Quetiapine Prevents Anhedonia Induced by Acute or Chronic Stress

Orsetti, Marco; Canonico, Pier Luigi; Dellarole, Anna; Colella, Luciana; Brisco, Fabio Di; Ghi, Piera

doi:10.1038/sj.npp.1301291

Cited by 46 publications

(28 citation statements)

References 31 publications

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“…Previous studies report that the second-generation antipsychotics olanzapine and quetiapine reverse CMS-induced 'anhedonia' (Orsetti et al, 2006(Orsetti et al, , 2007. In support of these results, we demonstrated that olanzapine reversed CMSinduced decreases in sucrose consumption without affecting controls.…”

Section: Discussionsupporting

confidence: 87%

Attenuation of chronic mild stress-induced ‘anhedonia’ by asenapine is not associated with a ‘hedonic’ profile in intracranial self-stimulation

et al. 2010

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Chronic mild stress (CMS)-induced 'anhedonia' is a predictive model of antidepressant activity. We assessed the reversal of CMS-induced behavioral changes by asenapine, the antidepressant imipramine, and the atypical antipsychotics olanzapine and risperidone. Secondarily, the ability of these agents to facilitate intracranial self-stimulation (ICSS) was assessed to ensure that any attenuation of CMS-induced anhedonia was not associated with an overt hedonic profile. After 2 weeks of CMS, male Wistar rats were administered asenapine (0.06-0.6 mg/kg), olanzapine (2 mg/kg), risperidone (0.5 mg/kg), or imipramine (10 mg/kg) by intraperitoneal injection over 5 weeks to examine their ability to reverse CMS-induced reductions in the intake of a sucrose solution. For the ICSS study, rats were trained to deliver an electrical stimulus to the ventral tegmental area. The effects of acute doses of subcutaneous asenapine (0.01-0.3 mg/kg), olanzapine (0.3 and 1 mg/kg), risperidone (0.1 and 0.3 mg/kg), and intraperitoneal imipramine (3-30 mg/kg), cocaine (5.0 mg/kg), or amphetamine (1.0 mg/kg) on ICSS were then examined. CMS significantly reduced sucrose intake (P < 0.001). All active agents (0.6 mg/kg asenapine, 2 mg/kg olanzapine, 0.5 mg/kg risperidone, and 10 mg/kg imipramine) reversed the effect of CMS (all P < 0.001). In the ICSS protocol, asenapine (0.01 and 0.03 mg/kg), olanzapine (1 mg/kg), and risperidone (0.3 mg/kg) impaired ICSS performance, whereas positive controls (5 mg/kg cocaine, 1 mg/kg amphetamine) facilitated ICSS. Asenapine reversed CMS-induced anhedonia without facilitating ICSS, providing support for a role of asenapine in treating bipolar disorder and aspects of negative and/or affective symptoms in schizophrenia.

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Section: Discussionsupporting

confidence: 87%

Attenuation of chronic mild stress-induced ‘anhedonia’ by asenapine is not associated with a ‘hedonic’ profile in intracranial self-stimulation

et al. 2010

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“…The involvement of a metabolite in quetiapine's antidepressant action in humans was also suggested by published animal studies showing antidepressant-like activity after chronic, but not acute, administration (Orsetti et al, 2007;Yan et al, 2007).…”

Section: Discussionmentioning

confidence: 87%

N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity

Jensen

Rodriguiz

Caron

et al. 2007

Neuropsychopharmacol

284

219

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Quetiapine is an atypical antipsychotic drug that is also US FDA approved for treating bipolar depression, albeit by an unknown mechanism. To discover the potential mechanism for this apparently unique action, we screened quetiapine, its metabolite N-Desalkylquetiapine, and dibenzo [b,f][1,4]thiazepine-11(10-H)-one (DBTO) against a large panel of G-protein-coupled receptors, ion channels, and neurotransmitter transporters. DBTO was inactive at all tested molecular targets. N-Desalkylquetiapine had a high affinity (3.4 nM) for the histamine H 1 receptor and moderate affinities (10-100 nM) for the norepinephrine reuptake transporter (NET), the serotonin 5-HT 1A , 5-HT 1E , 5-HT 2A , 5-HT 2B , 5-HT 7 receptors, the a 1B -adrenergic receptor, and the M 1 , M 3 , and M 5 muscarinic receptors. The compound had low affinities (100-1000 nM) for the 5-HT 1D , 5-HT 2C , 5-HT 3 , 5-HT 5 , 5-HT 6 , a 1A , a 2A , a 2B , a 2C , H 2 , M 2 , M 4 , and dopamine D 1 , D 2 , D 3 , and D 4 receptors. N-Desalkylquetiapine potently inhibited human NE transporter with a K i of 12 nM, about 100-fold more potent than quetiapine itself. N-Desalkylquetiapine was also 10-fold more potent and more efficacious than quetiapine at the 5-HT 1A receptor. N-Desalkylquetiapine was an antagonist at 5-HT 2A , 5-HT 2B , 5-HT 2C , a 1A , a 1D , a 2A , a 2C , H 1 , M 1 , M 3 , and M 5 receptors. In the mouse tail suspension test, N-Desalkylquetiapine displayed potent antidepressant-like activity in VMAT2 heterozygous mice at doses as low as 0.1 mg/kg. These data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-Desalkylquetiapine through NET inhibition and partial 5-HT 1A agonism. Possible contributions of this metabolite to the side effects of quetiapine are discussed.

