Introduction Schizophrenia is a complex disorder that can have a genetic and/or environmental etiology. Clinically, schizophrenia is characterized by three subsets of symptoms that are classed as positive (e.g. delusions, hallucinations; impulsive activity), negative (e.g. affective flattening, alogia, avolition, social withdrawal), and cognitive (e.g. disorganized thought, attentional, and speech processes) [1]. Although the etiology of schizophrenia remains elusive, structural and functional neuroimaging as well as the advance of new animal models have been providing great insights into its underlying pathophysiology [2, 3]. Herein, using T2-weighted and manganese-enhanced MRI (MEMRI) [4, 5] we aimed to investigate cytoarchitectural and morphological changes in methylazoxymethanol acetate (MAM)-treated rats – a neurodevelopmental model of schizophrenia [6, 7] – and to further evaluate the feasibility of translating these imaging data to schizophrenia patients. Materials and Methods Pregnant SD dams (Charles River, Portage, MI) were acquired on gestational day (GD) 10. On GD17, dams were administered saline or 25 mg/kg MAM i.p. Female offspring were weaned on postnatal day (PD) 21 and housed individually (n=11, saline-treated; n=8, MAM-treated) and later imaged on PD 45. Prior to imaging, rats were i.c.v. cannulated under isoflurane anesthesia. For MEMRI, MnCl2 (Sigma-Aldrich, St. Louis, MO) was dissolved in saline and injected via an i.c.v. cannula (0.08M, 5μL), 24-h before imaging. Rats were anesthetized and imaged using a 7T MRI scanner (Bruker Biospin, Karlsruhe, Germany) with a T1-weighted (TR/TE = 600/10 ms, NA=16), or T2weighted (TR/TE =3200/75ms, RARE factor = 8, NA=8) pulse sequence at a pixel size = 250 × 250 μm and slice thickness = 1.25 mm. Volumetric analysis was conducted using AFNI [8].

Background and purpose: Activation of cannabinoid CB1 and/or CB2 receptors mediates analgesic effects across a broad spectrum of preclinical pain models. Selective activation of CB2 receptors may produce analgesia without the undesirable psychotropic side effects associated with modulation of CB1 receptors. To address selectivity in vivo, we describe non-invasive, non-ionizing, functional data that distinguish CB1 from CB2 receptor neural activity using pharmacological MRI (phMRI) in awake rats.Experimental approach: Using a high field (7 T) MRI scanner, we examined and quantified the effects of non-selective CB1/CB2 (A-834735) and selective CB2 (AM1241) agonists on neural activity in awake rats. Pharmacological specificity was determined using selective CB1 (rimonabant) or CB2 (AM630) antagonists. Behavioural studies, plasma and brain exposures were used as benchmarks for activity in vivo.Key results: The non-selective CB1/CB2 agonist produced a dose-related, region-specific activation of brain structures that agrees well with published autoradiographic CB1 receptor density binding maps. Pretreatment with a CB1 antagonist but not with a CB2 antagonist, abolished these activation patterns, suggesting an effect mediated by CB1 receptors alone. In contrast, no significant changes in brain activity were found with relevant doses of the CB2 selective agonist.Conclusion and implications: These results provide the first clear evidence for quantifying in vivo functional selectivity between CB1 and CB2 receptors using phMRI. Further, as the presence of CB2 receptors in the brain remains controversial, our data suggest that if CB2 receptors are expressed, they are not functional under normal physiological conditions.