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

Abstract

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.

Additive, synergic and antagonistic interactions between maternal immune activation and peripubertal stress in cocaine addiction-like behaviour, morphofunctional brain parameters and striatal transcriptome

“…In our categorical analysis, MIA tended to increase the likelihood of acquiring cocaine self-administration; however, it did not affect drug intake among those animals that did acquire the self-administration behaviour. This absence of effects on cocaine intake is consistent with our previous reports that showed MIA had no effects on cocaine self-administration, extinction, progressive ratio performance, dose-response curves or cue-induced reinstatement (13,14). However, PUS had a remarkable effect on drug intake over the acquisition sessions, lowering the amount of cocaine earned by animals exposed to stress.…”

“…However, when we tested if MIA induced by the bacterial endotoxin lipopolysaccharide (LPS) would potentiate cocaine self-administration, we found no evidence of such effect even in the presence of sensorimotor gating and cognitive deficts (13) or sensorimotor gating and immune alterations (14). However, despite their translational validity, MIA models alone may not fully capture the complexity of the interactions between causative factors and, more recently, these models are incorporating a second hit during adolescence to increase their validity (15,16).…”

Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats

“…One of the widely implemented approaches is maternal immune activation (MIA), produced by the prenatal administration of lipopolysaccharide (LPS) [ 12 , 13 , 14 , 15 , 16 ]. When considering a neurodevelopmental model of schizophrenia, MIA with LPS has been described in terms of various behavioural disturbances, including affected sensorimotor gating [ 12 , 17 , 18 ], anxiety-like behaviour [ 13 , 19 ], social interactions [ 15 ], exploratory or locomotor activity [ 19 , 20 , 21 ] and cognitive deficits [ 22 , 23 ] as well as diverse biochemical alterations in the brains of the offspring, including the CX3CL1-CX3CR1 and CD200-CD200R pairs, which are crucial in neuron–microglia communication [ 13 , 19 ]. CX3CL1 is a chemokine that differs notably from other representatives of this group in both structure and role [ 24 ], whereas CD200 belongs to a class of surface antigens with immunosuppressive properties [ 25 ].…”

GPCR signaling: role in mediating the effects of early adversity in psychiatric disorders

“…These diverse models impinge upon a wide array of anxiety [35,48,84,107–109,112,120,125,142–149] and despair‐like behaviors [35,48,61,108,109,125,143,146,148,150–152] and also impact cognition [22,35,65,73,149,152–154], fear conditioning [35,110–112,152,155], social interaction [35,61,115,116,156–158], sensorimotor gating [38,59,60,91,93], and hallucinogen‐evoked 5‐HT 2A R‐mediated HTR [67,113,114]. Among the GPCRs reported to be dysregulated in these models of early adversity are the Gq‐, Gi‐, and Gs‐coupled receptors involved in the signaling downstream of monoamines such as serotonin (5‐HT 1A R, 5‐HT 2A R, 5‐HT 7 R) [26,38,49,67,73–78,83,84,100,107,109,110,113–115,117,120,125,146,147,149,150,159,160], DA (D 1 R, D 2 R, D 3 R, D 4 R, D 5 R) [31,101,161–164], and norepinephrine (α 2 AR, β 3 AR) [117,155], glutamate (mGluR 2 , mGluR 4 ) [38,59,60,85,91,93,113,117,151,161,165–167], endocannabinoids (CB 1 R) [21,63,162,168], and acetylcholine (M 1 ) [62], and CRFR 1 , CRFR 2 [22,37,64,84,112,142,145,154,158,169–174].…”