The drug-induced helplessness test: an animal assay for assessing behavioral despair in response to neuroleptic treatment

Ballard, Michael E.; Basso, Ana M.; Gallagher, Kelly B.; Browman, Kaitlin E.; Fox, Gerard B.; Drescher, Karla; Groß, Gerhard; Decker, Michael; Rueter, Lynne E.; Zhang, Min

doi:10.1007/s00213-006-0577-y

Cited by 14 publications

(7 citation statements)

References 61 publications

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“…Previous studies using preclinical animal models to detect antidepressant-like effects in atypical antipsychotics have been challenging, and atypical antipsychotics are known to be clinically useful for treating symptoms in patients with major depression or bipolar depression. Indeed, a previous report using the learned helplessness paradigm (Ballard et al, 2007) demonstrated that haloperidol, risperidone, olanzapine, and aripiprazole aggravated depressive behavior, whereas quetiapine showed no effect. As a result, it has been proposed that the learned helplessness paradigm may be a model for evaluating antipsychotic-induced dysphoria but not for evaluating the antidepressant effects in antipsychotics.…”

Section: Discussionmentioning

confidence: 97%

Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT₇) and 5-HT_1A Receptor Activity

Ishibashi¹,

Horisawa²,

Tokuda³

et al. 2010

J Pharmacol Exp Ther

385

304

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Lurasidone [(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; SM-13496] is an azapirone derivative and a novel antipsychotic candidate. The objective of the current studies was to investigate the in vitro and in vivo pharmacological properties of lurasidone. Receptor binding affinities of lurasidone and several antipsychotic drugs were tested under comparable assay conditions using cloned human receptors or membrane fractions prepared from animal tissue. Lurasidone was found to have potent binding affinity for dopamine D 2 , 5-hydroxytryptamine 2A (5-HT 2A ), 5-HT 7 , 5-HT 1A , and noradrenaline ␣ 2C receptors. Affinity for noradrenaline ␣ 1 , ␣ 2A , and 5-HT 2C receptors was weak, whereas affinity for histamine H 1 and muscarinic acetylcholine receptors was negligible. In vitro functional assays demonstrated that lurasidone acts as an antagonist at D 2 and 5-HT 7 receptors and as a partial agonist at the 5-HT 1A receptor subtype. Lurasidone showed potent effects predictive of antipsychotic activity, such as inhibition of methamphetamine-induced hyperactivity and apomorphine-induced stereotyped behavior in rats, similar to other antipsychotics. Furthermore, lurasidone had only weak extrapyramidal effects in rodent models. In animal models of anxiety disorders and depression, treatment with lurasidone was associated with significant improvement. Lurasidone showed a preferential effect on the frontal cortex (versus striatum) in increasing dopamine turnover. Anti-␣ 1 -noradrenergic, anticholinergic, and central nervous system (CNS) depressant actions of lurasidone were also very weak. These results demonstrate that lurasidone possesses antipsychotic activity and antidepressant-or anxiolytic-like effects with potentially reduced liability for extrapyramidal and CNS depressant side effects.

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Section: Discussionmentioning

confidence: 97%

Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT₇) and 5-HT_1A Receptor Activity

Ishibashi¹,

Horisawa²,

Tokuda³

et al. 2010

J Pharmacol Exp Ther

385

304

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“…It has been demonstrated that D2R density is significantly decreased in the core of the nucleus accumbens and in the medial and lateral caudate nuclei in rats that became "helpless" after the LH training [15]. D2R agonists have been shown to significantly decrease the number of escape failures after the LH training, whereas D2R antagonists have the opposite effect [1,34]. Also, tricyclic antidepressants that increase dopaminergic activity reverse the escape deficit produced by the LH training in rats, and D2R antagonists were shown to suppress the behavioral effect of tricyclic antidepressants in the LH paradigm [2,34].…”

Section: Discussionmentioning

confidence: 99%

“…First, if the behavioral phenotypes observed in the mutant are the consequence of increased expression of D2S, then D2S would have a functional effect opposite to that of D2L. As described previously, blockade of D2R using pharmacological agents increases the escape deficits in the LH paradigm in normal rodents [1,2,34]. The fact that mice lacking D2L displayed the enhanced escape deficits in LH paradigm suggested that the deficiencies were likely attributed to the lack of D2L; otherwise the reverse behavioral phenotype would be predicted.…”

