Sodium nitroprusside enhances the antipsychotic-like effect of olanzapine but not clozapine in the conditioned avoidance response test in rats.

The nitric oxide (NO)-donor, sodium nitroprusside (SNP) has been proposed as an adjunct treatment to enhance the effect of antipsychotic drugs (APDs). As NO constitutes an important downstream signaling molecule of N-methyl-D-aspartate receptors, SNP may alleviate symptoms of schizophrenia by modulating glutamatergic signaling. We previously showed that SNP enhances the antipsychotic-like effect of a sub-effective dose of risperidone in the conditioned avoidance response (CAR) test, indicating that adjunct SNP may be used to lower the dose of risperidone and in this way reduce the risk of side effects. By using the CAR test, we here investigated if SNP also enhances the antipsychotic-like effect of olanzapine or clozapine. Importantly, SNP (1.5 mg/kg) significantly enhanced the antipsychotic-like effect of olanzapine (1.25 and 2.5mg/kg) to a clinically relevant level, supporting the potential clinical use of SNP as an adjunct treatment to improve the effect of APDs. However, SNP (1.5 mg/kg) did not increase the antipsychotic-like effect of clozapine (5 and 6 mg/kg). Moreover, we found that the rats developed tolerance towards clozapine after repeated administrations. Thus, our study motivates further investigation using different preclinical models to assess the effect of adjunct treatment of SNP to APDs, also targeting the negative symptoms and cognitive deficits seen in schizophrenia.

Enhancement of the antipsychotic effect of risperidone by sodium nitroprusside in rats.

Recently, a single injection of the nitric oxide donor sodium nitroprusside (SNP) was found to induce a rapid and sustained antipsychotic effect in treatment-resistant schizophrenia (TRS). Moreover, a single i.p. injection of SNP in rats was found to generate both rapid and persisting changes in brain synaptic plasticity, including enhanced excitatory postsynaptic current responses and spine morphology in layer V pyramidal cells in the medial prefrontal cortex (mPFC) brain slices. Here we used the conditioned avoidance response (CAR) test in rats to investigate the antipsychotic-like efficacy of SNP in combination with low-dose risperidone. In addition, we performed microdialysis experiments in freely moving rats to measure neurotransmitter efflux in the mPFC and the nucleus accumbens (NAc). Risperidone caused only 20% suppression of CAR, which is far below the degree of CAR suppression required to predict a significant clinical antipsychotic effect. Addition of a low dose of SNP to risperidone dramatically enhanced the antipsychotic-like effect to a clinically relevant level. SNP significantly enhanced the risperidone-induced dopamine output in the mPFC but not in the NAc. The increased prefrontal dopamine release induced by the drug combination may also improve cognition as indicated by previous preclinical and clinical studies and, furthermore, via enhanced synaptic spine function and morphology in mPFC generate a both rapid and prolonged antipsychotic and pro-cognitive effect. Our results delineate SNP as a promising new treatment option for schizophrenia, including TRS, when added to currently available antipsychotic medication in order to improve efficacy at maintained or even reduced dosage.

Functional mechanism of ASP5736, a selective serotonin 5-HT5A receptor antagonist with potential utility for the treatment of cognitive dysfunction in schizophrenia.

The 5-HT5A receptor is arguably the least understood 5-HT receptor. Despite widespread expression in human and rodent brains it lacks specific ligands. Our previous results suggest that 5-HT5A receptor antagonists may be effective against cognitive impairment in schizophrenia. In this study, using behavioral, immunohistochemical, electrophysiological and microdialysis techniques, we examined the mechanism by which ASP5736, a novel and selective 5-HT5A receptor antagonist, exerts a positive effect in animal models of cognitive impairment. We first confirmed the effect of ASP5736 on cognitive deficits in rats treated subchronically with phencyclidine hydrochloride (PCP) using an attentional set shifting task. Subsequently, we identified 5-HT5A receptors in dopaminergic (DAergic) neurons and parvalbumin (PV)-positive interneurons in the ventral tegmental area (VTA) and in PV-positive interneurons in the medial prefrontal cortex (mPFC). Burst firing of the DAergic cells in the parabrachial pigmental nucleus (PBP) in the VTA, which predominantly project to the mPFC, was significantly enhanced by treatment with ASP5736. In contrast, ASP5736 exerted no significant effect on either the firing rate or burst firing in the DA cells in the paranigral nucleus (PN), that project to the nucleus accumbens (N. Acc.). ASP5736 increased the release of DA and gamma-aminobutyric acid (GABA) in the mPFC of subchronically PCP-treated rats. These results support our hypothesis that ASP5736 might block the inhibitory 5-HT5A receptors on DAergic neurons in the VTA that project to the mPFC, and interneurons in the mPFC, and thereby improve cognitive impairment by preferentially enhancing DAergic and GABAergic neurons in the mPFC.

