Effects of atypical antipsychotic agents on social behavior in rodents

Corbett, Rebecca; Hartman, Harold B.; Kerman, Lisa L.; Woods, A.T.; Strupczewski, Joseph T.; Helsley, Grover C.; Conway, P.C.; Dunn, Robert W.

doi:10.1016/0091-3057(93)90079-9

Cited by 118 publications

(46 citation statements)

References 33 publications

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“…at a volume of 5 ml/kg and doses between 0.5 and 1.25 mg/kg. The highest doses were chosen based on previous studies (Corbett et al, 1993;Dalvi and Rodgers, 1996;Stachowicz et al 2008).…”

Section: Specificity Of the Induced Social Fearmentioning

confidence: 99%

Social Fear Conditioning: A Novel and Specific Animal Model to Study Social Anxiety Disorder

Toth

Neumann

Slattery

2012

Neuropsychopharmacol

125

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Social anxiety disorder (SAD) is a major health concern with high lifetime prevalence. The current medication is rather unspecific and, despite considerable efforts, its efficacy is still unsatisfactory. However, there are no appropriate and specific animal models available to study the underlying etiology of the disorder. Therefore, we aimed to establish a model of specific social fear in mice and use this social fear conditioning (SFC) model to assess the therapeutic efficacy of the benzodiazepine diazepam and of the antidepressant paroxetine; treatments currently used for SAD patients. We show that by administering electric foot shocks (2-5, 1 s, 0.7 mA) during the investigation of a con-specific, the investigation of unfamiliar con-specifics was reduced for both the short-and long-term, indicating lasting social fear. The induced fear was specific to social stimuli and did not lead to other behavioral alterations, such as fear of novelty, general anxiety, depression, and impaired locomotion. We show that social fear was dose-dependently reversed by acute diazepam, at doses that were not anxiolytic in a non-social context, such as the elevated plus maze. Finally, we show that chronic paroxetine treatment reversed social fear. All in all, we demonstrated robust social fear after exposure to SFC in mice, which was reversed with both acute benzodiazepine and chronic antidepressant treatment. We propose the SFC model as an appropriate animal model to identify the underlying etiology of SAD and possible novel treatment approaches.

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“…at a volume of 5 ml/kg and doses between 0.5 and 1.25 mg/kg. The highest doses were chosen based on previous studies (Corbett et al, 1993;Dalvi and Rodgers, 1996;Stachowicz et al 2008).…”

Section: Specificity Of the Induced Social Fearmentioning

confidence: 99%

Social Fear Conditioning: A Novel and Specific Animal Model to Study Social Anxiety Disorder

Toth

Neumann

Slattery

2012

Neuropsychopharmacol

125

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“…On theoretical grounds, 5-HT 2C receptor antagonists might also be useful for the treatment of Parkinson's disease ). Iloperidone's affinity for 5-HT 2C receptors could, therefore help to explain the low propensity to induce catalepsy and the anxiolytic effects seen in animal studies (Corbett et al 1993). …”

