Adverse subjective experience with antipsychotics and its relationship to striatal and extrastriatal D2 receptors—a PET study in schizophrenia

Mizrahi, Romina; Rusjan, Pablo; Agid, Ofer; Graff, Ariel; Vitcu, Irina; Mamo, David C.; Zipursky, Robert B.; Kapur, S.

doi:10.1016/j.neuroimage.2006.04.161

Cited by 45 publications

(69 citation statements)

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“…) given to patients with schizophrenia over a number of days or months (Farde et al 1988). Importantly, this degree of occupancy is lower than that thought to induce hyperprolactinemia in patients (Kapur et al 2000) and lower than the occupancy associated with reduced subjective well-being in chronically treated patients (Mizrahi et al 2007), but sufficient to produce impairments in spatial working memory and learning, the former of which replicates previous findings ). If these impairments translate to the clinical setting, it would suggest that the level of occupancy that causes cognitive impairment might be much lower than the occupancy that produces extra-pyramidal symptoms, improvement in positive symptoms, or hyperprolactinemia in patients with schizophrenia.…”

Section: Discussionsupporting

confidence: 81%

Dopamine D2 receptor occupancy levels of acute sulpiride challenges that produce working memory and learning impairments in healthy volunteers

et al. 2007

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Doses of sulpiride typically used in human cognitive studies produced low levels of DA D2 receptor occupancy compared to that considered efficacious in the treatment of schizophrenia. The levels of occupancy were sufficient to replicate impairments on a spatial working memory task and impair spatial learning. The relationship between occupancy and working memory was suggestive of presynaptic effects, although the precise mechanism underlying the impairment will require studies of wider ranges of occupancy within and outside of the striatum.

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Section: Discussionsupporting

confidence: 81%

Dopamine D2 receptor occupancy levels of acute sulpiride challenges that produce working memory and learning impairments in healthy volunteers

et al. 2007

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“…One possibility is that KOR antagonists make stress less aversive. Stress activates intracellular signaling cascades that regulate dynorphin expression (Pliakas et al, 2001;McLaughlin et al, 2003); increased KOR stimulation in the NAc reduces dopamine function, which is associated with depressive and aversive effects in rodents (Nestler and Carlezon, 2006) and humans (Mizrahi et al, 2007). Dynorphin and KORs are expressed throughout brain regions involved in fear and anxiety (Fallon and Leslie, 1986;Mansour et al, 1995), making drug microinfusion studies a priority for future work.…”

Section: Discussionmentioning

confidence: 99%

Anxiolytic-Like Effects of κ-Opioid Receptor Antagonists in Models of Unlearned and Learned Fear in Rats

Knoll¹,

Meloni²,

Thomas³

et al. 2007

J Pharmacol Exp Ther

220

257

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Endogenous opioid systems regulate neurobiological responses to threatening stimuli. Stimulation of -opioid receptors (KORs) produces analgesia but induces prodepressive-like effects in a variety of animal models. In contrast, KOR antagonists have antidepressant-like effects. KORs and their endogenous ligand dynorphin are expressed throughout brain areas involved in fear and anxiety, including the extended amygdala. Here, we examined whether KOR antagonists would affect unlearned fear (anxiety) in the elevated plus maze (EPM) and open field (OF) paradigms and learned fear in the fear-potentiated startle (FPS) paradigm. These studies were designed to accommodate the slow onset (ϳ24 h) and extended time course (Ͼ3 weeks) of the prototypical KOR antagonists nor-binaltorphimine hydrochloride (norBNI) and JDTicRats received an i.p. injection of norBNI (3.0 -30 mg/kg) or JDTic (1.0 -10 mg/kg) 48 h before EPM testing. One day later, they were tested in the OF, and 5 and 7 days later, they were trained and tested in the FPS paradigm. Both KOR antagonists dose-dependently increased open arm exploration in the EPM without affecting OF behavior. They also decreased conditioned fear in the FPS paradigm. The anxiolytic-like effects of KOR antagonists were qualitatively similar to those of the benzodiazepine chlordiazepoxide in the EPM. The selective serotonin reuptake inhibitor fluoxetine had no effect in the EPM and anxiogenic-like effects in the OF. Our results indicate that KOR antagonists produce a unique combination of antidepressant-and anxiolytic-like effects and suggest that this class of drugs may be particularly effective for the treatment of comorbid depressive and anxiety disorders.Although the neurobiology of depression and anxiety disorders is not well understood, evidence suggests that these disorders share common genetic and neuroanatomic components. Depression and anxiety disorders are highly comorbid; more than half of individuals with anxiety disorders also co-present with a lifetime history of depression (Kaufman

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“…Dopamine is another important molecule in reward circuitry. High dopamine D2 receptor antagonism in humans is correlated with antipsychoticinduced dysphoria (Mizrahi et al, 2007) and rodent data shows dopamine D1 antagonism abolishes the antihistaminic potentiation of other substances of abuse (Suzuki et al, 1990(Suzuki et al, , 1991. Quetiapine, due to its low affinity and fast disassociation from both D1 and D2 receptors (Kapur and Seeman, 2000;Tauscher et al, 2004), may have less potential to disrupt any reinforcing antihistaminic effects.…”

Section: Possible Mechanismmentioning

confidence: 99%

The role of antihistaminic effects in the misuse of quetiapine: A case report and review of the literature

Fischer

Boggs

2010

Neuroscience & Biobehavioral Reviews

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Adverse subjective experience with antipsychotics and its relationship to striatal and extrastriatal D2 receptors—a PET study in schizophrenia

Cited by 45 publications

References 0 publications

Dopamine D2 receptor occupancy levels of acute sulpiride challenges that produce working memory and learning impairments in healthy volunteers

Dopamine D2 receptor occupancy levels of acute sulpiride challenges that produce working memory and learning impairments in healthy volunteers

Anxiolytic-Like Effects of κ-Opioid Receptor Antagonists in Models of Unlearned and Learned Fear in Rats

The role of antihistaminic effects in the misuse of quetiapine: A case report and review of the literature

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