The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism.

Brexpiprazole (Rexulti®), a novel D2/3 receptor (R) partial agonist, was recently approved as monotherapy for schizophrenia, demonstrating effectiveness against both positive and negative symptoms, and also approved as add-on treatment to antidepressant drugs, inducing a potent antidepressant effect with a faster onset compared to an antidepressant given alone. Moreover, brexpiprazole has demonstrated pro-cognitive effects in preclinical studies. To explore whether the observed effects may be mediated via modulation of prefrontal glutamatergic transmission, we investigated the effect of brexpiprazole, alone and in combination with the SSRI escitalopram, on prefrontal glutamatergic transmission using in vitro electrophysiological intracellular recordings of deep layer pyramidal cells of the rat medial prefrontal cortex (mPFC). Nanomolar concentrations of brexpiprazole potentiated NMDAR-induced currents and electrically evoked EPSPs via activation of dopamine D1Rs, in similarity with the effect of the atypical antipsychotic drug clozapine. The effect of an ineffective concentration of brexpiprazole was significantly potentiated by the addition of escitalopram. When combined with escitalopram, brexpiprazole also potentiated AMPAR-mediated transmission, in similarity with the clinically rapid acting antidepressant drug ketamine. The effect on the AMPAR-mediated currents was also D1R dependent. In conclusion, our data propose that brexpiprazole exerts a clozapine-like potentiation of NMDAR-mediated currents in the mPFC, which can explain its efficacy on negative symptoms of schizophrenia and the pro-cognitive effects observed preclinically. Moreover, add-on brexpiprazole to escitalopram also potentiated AMPAR-mediated transmission, which may provide a neurobiological explanation to the faster antidepressant effect of add-on brexpiprazole in major depression.

Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study.

Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.

Ketamine-like effects of a combination of olanzapine and fluoxetine on AMPA and NMDA receptor-mediated transmission in the medial prefrontal cortex of the rat.

Preclinical studies indicate that the rapid antidepressant effect of ketamine is dependent on activation of AMPA receptors in the medial prefrontal cortex (mPFC) resulting in a prolonged enhancement of glutamatergic transmission in the mPFC. In similarity, addition of atypical antipsychotic drugs (APDs) to SSRIs has also been found to induce a rapid and potent antidepressant effect. Using intracellular recordings in layer V/VI pyramidal cells of the rat mPFC in vitro, we found that a combination of low, clinically relevant concentrations of the atypical APD olanzapine and the SSRI fluoxetine facilitated NMDA and AMPA-induced currents in pyramidal cells via activation of dopamine D1 receptors. A single ketamine injection (10mg/kg, 24h before the experiment) enhanced AMPA-and apparently to some extent also NMDA-induced currents. Our results propose that the rapid and potent antidepressant effects of both treatments may be related to a common mechanism of action, namely facilitation of glutamatergic, in particular AMPA receptor-mediated transmission, in the mPFC.

Deuterium-substituted L-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson's disease: comparison with the effects produced by L-DOPA and an MAO-B inhibitor.

The most effective treatment of Parkinson's disease (PD) L-DOPA is associated with major side effects, in particular L-DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted L-DOPA (D3-L-DOPA), compared with L-DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3-L-DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO). Therefore, a comparative neurochemical analysis was here performed studying the effects of D3-L-DOPA and L-DOPA on dopamine output and metabolism in 6-OHDA-lesioned animals using in vivo microdialysis. The effects produced by D3-L-DOPA and L-DOPA alone were additionally compared with those elicited when the drugs were combined with the MAO-B inhibitor selegiline, used in PD treatment. The different treatment combinations were first evaluated for motor activation; here the increased potency of D3-L-DOPA, as compared to that of L-DOPA, was confirmed and shown to be of equal magnitude as the effect produced by the combination of selegiline/L-DOPA. The extracellular levels of dopamine were also increased following both D3-L-DOPA and selegiline/L-DOPA administration compared with L-DOPA administration. The enhanced behavioral and neurochemical effects produced by D3-L-DOPA and the combination of selegiline/L-DOPA are attributed to decreased metabolism of released dopamine by MAO-B. The similar effect produced by D3-L-DOPA and selegiline/L-DOPA, respectively, is of considerable clinical interest since D3-L-DOPA, previously shown to exhibit a wider therapeutic window, in addition may reduce the need for adjuvant MAO-B inhibitor treatment.