Section: Affinity For 5-ht 2c Receptorsmentioning

confidence: 99%

Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

Kalkman

Subramanian

Hoyer

2001

Neuropsychopharmacology

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Iloperidone is a novel psychotropic compound currently undergoing Phase III trials. Its affinity for human dopamine and 5-HT receptors has been reported previously (Kongsamut et al. 1996). This report presents the affinity of iloperidone for a largely extended number of human neurotransmitter receptors. In a few instances human receptors were not available and receptor studies were performed on tissues from laboratory animals. The present data, supplemented with those of Kongsamut et al. (1996) The prototypical classical neuroleptic agent haloperidol is an effective antipsychotic compound (Leucht et al. 1999) which, unfortunately, also induces severe extrapyramidal side effects (EPS) and hyperprolactinemia. The term "atypical antipsychotic" was originally introduced to describe compounds, such as clozapine, which not only suppressed psychotic symptoms, but differed from haloperidol by having a low tendency to induce EPS and increase plasma prolactin levels. It is postulated that dopamine D 2 receptor blockade is the mechanism by which antipsychotic activity is achieved (Creese et al. 1976;Seeman et al. 1976 Conley et al. 1999;Taylor and Duncan-McConnell 2000). The elucidation of the multiple receptor interactions of clozapine suggested that other neurotransmitter systems may also play a role in the efficacy and tolerability of that molecule. Particularly, the antiadrenergic effects of clozapine are now receiving increased attention (Nutt 1994;Litman et al. 1996;Hertel et al. 1999). Iloperidone is a new psychotropic agent currently undergoing Phase III trials for the treatment of psychotic disorders (Figure 1). Iloperidone was selected from a large series of piperidinyl-benzisoxazoles because it showed a 300-fold greater potency in a test for limbic activity (inhibition of apomorphine-induced climbing) than in a test for nigrostriatal activity (inhibition of apomorphine-induced stereotypy) . The large difference of potency of iloperidone in these tests is expected to result in an improved ratio of therapeutic effect to EPS liability compared with standard antipsychotics. Previous studies have investigated the receptor binding profile of iloperidone with rat receptors ) and a limited number of human homologues of dopamine and 5-HT receptor subtypes (Kongsamut et al. 1996). These experiments demonstated that iloperidone displays the desired 5-HT 2A /D 2 affinity ratio. The aim of the present study was to determine the receptor affinity profile of iloperidone at a wider range of human neurotransmitter receptors. In resemblance to clozapine, it was noted that iloperidone possesses high affinity for norepinephrine ␣ 1 -and ␣ 2C adrenergic receptors. METHODSThe radioligand receptor binding assays are listed in Table 1. MaterialsRadioligands were purchased from NEN Life Science Products, USA, except for 3 H-RX821002 and 3 H-Mesulergine, which were obtained from Amersham Pharmacia Biotech Ltd, UK, and 125 I-GTI which was obtained from ANAWA, Switzerland. Iloperidone was synthesized by Hoechst Marion Roussel. Unless speci...

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“…5-HT receptor antagonists and drugs known to deplete brain 5-HT content can produce an anxiolytic effect in animal models sensitive to benzodiazepines, but usually to a lesser degree and less consistently than benzodiazepines themselves. Some antipsychotics have been found to be active in animal models of anxiety (13,15,47,57,58,61). Many of the atypical antipsychotic drugs with 5-HT 2 and D 2 receptor antagonist properties, such as clozapine and risperidone, have demonstrated anxiolytic potential in animal models of fear and anxiety (14,25,47,57) as well as some clinical evidence in schizophrenics (9).…”

Section: Antipsychotic Activitymentioning

confidence: 99%

Preclinical and Clinical Pharmacology of Cyamemazine: Anxiolytic Effects and Prevention of Alcohol and Benzodiazepine Withdrawal Syndrome

Bourin

Dailly²,

Hascoët³

2004

CNS Drug Reviews

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Several studies have suggested that the antipsychotic compound, cyamemazine, possesses anxiolytic properties in humans. The original pharmacological profile of cyamemazine (D 2 , 5-HT 2A , 5-HT 2C , and 5-HT 3 receptor antagonist), which was established by binding, microdialysis and behavioral studies, is consistent with these observations. In the light/dark exploration test, cyamemazine demonstrated anxiolytic-like activity by acute, but not chronic administration. By chronic administration, however, cyamemazine increased the time spent in the open arms of the elevated plus maze (EPM) test demonstrating anxiolytic-like activity. The discrepancy between the results obtained in these tests by acute and chronic administration, could be due to a combination of dopamine D 2 receptor antagonism with antagonism of the 5-HT 2C and 5-HT 3 receptors. The action of cyamemazine on both the dopaminergic system and 5-HT 3 receptors could also explain the activity of cyamemazine in the management of alcohol withdrawal demonstrated in preclinical studies. This potential indication for cyamemazine and its activity in benzodiazepine withdrawal syndrome have recently been investigated in clinical trials and the results of these studies are presented in this review.

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Effects of atypical antipsychotic agents on social behavior in rodents

Cited by 118 publications

References 33 publications

Social Fear Conditioning: A Novel and Specific Animal Model to Study Social Anxiety Disorder

Social Fear Conditioning: A Novel and Specific Animal Model to Study Social Anxiety Disorder

Extended Radioligand Binding Profile of Iloperidone A Broad Spectrum Dopamine/Serotonin/Norepinephrine Receptor Antagonist for the Management of Psychotic Disorders

Preclinical and Clinical Pharmacology of Cyamemazine: Anxiolytic Effects and Prevention of Alcohol and Benzodiazepine Withdrawal Syndrome

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