The vacuous chewing movement (VCM) model of tardive dyskinesia revisited: is there a relationship to dopamine D2 receptor occupancy?

Turrone, Peter; Remington, Gary; Nóbrega, José N.

doi:10.1016/s0149-7634(02)00008-8

Cited by 72 publications

(57 citation statements)

References 129 publications

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“…In addition, a dose-dependent effect was found only in the group exposed to sustained blockade, with syndromedefining levels (48 VCMs/2 min) beginning to emerge at the 0.25 mg/kg/day haloperidol dose, a finding reported in other studies using haloperidol in the VCM model (Turrone et al, 2002(Turrone et al, , 2003. Moreover, there is also some evidence that AP dose is a risk factor for TD, with higher doses increasing the likelihood that a patient will develop TD (Kane et al, 1986).…”

Section: Discussionsupporting

confidence: 72%

“…To this end, we recently found that only haloperidol administered through tri-weekly decanoate injections, but not daily intraperitoneal (i.p.) injections, led to high levels of VCMs (Turrone et al, 2002). These observations, coupled with evidence demonstrating that acute subcutaneous (s.c.) injections of haloperidol leads to only transiently high levels of D 2 occupancy (Kapur et al, 2000c), raised the hypothesis that transient D 2 occupancy might also not induce VCMs and TD.…”

Section: Introductionmentioning

confidence: 62%

“…We recently conducted an 8-week study involving daily i.p. injections of haloperidol that failed to demonstrate either a significant increase in VCMs vs placebo or a clear dose-response relationship (Turrone et al, 2002). Another study involving daily administration of haloperidol via the intracerebroventricular (i.c.v.)…”

Section: Discussionmentioning

confidence: 99%

“…While our study was limited to 8 weeks, the decision to reduce the length of the study was based on the finding that the VCM behavior plateaus beyond 5 weeks of treatment in this study and in other VCM experiments conducted in our laboratory (Turrone et al, 2002(Turrone et al, , 2003. In addition, there are other groups that utilize this model for an even shorter time period (3 weeks) within the context of TD research (Naidu et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…To this end, we have chosen to study vacuous chewing movement (VCM) in rats, an animal model that shares substantive features with human TD (for a review see Turrone et al, 2002). VCMs are characterized by purposeless (nondirected) mouth openings in the vertical plane, with or without tongue protrusion (eg Iversen et al, 1980).…”

Section: Introductionmentioning

confidence: 99%

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Differential Effects of Within-Day Continuous Vs Transient Dopamine D2 Receptor Occupancy in the Development of Vacuous Chewing Movements (VCMs) in Rats

Turrone

Remington

Kapur

et al. 2003

Neuropsychopharmacol

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Accumulating evidence suggests that antipsychotics (APs) that lead to sustained blockade of dopamine D 2 receptors are more likely to induce acute extrapyramidal side effects (EPS) compared to APs that only occupy D 2 receptors transiently. It is unclear, however, whether a similar relationship exists for long-term AP-induced motoric side effects like tardive dyskinesia (TD). The objective of this study was to ascertain whether transient (via daily subcutaneous (s.c.) injections) vs continuous (via osmotic minipump) AP-induced D 2 receptor occupancy differentially affects the development of haloperidol-induced vacuous chewing movements (VCMs), an animal model of TD. Six groups of 12 rats received 0.1, 0.25, or 1 mg/kg of haloperidol or vehicle (n ¼ 36) via osmotic minipump (to provide within-day sustained) or daily s.c. injection (within-day transient) for 8 weeks. VCMs were measured on a weekly basis and D 2 occupancy levels were measured in vivo using [ 3 H]-raclopride at the end of the experiment. Minipump-treated rats developed HAL dose-dependent D 2 occupancies of 0.1 mg/kg/day (57%), 0.25 mg/kg/day (70%), and 1 mg/kg/day (88%). S.C.-treated rats also developed HAL dosedependent D 2 occupancies of 0.1 mg/kg/day (83% peak, 3% trough), 0.25 mg/kg/day (89% peak, 0% trough), and 1 mg/kg/day (94% peak, 17% trough). A total of 43% of rats given 0.25 and 1 mg/kg/day of HAL via minipump developed high VCMs compared to only 8% of the rats given the same doses via daily s.c. injections. The 0.1 mg/kg dose did not give rise to VCMs beyond vehicle levels regardless of the route of administration. These findings support the contention that D 2 occupancy levels induced by chronic HAL must be high and sustained through the day before significant risk of VCMs, and perhaps also TD, emerges.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential Effects of Within-Day Continuous Vs Transient Dopamine D2 Receptor Occupancy in the Development of Vacuous Chewing Movements (VCMs) in Rats

Turrone

Remington

Kapur

et al. 2003

Neuropsychopharmacol

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Antipsychotic Agents

Brown¹,

Li²,

Sinz³

2010

Burger's Medicinal Chemistry and Drug Discovery

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The medicinal chemistry of antipsychotic agents is reviewed in this chapter. The definition of schizophrenia is summarized in two categories, namely, symptom domains and pathology. An overview is given for antipsychotic medications including their clinical applications and side effects. This chapter also describes many animal models for schizophrenia. After an introduction of the FDA approved antipsychotic drugs, the structure–activity relationship, pharmacokinetics, biotransformation, and drug–drug interactions are discussed for both conventional and atypical antipsychotics in details. Finally, eight different strategies for drug discovery of antipsychotics are delineated.

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Antipsychotic Agents

Ablordeppey

Ofori

2021

Burger's Medicinal Chemistry and Drug Discovery

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Schizophrenia is one of the most severe diseases of the brain and is characterized by a spectrum of symptoms including positive, negative, and cognitive symptoms. Even though schizophrenia has a low worldwide prevalence (0.4–0.7%), it is one of the most devastating diseases of the central nervous system (CNS). Despite the immense studies on schizophrenia over the years, the exact cause of the disorder remains unknown. Therefore, morbidity studies and their outcomes for schizophrenia continue to rely on descriptive definitions spelled out in the Diagnostic and Statistical Manual of Mental Disorders‐fifth edition (DSM‐5). Current pharmacotherapy of the disease involves the use of antipsychotic agents that target CNS receptors including dopamine and serotonin receptor subtypes. Despite the success in the management of psychiatric illness most of the current antipsychotics are saddled with problems such as inefficacy across patient populations and disease domains and intolerable side effects that limit their widespread utility. Evolving paradigm shift in antipsychotic drug discovery efforts over the last decade has begun to address these issues opening the door for new hypotheses that integrate well‐known neurotransmitter systems with neuronal circuits. Recent advances in molecular biology and genetics are also paving the way for a better understanding of the etiology and pathophysiology of schizophrenia. In addition to reviewing currently used agents, this article will focus on the advances made to address the stated problems and highlight the paradigm shift in the antipsychotic drug discovery area.

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The vacuous chewing movement (VCM) model of tardive dyskinesia revisited: is there a relationship to dopamine D2 receptor occupancy?

Cited by 72 publications

References 129 publications

Differential Effects of Within-Day Continuous Vs Transient Dopamine D2 Receptor Occupancy in the Development of Vacuous Chewing Movements (VCMs) in Rats

Differential Effects of Within-Day Continuous Vs Transient Dopamine D2 Receptor Occupancy in the Development of Vacuous Chewing Movements (VCMs) in Rats

Antipsychotic Agents

Antipsychotic Agents

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