Adjunctive treatment with asenapine augments the escitalopram-induced effects on monoaminergic outflow and glutamatergic neurotransmission in the medial prefrontal cortex of the rat.

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.

Problems and solutions to filling the drying drug pipeline for psychiatric disorders: a report from the inaugural 2012 CINP Think Tank.

The inaugural Collegium Internationale Neuro-Psychopharmacologicum (CINP) Think Tank, a small open meeting sponsored by the CINP, discussed impediments to developing new drugs for psychiatric disorders and approaches to overcome these impediments. Whilst neuropsycharmacology has a rich pharmacopeia (current treatments benefiting many individuals), issues of treatment resistance, sub-optimal response and unwanted side effects remain problematic. Many scientific, economic and social issues are impeding the development of drugs (e.g. higher risk of failure, placebo effects, problematic regulatory environments, pressures imposed by patent protection, downward pressure on reimbursements and financial, legal and social risk aversion). A consensus of the meeting was that efforts to understanding the core pathophysiology of psychiatric disorders are fundamental to increasing the chance of developing new drugs. However, findings from disorders such as Huntington's chorea, have shown that knowing the cause of a disorder may not reveal new drug targets. By contrast, clinically useful biomarkers that define target populations for new drugs and models that allow findings to be accurately translated from animals to humans will increase the likelihood of developing new drugs. In addition, a greater accent on experimental medicine, creative clinical investigations and improved communication between preclinical neuropsychopharmacologists, clinicians committed to neuropsychopharmacological research, industry and the regulators would also be a driver to the development of new treatments. Finally, it was agreed that the CINP must continue its role as a conduit facilitating vibrant interactions between industry and academia as such communications are a central component in identifying new drug targets, developing new drugs and transitioning new drugs into the clinic.

Niccine®, a nicotine vaccine, for relapse prevention: a phase II, randomized, placebo-controlled, multicenter clinical trial.

INTRODUCTION: A nicotine vaccine could prevent relapse to smoking by hindering blood nicotine from reaching the brain. Niccine® is a nicotine hapten tetanus-toxoid conjugate vaccine. The present study evaluated the clinical efficacy of Niccine for tobacco smoking relapse prevention. METHODS: Cigarette smokers (n = 355) aged 25-50 years were enrolled in a randomized, double-blind, parallel group 1-year trial encompassing 16 visits and 16 telephone calls. Niccine 40 µg or placebo was administered on Days 0, 28, 56, 90, 150, and 210. Between Days 56-98, subjects were treated with varenicline to aid cessation, targeted for Day 70. Only individuals abstinent between Days 90-98 (n = 265) were allowed to continue to 1 year (n = 219). Relapse to smoking was defined as >5 cigarettes within 7 days or since the last contact, or smoking on >5 occasions within 7 days or since the last contact. RESULTS: At 1 year, nonrelapse was 43.3% in the Niccine versus 51.1% in the placebo groups (difference = -7.9%; 95% CI = -20.6% to 4.9%). There was no benefit of Niccine on smoking status at 6 or 9 months, exhaled carbon monoxide levels, time to relapse, abstinence, withdrawal symptoms, or smoking reinforcement. Nicotine antibody levels increased (mean = 1.34 µg/ml; SD = 2.84 µg/ml) in the Niccine group, but were not related to relapse. Adverse events except hypersensitivity and compensatory smoking did not differ between groups. CONCLUSIONS: This nicotine vaccine appeared well tolerated but did not influence trajectories of relapse possibly because of insufficient antibody levels or lack of efficacy of the vaccine concept for relapse prevention.

Role of concomitant inhibition of the norepinephrine transporter for the antipsychotic effect of quetiapine.