Section: Discussionmentioning

confidence: 99%

Emotional response in dopamine D2L receptor-deficient mice

Hranilović¹,

Bućan²,

Wang³

2008

Behavioural Brain Research

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The dopamine D2 receptor (D2R) system has been implicated in emotional processing which is often impaired in neuropsychiatric disorders. The long (D2L) and the short (D2S) isoforms of D2R are generated by alternative splicing of the same gene. To study differential roles of the two D2R isoforms, D2L-deficient mice (D2L−/−) expressing functional D2S were previously generated. In this study the contribution of D2L isoform to emotional response was investigated by examining behaviors that reflect emotionality (exploratory behavior, anxiety-like behavior and learned helplessness) in D2L−/− and (wild-type) WT mice. While the thigmotactic, locomotor and general components of anxiety in zero maze did not differ among the genotypes, D2L−/− mice displayed significantly lower level of exploration in a hole board and zero maze, and significantly higher increase in latency to escape from a foot shock after the learned helplessness training, compared with WT mice. These results suggest that D2L may play a more prominent role than D2S in mediating emotional response, such as behavioral reactions to novelty and inescapable stress. Our findings contribute to a better understanding of the molecular and cellular mechanisms underlying emotional responses.

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“…In Study 2, rats received cumulative increasing doses of morphine (3.75, 15 and 22.5 mg/kg), morphine + quetiapine (3.75 + 3, 15 + 10 and 22.5 + 30 mg/kg) or vehicle. The chosen doses were based on previous studies 15–19 and a pilot study with three rats before the start of both Studies 1 and 2. Intraperitoneal (i.p.)…”

Section: Methodsmentioning

confidence: 99%

Combined effects of quetiapine and opioids: A study of autopsy cases, drug users and sedation in rats

et al. 2022

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Fatal opioid poisonings often involve methadone or morphine. This study aimed to elucidate if quetiapine, a widely used sedative antipsychotic medication, may increase the risk of fatal opioid poisoning by additive inhibitory effects on the central nervous system. We used data from 323 cases of fatal methadone or/and morphine poisonings autopsied from 2013 to 2020, a survey of 34 drug users, and performed blinded placebo-controlled studies in 75 Flinders Resistant Line rats receiving three cumulative intraperitoneal doses of vehicle, methadone (2.5, 10 and 15 mg/kg), morphine (3.75, 15 and 22.5 mg/kg), quetiapine (3, 10 and 30 mg/kg) or quetiapine combined with methadone or morphine. Quetiapine was detected in 20.4% of fatal opioid poisonings with a significantly increased frequency over time, primarily in low or therapeutic concentrations, and was not associated with methadone or morphine concentrations. Use of quetiapine, most commonly in low-to-moderate doses to obtain a sleep-inducing or tranquillizing effect, was reported by 67.6% of survey respondents. In the animal studies, a significant impairment of sedation score, performance on the rotarod and open field mobility was observed in all treatment groups compared with vehicle. However, the effect of quetiapine plus the opioid was not significantly different from that of the opioid alone. Thus, no additive sedative effects were observed in rats. Our results suggest that quetiapine is more often an innocent bystander than a contributor to fatal opioid poisoning. However, the combined effects on other parameters, including blood pressure, cardiac rhythm and respiratory rate, need investigation.

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The drug-induced helplessness test: an animal assay for assessing behavioral despair in response to neuroleptic treatment

Abstract: After discussing potential alternative interpretations of the drug-induced changes of EFs, we propose the DH test as a useful test for assessing a drug-induced, depressive-like state that may contribute to neuroleptic dysphoria.

Cited by 14 publications

References 61 publications

Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT₇) and 5-HT_1A Receptor Activity

Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT₇) and 5-HT_1A Receptor Activity

Emotional response in dopamine D2L receptor-deficient mice

Combined effects of quetiapine and opioids: A study of autopsy cases, drug users and sedation in rats

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The drug-induced helplessness test: an animal assay for assessing behavioral despair in response to neuroleptic treatment

Abstract: After discussing potential alternative interpretations of the drug-induced changes of EFs, we propose the DH test as a useful test for assessing a drug-induced, depressive-like state that may contribute to neuroleptic dysphoria.

Cited by 14 publications

References 61 publications

Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT7) and 5-HT1A Receptor Activity

Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT7) and 5-HT1A Receptor Activity

Emotional response in dopamine D2L receptor-deficient mice

Combined effects of quetiapine and opioids: A study of autopsy cases, drug users and sedation in rats

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Product

Resources

About

Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT₇) and 5-HT_1A Receptor Activity

Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT₇) and 5-HT_1A Receptor Activity