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“…In contrast, the atypical antipsychotics olanzapine and quetiapine, but not the classical agent haloperidol, reverse stress-induced anhedonia (Orsetti et al, 2007), suggesting the possible relevance of this procedure for assessing novel antipsychotics.…”

Section: Anhedoniamentioning

confidence: 99%

Behavioral Indices in Antipsychotic Drug Discovery

Porsolt

Moser²,

Castagné³

2010

J Pharmacol Exp Ther

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Schizophrenia is characterized by three major symptom classes: positive symptoms, negative symptoms, and cognitive deficits. Classical antipsychotics (phenothiazines, thioxanthenes, and butyrophenones) are effective against positive symptoms but induce major side effects, in particular, extrapyramidal symptoms (EPS). The discovery of clozapine, which does not induce EPS and is thought effective against all three classes of symptom, has driven research for novel antipsychotics with a wider activity spectrum and lower EPS liability. To increase predictiveness, current efforts aim to develop translational models where direct parallels can be drawn between the processes studied in animals and in humans. The present article reviews existing procedures in animals for their ability to predict compound efficacy and EPS liability in relation to their translational validity. Rodent models of positive symptoms include procedures related to dysfunction in central dopamine and glutamatergic (N-methyl-D-aspartate) and serotonin (5-hydroxytryptamine) neurotransmission. Procedures for evaluating negative symptoms include rodent models of anhedonia, affective flattening, and diminished social interaction. Cognitive deficits can be assessed in rodent models of attention (prepulse inhibition) and of learning/memory (object and social recognition, Morris water maze and operant-delayed alternation). The relevance of the conditioned avoidance response is also discussed. A final section reviews procedures for assessing EPS liability, in particular, parkinsonism (catalepsy in rodents), acute dystonia (purposeless chewing in rodents, dystonia in monkeys), akathisia (defecation in rodents), and tardive dyskinesia (long-term antipsychotic treatment in rodents and monkeys). It is concluded that, with notable exceptions (attention, learning/ memory, EPS liability), current predictive models for antipsychotics fall short of clear translational validity.Schizophrenia is characterized by three major classes of symptom: positive symptoms (delusions, hallucinations, bizarre speech and thought, paranoia); negative symptoms (anhedonia, affective flattening, impoverishment of speech and thought, social withdrawal); and cognitive deficits (impairments in attention, learning, and memory).Despite intensive research, the etiology of schizophrenia remains far from understood. Most hypotheses have evolved from the actions of drugs in clinical use or as a result of similarities between the symptoms of schizophrenia and the effects of certain drugs of abuse, notably the indirect dopamine (DA) receptor agonist amphetamine, the glutamate receptor antagonist phencyclidine (PCP), and the 5-HT 2 receptor agonist lysergic acid diethylamide. The major hypothesis has centered around central DA neurotransmission because all classical antipsychotics (phenothiazines, thioxanthenes, and butyrophenones) have as principal mechanism the blockade of central DA receptors (Carlsson, 1988).The introduction of the atypical antipsychotic clozapine in the early 1970s an...

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Quetiapine Prevents Anhedonia Induced by Acute or Chronic Stress

Cited by 46 publications

References 31 publications

Attenuation of chronic mild stress-induced ‘anhedonia’ by asenapine is not associated with a ‘hedonic’ profile in intracranial self-stimulation

Attenuation of chronic mild stress-induced ‘anhedonia’ by asenapine is not associated with a ‘hedonic’ profile in intracranial self-stimulation

N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity

Behavioral Indices in Antipsychotic Drug Discovery

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