Quetiapine alleviates both positive and negative symptoms as well as certain cognitive impairments in schizophrenia despite a low D2 receptor occupancy and may also be used as monotherapy in bipolar and major depressive disorder. The mechanisms underlying the broad clinical utility of quetiapine remain to be clarified, but may be related to the potent inhibition of the norepinephrine transporter (NET) by norquetiapine, the major metabolite of quetiapine in humans. Since norquetiapine is not formed in rodents we here investigated in rats whether NET-inhibition may, in principle, contribute to the clinical effectiveness of quetiapine and allow for its low D2 receptor occupancy, by combining quetiapine with the selective NET-inhibitor reboxetine. Antipsychotic-like activity was assessed using the conditioned avoidance response (CAR) test, dopamine output in the medial prefrontal cortex (mPFC) and the nucleus accumbens was measured using in vivo microdialysis, and NMDA receptor-mediated transmission was measured using intracellular electrophysiological recordings in pyramidal cells of the mPFC in vitro. Adjunct reboxetine potentiated the suppression of CAR by quetiapine. Moreover, concomitant administration of quetiapine and reboxetine resulted in a synergistic increase in cortical, but not accumbal, dopamine output. The combination of low, clinically relevant concentrations of quetiapine (60 nM) and reboxetine (20 nM) markedly facilitated cortical NMDA receptor-mediated transmission in contrast to either drug alone, an effect that could be inhibited by the D1 receptor antagonist SCH23390. We conclude that concomitant NET-inhibition by norquetiapine may contribute to the overall antipsychotic effectiveness of quetiapine in spite of its relatively low level of D2 occupancy.

Celecoxib enhances the effect of reboxetine and fluoxetine on cortical noradrenaline and serotonin output in the rat.

A substantial number of patients with major depressive disorder (MDD) do not respond adequately to current antidepressant pharmacological treatments, which are all more or less based on a gradually increased enhancement of monoaminergic neurotransmission. Although a functional deficiency in monoaminergic neurotransmission may contribute to MDD, the etiology and pathophysiology are far from clarified. Recent studies suggest that inflammatory processes may contribute, since increased levels of pro-inflammatory cytokines and prostaglandin E(2) (PGE(2)) have repeatedly been observed in a subset of patients suffering from MDD. Interestingly, adjunct treatment with the anti-inflammatory drug celecoxib, a cyclo-oxygenase-2 (COX-2) inhibitor which blocks the PGE(2)-production, has shown to enhance the efficacy of both reboxetine, a selective noradrenaline reuptake inhibitor, as well as fluoxetine, a selective serotonin reuptake inhibitor, in treatment-resistant depression. To examine the neurobiological underpinnings to the clinical observations, we here studied the acute effects of a combined treatment with celecoxib and reboxetine on noradrenaline and dopamine output, as well as celecoxib and fluoxetine on 5-HT output in the medial prefrontal cortex, using in vivo microdialysis in awake freely moving rats. Celecoxib significantly potentiated the effects of reboxetine and fluoxetine on cortical noradrenaline and 5-HT output, respectively, but not the reboxetine-induced dopamine output. Moreover, celecoxib, when given alone, enhanced 5-HT output. These findings provide, in principle, novel experimental support for the clinical utility of combined treatment with antidepressant and anti-inflammatory drugs, such as COX-2 inhibitors, in MDD.

Involvement of 5-HT2A receptor and α2-adrenoceptor blockade in the asenapine-induced elevation of prefrontal cortical monoamine outflow.

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.

Smoking, quitting, and psychiatric disease: a review.

Tobacco smoking among patients with psychiatric disease is more common than in the general population, due to complex neurobiological, psychological, and pharmacotherapeutic mechanisms. Nicotine dependence exposes smokers with co-occurring mental illness to increased risks of smoking-related morbidity, mortality, and to detrimental impacts on their quality of life. The neurobiological and psychosocial links to smoking appear stronger in certain comorbidities, notably depression and schizophrenia. Through its action on the cholinergic system, nicotine may have certain beneficial effects across a range of mental health domains in these patients, including improved concentration and cognition, relief of stress and depressive affect, and feeling pleasurable sensations. Despite the availability of effective smoking cessation pharmacotherapies and psychosocial interventions, as well as increasing evidence that individuals with psychiatric disorders are motivated to quit, nicotine dependence remains an undertreated and under-recognized problem within this patient population. Evidence suggests that provision of flexible and individualized treatment programs may be successful. Furthermore, the complicated relationship observed between nicotine dependence, nicotine withdrawal symptoms, and mental illness necessitates integration of close monitoring in any successful smoking cessation program.

