased cortical noradrenaline and serotonin output. Local asenapine administration increased all three monoamines in the cortex but did not affect accumbal dopamine output. Intra-VTA tetrodotoxin perfusion blocked asenapine-induced accumbal but not cortical dopamine outflow. CONCLUSION: Asenapine at doses associated with antipsychotic activity enhanced cortical monoamine efflux. Whereas the asenapine-induced dopamine increase in nucleus accumbens is dependent on activation of dopaminergic neurons in the VTA, the increase of cortical dopamine outflow involves largely a local action at nerve terminals. Our data provide further insight on the pharmacologic characteristics of asenapine that may have bearing on its clinical efficacy in the treatment of schizophrenia and bipolar disorder.