Chronic haloperidol-induced spatial memory deficits accompany the upregulation of D1 and D2 receptors in the caudate putamen of C57BL/6 mouse

Xu, Haiyun; Yang, Hongju; Rose, Gregory M.

doi:10.1016/j.lfs.2012.07.025

Cited by 21 publications

(15 citation statements)

References 71 publications

(72 reference statements)

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“…In previous researches, haloperidol and olanzapine disturbed cognitive function in MWM test in naïve mice (Mutlu et al, 2011;Xu et al, 2012), which is consistent with our results. However, PHA-543613 also performed negative effect on spatial learning and memory in naïve mice.…”

Section: Discussionsupporting

confidence: 93%

“…Haloperidol is a typical antipsychotic with a high affinity for dopamine D 2 receptors that are the targets of antipsychotic drugs, which was shown to impair the spatial learning memory in Morris water maze (MWM) in mice (Xu, Yang, & Rose, 2012). Olanzapine is an atypical antipsychotic agent widely used in treatment of schizophrenia and schizoaffective disorder (Volavka et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Effects of haloperidol, olanzapine, ziprasidone, and PHA‐543613 on spatial learning and memory in the Morris water maze test in naïve and MK‐801‐treated mice

et al. 2017

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Introduction Cognitive impairment is the core symptom of schizophrenia, significantly impacting the functional outcome. Improvement of cognitive function has been an important aspect of the treatment of schizophrenia. Therefore, this study is to demonstrate the effects of first‐generation antipsychotic haloperidol, second‐generation antipsychotic olanzapine and ziprasidone, and alpha‐7 nicotinic acetylcholine receptor agonist PHA ‐543613 on spatial learning and memory. Material and Methods C57 BL /6 mice received intraperitoneal injections of haloperidol (2 mg/kg), olanzapine (2.5 mg/kg), ziprasidone (2 mg/kg), and PHA ‐543613 (1 mg/kg), and cognitive dysfunctions were induced by MK ‐801 (0.1 mg/kg). Morris water maze was used for investigating the effects of all agents. Results Mk‐801 significantly increased the mean escape latency to the platform and decreased the number of platform area crossings. Ziprasidone had no effect on the mean escape latency to platform and the number of platform area crossings in naïve mice, but haloperidol, olanzapine, and PHA ‐543613 did not. Haloperidol and olanzapine significantly increased the mean escape latency to platform and decreased the number of platform area crossings, while ziprasidone and PHA ‐543613 did not. All the agents had no effect on swimming speed. Conclusions Ziprasidone and alpha‐7 nicotinic acetylcholine receptor agonist PHA ‐543613 might be helpful in the treatment of CIAS .

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Effects of haloperidol, olanzapine, ziprasidone, and PHA‐543613 on spatial learning and memory in the Morris water maze test in naïve and MK‐801‐treated mice

et al. 2017

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“…The first nest score was measured without application of any drug. The second nest score was obtained after application of vehicle (0.9% saline, 1 mL/ 100 g body weight) or haloperidol (1 mg/kg) (Xu et al, 2012) by intraperitoneal (i.p.) injection.…”

Section: Methodsmentioning

confidence: 99%

Transcriptional dysregulation causes altered modulation of inhibition by haloperidol

Brady

Bartley

et al. 2016

Neuropharmacology

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Many neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism involve interneuron transcriptional dysregulation. The transcriptional coactivator PGC-1α regulates gene expression in GABAergic interneurons, which are important for regulating hippocampal network activity. Genetic deletion of PGC-1α causes a decrease in parvalbumin expression, similar to what is observed in schizophrenia postmortem tissue. Our lab has previously shown that PGC-1α−/− mice have enhanced GABAergic inhibition onto CA1 pyramidal cells, which increases the inhibition/excitation (I/E) ratio, alters hippocampal circuit function, and impairs hippocampal dependent behavior. The typical antipsychotic haloperidol, a dopamine receptor antagonist with selectivity for D2-like receptors, has previously been shown to increase excitation in the CA1 region of hippocampus. We therefore tested whether haloperidol could normalize the I/E balance in CA1 of PGC-1α−/− mice, potentially improving circuit function and behavior. Surprisingly, we discovered instead that interneuron transcriptional dysregulation caused by loss of PGC-1α alters the effects of haloperidol on hippocampal synaptic transmission and circuit function. Acute administration of haloperidol causes disinhibition in CA1 and decreases the I/E ratio onto CA1 pyramidal cells in slices from PGC-1α+/+ mice, but not PGC-1α−/− mice. The spread of activity in CA1, assessed by voltage sensitive dye imaging, is increased by haloperidol in slices from PGC-1α+/+ mice; however haloperidol decreases the spread of activity in slices from PGC-1α−/− mice. Haloperidol increased the power of hippocampal gamma oscillation in slices from PGC-1α+/+ mice but reduced the power of gamma oscillations in slices from PGC-1α−/− mice. Nest construction, an innate hippocampal-dependent behavior, is inhibited by haloperidol in PGC-1α+/+ mice, but not in PGC-1α−/− mice, which already have impaired nest building. The effects of haloperidol are mimicked and occluded by a D2 receptor antagonist in slices from PGC-1α+/+ mice, and the effects of blocking D2 receptors are lost in slices from PGC-1α−/− mice, although there is no change in D2 receptor transcript levels. Together, our results show that hippocampal inhibitory synaptic transmission, CA1 circuit function, and hippocampal dependent behavior are modulated by the antipsychotic haloperidol, and that these effects of haloperidol are lost in PGC-1α−/− mice. These results have implications for the treatment of individuals with conditions involving PGC-1α deficiency.

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“…Other neuro-receptor changes such as increased D2 and D4 binding in the NAc and the striatum were observed with both adolescent and adult exposure to risperidone and olanzapine. Another study in mice has also reported that the protein levels of striatal D1 and D2 receptors and hippocampal D2 receptors were elevated, without a significant change in the PFC dopamine receptors, at 3-6 days after chronic haloperidol exposure in mid-adolescence (1 or 2 mg/kg/day for 3 or 6 weeks from PND42) (Xu et al 2012). …”

Section: Neurochemical Effects Proximal To Adolescent Apd Administrationmentioning

confidence: 93%

“…(1 or 2 mg/kg/day for 3 or 6 weeks) in mid-adolescent mice (PND42) could decrease the performance in both Y maze and MWM tests when examined at 2 or 4 days after treatment (Xu et al 2012). Given the age of mice being 6-week old (i.e.…”

Section: Cognition Anxiety and Social Interactionmentioning

confidence: 99%

Evaluating long-term consequences of adolescent antipsychotic exposure

Moe¹

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Antipsychotic drugs (APDs) are being used increasingly to treat a variety of conditions in adolescence. Accordingly there has been a dramatic increase in the prescription of APDs to adolescents over the past twenty years. Adolescence is an important postnatal developmental period in which major maturation changes occur in both brain structures and multiple neurotransmitter systems. Therefore, adolescence may represent a period of sensitivity to environmental perturbations including exposure to such pharmacological agents. The specific neurobiological consequences of APDs on the adolescent brain are however still poorly understood. The aim of the work presented in this thesis is to investigate how APD administration in adolescence can affect the immature adolescent brain, using a rodent model of adolescence.In this thesis, I examined chronic risperidone treatment (1.3 mg/kg/day for 21-22 days) in adolescent rats (postnatal day (PND) 36-PND56/57) with respect to short-and long-term neurobiological changes. Short-term alterations were measured either during or proximal to chronic treatment. Long-term effects were measured after a lengthy drug-free interval of 36 -60 days.Risperidone-induced neurobiological effects in adolescents were compared with those in adult rats (PND80-PND100/101) treated with the same risperidone regimen. Risperidone was chosen for detailed examination given this is the atypical APD that is most commonly prescribed to adolescents in the clinic. Behavioural effects were assessed using two well-validated tests for APD action, namely suppression of the conditioned avoidance response (CAR) and the horizontal bar test for catalepsy. Risperidone-induced changes in brain structures and metabolism of the nucleus accumbens (NAc) were examined with clinical comparable methods namely magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ( 1 H MRS), respectively.Neurochemical alterations and gene expression in the NAc and the striatum were assessed with high performance liquid chromatography (HPLC) and real-time polymerase chain reaction respectively.My data reveal that, during chronic risperidone treatment, adolescent rats were less sensitive to risperidone-induced increases in catalepsy (when tested in horizontal bar test) and escape failures (when tested in CAR paradigm), both of which are striatum-dependent behaviours. By contrast, adult rats were observed to develop a progressive increase in these behaviours during chronic risperidone treatment. Accompanying these behavioural findings, increased levels of dopamine metabolites were observed selectively in the striatum of rats treated with risperidone in adolescence.Increased dopamine metabolites represent increased turnover of dopamine and/or increased dopamine availability, which both suggest increased dopaminergic signalling. Increased dopamine neurotransmission in adolescent-treated rats may overcome the behavioural effects of dopaminergic blockade by risperidone. When assessed after an equivalent drug-free interval o...

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Chronic haloperidol-induced spatial memory deficits accompany the upregulation of D1 and D2 receptors in the caudate putamen of C57BL/6 mouse

Cited by 21 publications

References 71 publications

Effects of haloperidol, olanzapine, ziprasidone, and PHA‐543613 on spatial learning and memory in the Morris water maze test in naïve and MK‐801‐treated mice

Effects of haloperidol, olanzapine, ziprasidone, and PHA‐543613 on spatial learning and memory in the Morris water maze test in naïve and MK‐801‐treated mice

Transcriptional dysregulation causes altered modulation of inhibition by haloperidol

Evaluating long-term consequences of adolescent antipsychotic exposure

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