Differential effects of AMPA receptor potentiators and glycine reuptake inhibitors on antipsychotic efficacy and prefrontal glutamatergic transmission.

RATIONALE: The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive allosteric modulators (AMPA-PAMs), Org 24448 and Org 26576, and the glycine transporter-1 (GlyT-1) inhibitor Org 25935 are developed for treatment of schizophrenia. OBJECTIVES: Here we examined experimentally the ability of co-administration of these AMPA-PAMs or the GlyT-1 inhibitor to augment the antipsychotic activity and effect on cortical N-methyl-D: -aspartate (NMDA) receptor-mediated transmission of risperidone, olanzapine, or haloperidol. METHODS: We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect liability using a catalepsy test, and cortical NMDA receptor-mediated glutamatergic transmission using intracellular electrophysiological recording technique in vitro. RESULTS: Both AMPA-PAMs enhanced the suppression of CAR induced by risperidone or olanzapine, and Org 24448 also enhanced the effect of haloperidol. In contrast, the GlyT-1 inhibitor did not cause any behaviorally significant effect in the CAR test. However, the GlyT-1 inhibitor, but not the AMPA-PAMs, produced a large facilitation of NMDA-induced currents. All three drugs potentiated the effect of risperidone but not haloperidol on these currents. The GlyT-1 inhibitor also facilitated the effect of olanzapine. All drugs potentiated the effect of risperidone on electrically stimulated excitatory postsynaptic potentials (EPSP) in cortical pyramidal cells, whereas only the GlyT inhibitor facilitated the effect of olanzapine. CONCLUSIONS: Our results suggest that the AMPA-PAMs, when compared to the GlyT-1 inhibitor, show differential effects in terms of augmentation of antipsychotic efficacy, particularly when combined with risperidone or olanzapine. Both AMPA-PAMs and the GlyT-1 inhibitor may also improve negative symptoms and cognitive impairments in schizophrenia, in particular when combined with risperidone.

Augmentation by escitalopram, but not citalopram or R-citalopram, of the effects of low-dose risperidone: behavioral, biochemical, and electrophysiological evidence.

Antidepressant drugs are frequently used to treat affective symptoms in schizophrenia. We have recently shown that escitalopram, but not citalopram or R-citalopram, increases firing rate and burst firing of midbrain dopamine neurons, potentiates cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission and enhances cognition, effects that might influence the outcome of concomitant antipsychotic medication. Here, we studied, in rats, the behavioral and neurobiological effects of adding escitalopram, citalopram, or R-citalopram to the second-generation antipsychotic drug risperidone. We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect (EPS) liability using a catalepsy test, dopamine outflow in the medial prefrontal cortex (mPFC) and nucleus accumbens using in vivo microdialysis in freely moving animals, and NMDA receptor-mediated transmission in the mPFC using intracellular electrophysiological recording in vitro. Only escitalopram (5 mg/kg), but not citalopram (10 mg/kg), or R-citalopram (10 mg/kg), dramatically enhanced the antipsychotic-like effect of a low dose of risperidone (0.25 mg/kg), without increasing catalepsy. Given alone, escitalopram, but not citalopram or R-citalopram, markedly enhanced both cortical dopamine output and NMDA receptor-mediated transmission. Addition of escitalopram and to some extent R-citalopram, but not citalopram, significantly enhanced both cortical dopamine output and cortical NMDA receptor-mediated transmission induced by a suboptimal dose/concentration of risperidone. These results suggest that adjunct treatment with escitalopram, but not citalopram, may enhance the effect of a subtherapeutic dose of risperidone on positive, negative, cognitive, and depressive symptoms in schizophrenia, yet without increased EPS liability.

Effects of S-citalopram, citalopram, and R-citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, N-methyl-D-aspartate receptor-mediated transmission in the medial prefrontal cortex and cognitive function in the rat.

