Early Blockade of CB1 Receptors Ameliorates Schizophrenia-like Alterations in the Neurodevelopmental MAM Model of Schizophrenia

Abstract

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.

The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology

“…Methylazoxymethanol acetate (MAM; Midwest Research Institute, Kansas City, MO, USA) was dissolved in saline and administered intraperitoneally (i.p.) at dose of 22 mg/kg in 1 mL/kg volume on GD 17 with saline solution as a control (CNT), as previously described [ 17 , 18 , 38 , 39 , 40 , 41 ] ( Figure 1 , MAM model. THC (10 mg/mL in ethanol solution) obtained from the University of Chemistry and Technology, Prague, was prepared as previously described [ 42 , 43 ] ( Figure 1 , THC model).…”

“…The test was carried out in a moderately illuminated room (120 lx), as previously described [ 17 , 43 , 46 , 47 ]. Each animal was allowed to freely explore an unfamiliar congener in a metal arena (60 × 60 × 60 cm) for 10 min.…”

“…Each animal was placed in the arena and allowed to explore two identical, previously unseen objects for 5 min (familiarization phase). After an inter-trial interval of 3 min, one of the two familiar objects was replaced by a novel, previously unseen object, and rats were returned to the arena for the 5 min test phase [ 13 , 17 , 20 ]. Each phase was recorded and analyzed separately by two observers blinded to the treatment groups.…”

“…Based on this background, the present study aimed to investigate if aTHC exposure could modify the effects of pre/perinatal insult induced by gestational methylazoxymethanol acetate (MAM) or perinatal THC (pTHC) exposure, two well-validated neurodevelopmental models of psychopathology [ 13 , 17 , 18 ], which are characterized by behavioral and molecular alterations similar to those described in subjects with neurodevelopmental disorders, further supporting their translational value [ 13 , 19 ]. More specifically, in adulthood, we assessed whether the cognitive deficits and social impairment typically described in the pTHC and MAM offspring and usually paralleled by changes in the ECS and/or DAergic system at the PFC level [ 13 , 17 ], might be modified by aTHC exposure ( Figure 1 ).…”

Systematic Review of the Therapeutic Role of Apoptotic Inhibitors in Neurodegeneration and Their Potential Use in Schizophrenia

“…In order to study dendritic pruning during brain maturation, several key neurodevelopmental animal models of SZ have been developed. Some neurodevelopmental models of SZ include the maternal immune activation model [ 5 ] or the use of antagonists of the n-methyl-D-aspartate (NMDA) receptors, such as MK-801 [ 6 ] ketamine [ 7 ] and phencyclidine [ 8 , 9 ] or prenatal methylazoxymethanol acetate exposure [ 10 , 11 , 12 , 13 ], with the latter being one of the most validated neurodevelopmental model of SZ, in terms of face, construct and predictive validity [ 14 , 15 , 16 , 17 , 18 ].…”