Maternal immune activation alters sensitivity to action-outcome contingency in adult rat offspring

Millar, Jessica; Bilkey, David K.; Ward, Ryan D.

doi:10.1016/j.bbi.2016.08.020

Cited by 15 publications

(15 citation statements)

References 44 publications

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“…However, when the immune activation took place at an earlier gestational day (GD12), the motivation for the food pellets under an amphetamine challenge was reduced in the absence of detectable disruptions in the dopaminergic system. Contrarily, the work by Millar and colleagues showed that Poly I:C administration at GD15 increased the motivation for food, possibly due to an inability to detect changes in the contingency between their behaviour and the resulting rewarding outcome (Millar et al, 2017). It must be noted that these experiments were performed using food pellets as reinforcers while we have examined the motivation for cocaine which may explain the differences in the results obtained.…”

Section: Discussionmentioning

confidence: 85%

Maternal immune activation is associated with a lower number of dopamine receptor 3-expressing granulocytes with no alterations in cocaine reward, resistance to extinction or cue-induced reinstatement

Santos-Toscano

Ucha

Borcel

et al. 2020

Pharmacology Biochemistry and Behavior

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There is evidence for increased rates of drug use among schizophrenic patients. However, the causality in this relationship remains unclear. In addition, biomarkers of schizophrenia are vital, given the heterogeneous nature of the disorder that can lead to difficulties in the early diagnosis. In the present work, we use a maternal immune activation model to experimentally test whether animals at high risk of developing a schizophrenia-like condition are more prone to acquire cocaine selfadministration, show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction or vulnerable to relapse. Pregnant rats were injected with lipopolysaccharide (LPS) (2 mg/kg s.c.) or saline every other day during pregnancy, and the offspring was tested for sensorimotor gating (prepulse inhibition -PPI-). After this test, one group of rats was submitted to cocaine self-administration (0.5 mg/kg) under fixed and progressive ratio schedules, dose-response testing, extinction and cue-induced drug-seeking. Another group was sacrificed to study potential biomarkers in the immune blood cells by flow cytometry. While rats born to LPS-treated mothers showed impaired PPI, there were no differences in cocaine self-administration acquisition, responsiveness to dose shifts, extinction or cue-induced reinstatement.Finally, there were fewer DRD3 + granulocytes in the LPS-offspring and an exciting trend for CNR2 + lymphocytes to be more abundant in LPS-exposed rats. Our results indicate that the higher prevalence of cocaine abuse among people with schizophrenia is not due to a pre-existing pathology and suggest that DRD3 + granulocytes and possibly CNR2 + lymphocytes could be potential biomarkers of schizophrenia.

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Section: Discussionmentioning

confidence: 85%

Maternal immune activation is associated with a lower number of dopamine receptor 3-expressing granulocytes with no alterations in cocaine reward, resistance to extinction or cue-induced reinstatement

Santos-Toscano

Ucha

Borcel

et al. 2020

Pharmacology Biochemistry and Behavior

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“…For example, the maternal immune activation model (wherein early developmental immune activation) of schizophrenia resulted in an elevated breakpoint in a progressive ratio breakpoint task. 50 This finding is in direct contrast with schizophrenia patients who exhibit reduced breakpoints, 25 but the authors maintained that the elevated breakpoint may have been related to an inability to detect changes in reward/behavior contingencies, leading to perseverative-like behaviors. 50 The increased breakpoint is similar, however, to our recent studies demonstrating that repeated phencyclidine treatment (a commonly used manipulation for modeling schizophrenia), also increased breakpoint in rats, even after a 2-week washout period.…”

Section: Introductionmentioning

confidence: 99%

“…50 This finding is in direct contrast with schizophrenia patients who exhibit reduced breakpoints, 25 but the authors maintained that the elevated breakpoint may have been related to an inability to detect changes in reward/behavior contingencies, leading to perseverative-like behaviors. 50 The increased breakpoint is similar, however, to our recent studies demonstrating that repeated phencyclidine treatment (a commonly used manipulation for modeling schizophrenia), also increased breakpoint in rats, even after a 2-week washout period. In contrast, isolation rearing-induced deficits Effort-based decision making is a critical component of negative symptoms in schizophrenia and can be readily assessed in humans and rodents.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Models to Investigate Mechanisms of Negative Symptoms in Schizophrenia

Barnes

Der-Avakian

Young

2017

Schizophrenia Bulletin

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“…NMDA receptor dysfunction has also been implicated as one outcome of maternal immune activation (MIA), a risk factor for the development of schizophrenia (Hao et al, 2019;Meyer et al, 2008aMeyer et al, , 2008b. MIA during the first and early second trimester has emerged as a significant etiological risk factor for the development of schizophrenia (Brown and Derkits, 2010;Khandaker et al, 2013;Patterson, 2009), and rodent models of MIA have shown a broad range of schizophrenia-relevant anatomical, neurochemical, and behavioral deficits (Boksa, 2010;Deane et al, 2017;Luchicchi et al, 2016;Meyer et al, 2005;Millar et al, 2017;Patterson, 2009), including NMDAR receptor hypofunction (Roenker et al, 2011). Because both MIA and ketamine influence NMDA receptor functioning and both manipulations are used to model schizophrenia, it raises the question of whether the MIA-induced changes in subjective state are similar to those induced by ketamine.…”

Section: Introductionmentioning

confidence: 99%

Impaired discrimination of a subanesthetic dose of ketamine in a maternal immune activation model of schizophrenia risk

et al. 2021

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Background: Animal models of psychiatric diseases suffer from a lack of reliable methods for accurate assessment of subjective internal states in nonhumans. This gap makes translation of results from animal models to patients particularly challenging. Aims/methods: Here, we used the drug-discrimination paradigm to allow rats that model a risk factor for schizophrenia (maternal immune activation, MIA) to report on the subjective internal state produced by a subanesthetic dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Results/outcomes: The MIA rats’ discrimination of ketamine was impaired relative to controls, both in the total number of rats that acquired and the asymptotic level of discrimination accuracy. This deficit was not due to a general inability to learn to discriminate an internal drug cue or internal state generally, as MIA rats were unimpaired in the learning and acquisition of a morphine drug discrimination and were as sensitive to the internal state of satiety as controls. Furthermore, the deficit was not due to a decreased sensitivity to the physiological effects of ketamine, as MIA rats showed increased ketamine-induced locomotor activity. Finally, impaired discrimination of ketamine was only seen at subanesthetic doses which functionally correspond to psychotomimetic doses in humans. Conclusion: These data link changes in NMDA responses to the MIA model. Furthermore, they confirm the utility of the drug-discrimination paradigm for future inquiries into the subjective internal state produced in models of schizophrenia and other developmental diseases.

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Maternal immune activation alters sensitivity to action-outcome contingency in adult rat offspring

Cited by 15 publications

References 44 publications

Maternal immune activation is associated with a lower number of dopamine receptor 3-expressing granulocytes with no alterations in cocaine reward, resistance to extinction or cue-induced reinstatement

Maternal immune activation is associated with a lower number of dopamine receptor 3-expressing granulocytes with no alterations in cocaine reward, resistance to extinction or cue-induced reinstatement

Preclinical Models to Investigate Mechanisms of Negative Symptoms in Schizophrenia

Impaired discrimination of a subanesthetic dose of ketamine in a maternal immune activation model of schizophrenia risk

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