Escitalopram, the S-enantiomer of citalopram, possesses superior efficacy compared to other selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression. Escitalopram binds to an allosteric site on the serotonin transporter, which further enhances the blockade of serotonin reuptake, whereas R-citalopram antagonizes this positive allosteric modulation. Escitalopram's effects on neurotransmitters other than serotonin, for example, dopamine and glutamate, are not well studied. Therefore, we here studied the effects of escitalopram, citalopram, and R-citalopram on dopamine cell firing in the ventral tegmental area, using single-cell recording in vivo and on NMDA receptor-mediated currents in pyramidal neurons in the medial prefrontal cortex using in vitro electrophysiology in rats. The cognitive effects of escitalopram and citalopram were also compared using the novel object recognition test. Escitalopram (40-640 µg/kg i.v.) increased both firing rate and burst firing of dopaminergic neurons, whereas citalopram (80-1280 µg/kg) had no effect on firing rate and only increased burst firing at high dosage. R-citalopram (40-640 µg/kg) had no significant effects. R-citalopram (320 µg/kg) antagonized the effects of escitalopram (320 µg/kg). A very low concentration of escitalopram (5 nM), but not citalopram (10 nM) or R-citalopram (5 nM), potentiated NMDA-induced currents in pyramidal neurons. Escitalopram's effect was antagonized by R-citalopram and blocked by the dopamine D(1) receptor antagonist SCH23390. Escitalopram, but not citalopram, improved recognition memory. Our data suggest that the excitatory effect of escitalopram on dopaminergic and NMDA receptor-mediated neurotransmission may have bearing on its cognitive-enhancing effect and superior efficacy compared to other SSRIs in major depression.

Effects of asenapine on prefrontal N-methyl-D-aspartate receptor-mediated transmission: involvement of dopamine D1 receptors.

Asenapine is a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder. Like clozapine, asenapine facilitates cortical dopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediated transmission in rats. The facilitation of NMDA-induced currents in cortical pyramidal cells by clozapine is dependent on dopamine and D(1) receptor activation. Moreover, previous results show that clozapine prevents and reverses the blockade of NMDA-induced currents and firing activity in the pyramidal cells by the noncompetitive NMDA receptor antagonist phencyclidine (PCP). Here, we investigated the effects of asenapine in these regards using intracellular electrophysiological recording in vitro. Asenapine (5 nM) significantly facilitated NMDA-induced currents (162 ± 15% of control) in pyramidal cells of the medial prefrontal cortex (mPFC). The asenapine-induced facilitation was blocked by the D(1) receptor antagonist SCH23390 (1 µM). Furthermore, the PCP-induced blockade of cortical NMDA-induced currents was effectively reversed by 5 nM asenapine. Our results demonstrate a clozapine-like facilitation of cortical NMDA-induced currents by asenapine that involves prefrontal dopamine and activation of D(1) receptors. Asenapine and clozapine also share the ability to reverse functional PCP-induced hypoactivity of cortical NMDA receptors. The ability of asenapine to increase both cortical dopaminergic and NMDA receptor-mediated glutamatergic transmission suggests that this drug may have an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.

Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias.

Treatment of Parkinson's disease is complicated by a high incidence of L-DOPA-induced dyskinesias (LID). Strategies to prevent the development of LID aim at providing more stable dopaminergic stimulation. We have previously shown that deuterium substitutions in the L-DOPA molecule (D3-L-DOPA) yield dopamine that appears more resistant to enzymatic breakdown. We here investigated the effects of D3-L-DOPA on motor performance and development of dyskinesias in a rodent model of Parkinson's disease. Through acute experiments, monitoring rotational behavior, dose-effect curves were established for D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA was estimated to be 60% of L-DOPA. Subsequently, animals were treated with either the equipotent dose of D3-L-DOPA (5 mg/kg), the equivalent dose of D3-L-DOPA (8 mg/kg), L-DOPA (8 mg/kg) or vehicle. The equivalent dose of D3-L-DOPA produced superior anti-akinetic effects compared to L-DOPA in the cylinder test (p<0.05), whereas the equipotent dose of D3-L-DOPA produced an anti-akinetic effect similar to L-DOPA. Dyskinesias developed to the same degree in the groups treated with equivalent doses of D3-L-DOPA and L-DOPA. The equipotent dose of D3-L-DOPA induced fewer dyskinesias than L-DOPA (p<0.05). In conclusion, our study provides evidence for improved potency and reduced side-effects of L-DOPA by deuterium substitutions in the molecule. These results are of clinical interest since the occurrence of LID is related to the total L-DOPA dose administered. D3-L-DOPA may thus represent a novel strategy to reduce the total dose requirement and yet achieve an effective control of parkinsonian symptoms.

Reboxetine enhances the olanzapine-induced antipsychotic-like effect, cortical dopamine outflow and NMDA receptor-mediated transmission.

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D(2/3) antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6 mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25 mg/kg), but not an optimal (2.5 mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain.