Unaltered cocaine self-administration in the prenatal LPS rat model of schizophrenia

Santos-Toscano, Raquel; Borcel, Érika; Ucha, Marcos; Orihuel, Javier; Capellán, Roberto; Roura-Martínez, David; Ambrosio, Emilio; Higuera-Matas, Alejandro

doi:10.1016/j.pnpbp.2016.04.008

“…We also explored the potential of some immune populations to serve as diagnostic tools or biomarkers of the disease. While there were no alterations in cocaine-related behaviours, consistent with our previous results (Santos-Toscano et al, 2016), we found a lower number of DR3D-expressing granulocytes and a trend for an increased number of CNR2expressing lymphocytes in LPS-exposed rats.…”

Section: Discussionsupporting

confidence: 93%

“…These MIA models offer an excellent means to examine the causal relationships that exist between schizophrenia and the increased prevalence of addictive disorders in these patients. Contrary to our expectations, we observed no increased cocaine selfadministration in the offspring of rats exposed to LPS during pregnancy (Santos-Toscano et al, 2016). However, in this previous study, we did not test for other aspects cocaine-related behaviours that are relevant to addiction such as sensitivity to the rewarding actions of the drug in a dose-response setting, motivation to obtain the drug, resistance to extinction or vulnerability to cue-induced relapse.…”

Section: Introductioncontrasting

confidence: 99%

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

¹

,

Ucha

²

,

Borcel

³

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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“…Contrary to our expectations, we observed no increased cocaine selfadministration in the offspring of rats exposed to LPS during pregnancy (Santos-Toscano et al, 2016). However, in this previous study, we did not test for other aspects cocaine-related behaviours that are relevant to addiction such as sensitivity to the rewarding actions of the drug in a dose-response setting, motivation to obtain the drug, resistance to extinction or vulnerability to cue-induced relapse.…”

Section: Introductioncontrasting

confidence: 99%

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

Santos-Toscano¹,

Ucha²,

Borcel³

et al. 2019

Preprint

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0

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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.

show abstract

“…In the MAM neurodevelopmental model of maternal infection, there are no differences in cocaine self-administration under fixed and progressive schedules of reinforcement, nor in extinction or drug-induced reinstatement for cocaine [94]. Similarly, offspring of dams treated with LPS show unaltered cocaine self-administration, dose-response curves and extinction, despite working memory and sensorimotor gating impairment in this model [95]. Acute locomotor activity in response to various doses of cocaine is unaltered in MAM rats, compared to controls [94].…”

Section: Psychostimulants: Cocainementioning

confidence: 79%

Schizophrenia and drug addiction comorbidity: recent advances in our understanding of behavioural susceptibility and neural mechanisms

Menne

¹

,

Chesworth

²

2020

Neuroanatomy and Behaviour

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Schizophrenia is a severe psychiatric disorder which is worsened substantially by substance abuse/addiction. Substance abuse affects nearly 50% of individuals with schizophrenia, extends across several drug classes (e.g. nicotine, cannabinoids, ethanol, psychostimulants) and worsens overall functioning of patients. Prominent theories explaining schizophrenia and addiction comorbidity include the primary addiction hypothesis (i.e. schizophrenia susceptibility primes drug reward circuits, increasing drug addiction risk following drug exposure), the two-hit hypothesis (i.e. drug abuse and other genetic and/or environmental risk factors contribute to schizophrenia development) and the self-medication hypothesis (i.e. drug use alleviates schizophrenia symptoms). Animal models can be used to evaluate the utility and validity of these theories. Since this literature was last reviewed by Ng and colleagues in 2013 [Neurosci Biobehav Rev, 37(5)], significant advances have been made to our understanding of schizophrenia and substance abuse comorbidity. Here we review advances in the field since 2013, focussing on two key questions: 1) Does schizophrenia susceptibility increase susceptibility to drug addiction (assessing the primary addiction hypothesis), and 2) Do abused drugs exacerbate or ameliorate schizophrenia symptoms (assessing the two-hit hypothesis and the self-medication hypothesis). We addressed these questions using data from several schizophrenia preclinical models (e.g. genetic, lesion, neurodevelopmental, pharmacological) across drug classes (e.g. nicotine, cannabinoids, ethanol, psychostimulants). We conclude that addiction-like behaviour is present in several preclinical schizophrenia models, and drugs of abuse can exacerbate but also ameliorate schizophrenia-relevant behaviours. These behavioural changes are associated with altered receptor system function (e.g. dopaminergic, glutamatergic, GABAergic) critically implicated in schizophrenia and addiction pathology.

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Unaltered cocaine self-administration in the prenatal LPS rat model of schizophrenia

Cited by 15 publications

References 62 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

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

Schizophrenia and drug addiction comorbidity: recent advances in our understanding of behavioural susceptibility and neural mechanisms

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